Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Impact of the Aversive Effects of Drugs on Their Use and Abuse

Impact of the Aversive Effects of Drugs on Their Use and Abuse Hindawi Behavioural Neurology Volume 2022, Article ID 8634176, 27 pages https://doi.org/10.1155/2022/8634176 Review Article Anthony L. Riley , Hayley N. Manke , and Shihui Huang Psychopharmacology Laboratory, Department of Neuroscience, Center for Neuroscience and Behavior, American University, 4400 Massachusetts Ave NW, Washington, D.C. 20016, USA Correspondence should be addressed to Anthony L. Riley; alriley@american.edu Received 27 November 2021; Revised 16 January 2022; Accepted 30 March 2022; Published 20 April 2022 Academic Editor: Andrew Huang Copyright © 2022 Anthony L. Riley et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Drug use and abuse are complex issues in that the basis of each may involve different determinants and consequences, and the transition from one to the other may be equally multifaceted. A recent model of the addiction cycle (as proposed by Koob and his colleagues) illustrates how drug-taking patterns transition from impulsive (acute use) to compulsive (chronic use) as a function of various neuroadaptations leading to the downregulation of DA systems, upregulation of stress systems, and the dysregulation of the prefrontal/orbitofrontal cortex. Although the nature of reinforcement in the initiation and mediation of these effects may differ (positive vs. negative), the role of reinforcement in drug intake (acute and chronic) is well characterized. However, drugs of abuse have other stimulus properties that may be important in their use and abuse. One such property is their aversive effects that limit drug intake instead of initiating and maintaining it. Evidence of such effects comes from both clinical and preclinical populations. In support of this position, the present review describes the aversive effects of drugs (assessed primarily in conditioned taste aversion learning), the fact that they occur concurrently with reward as assessed in combined taste aversion/place preference designs, the role of aversive effects in drug-taking (in balance with their rewarding effects), the dissociation of these affective properties in that they can be affected in different ways by the same manipulations, and the impact of various parametric, experiential, and subject factors on the aversive effects of drugs and the consequent impact of these factors on their use and abuse potential. 1. Drug Use and Abuse once in the past two weeks) was at 5%, 10%, and 17% for th th th 8 , 10 , and 12 graders, respectively [1]. Related findings According to recent results from Monitoring the Future have been reported by the NSDUH that found that 40.3 mil- th th (MTF, 2021), a national survey on drug use by 8 , 10 , lion people had a past year substance use disorder [2] as th and 12 graders, 27.3% of students (averaged across grades) defined by the Diagnostic and Statistical Manual of Mental reported use of illicit drugs in the past year [1] (for more Disorders (DSM-5) (see [2] for the basis of the dramatic dif- recent unpublished findings, see https://www.drugabuse ference in the rates of drug abuse when diagnoses are based .gov/drug-topics/trends-statistics/monitoring-future). In a on the DSM-4 vs. the DSM-5). Further, according to the sample of participants aged 12 years and older in 2020, the World Drug Report (2021), the Global Burden of Disease National Survey of Drug Use and Health (NSDUH, 2020) Study (GBD) in 2019 found that substance use disorders found that 13.5% used an illicit drug in the past month [2]. accounted for the largest portion of disability-adjusted life These surveys clearly indicate that a variety of drugs are years (DALYs), a measure of disease burden taken from used, but importantly, they also indicate that a smaller sub- the combination of both the number of years of life lost set of individuals abuse these same drugs. For example, MTF because of premature death and the number of years of life reported patterns and amounts of drug intake generally lived with disability [3]. In fact, drug use disorders associated with abuse. Specifically, daily marijuana preva- accounted for 59% of DALYs with approximately 18.1 mil- lence in 2020 was at 1.1%, 4.4%, and 6.9%, and binge drink- lion years of “healthy” life lost due to disabilities or prema- ing (defined as at least 5 or more drinks in a row at least ture death [3]. Interestingly, among people aged 12 or 2 Behavioural Neurology older, only 1.4% received any treatment for substance use [2]. Abstinence Abstinence Abstinence 2. Allostatic Model of Drug Use and Abuse Relapse Relapse Relapse Given the multiple causes and consequences of drug use and Late dependence- Use Heavy Use Early abuse, understanding this complexity is critical to preven- neuroadapted state dependence tion and treatment strategies [4]. One comprehensive model Impulsive Stage Compulsive Stage of these issues has recently been presented by Koob and his Prolonged Binge colleagues who describe the various stages of drug use and Intoxication Intoxication abuse, the factors important in their display, and the neuro- Reward Pleasurable Relief Relief biological substrates of each (as well as the role of these sub- craving effects craving strates in the transition from use to abuse, drug Protracted maintenance, and relapse; see [4–7]). Specifically, Koob Abstinence abstinence and his colleagues describe a neuroadaptation model of Neutral affect Negative affect addiction that consists of three distinct stages: binge/intoxi- Figure 1: Transition from the impulsive (acute) to the compulsive cation, withdrawal/negative affect, and preoccupation/antic- (abuse) patterns of drug-taking. Adapted from Meyer and Quenzer ipation, which differ significantly between acute and chronic [8] using BioRender.com. drug use (see Figure 1). Acute use represents a pattern of drug intake in the majority of the population using drugs (roughly between anxiety, irritability, and sleep disturbances) when the drug 85 and 90%) that is more impulsive and controlled. Applica- is no longer present. This negative affect drives further drug tion of Koob’s model to individuals in this group reveals a intake by negative reinforcement which is exacerbated by sensitized brain stress systems (primarily in the extended specific characterization of the effects of the drug (binge/ intoxication), the affective state of the individual following amygdala, i.e., central nucleus of the amygdala, the bed the cessation of the drug effect (withdrawal/negative affect), nucleus of the stria terminalis, and a transition zone in the and the subsequent desire for the drug in its absence (preoc- nucleus accumbens) that reflect further compensation to ele- cupation/anticipation). As noted in Figure 1, for acute use vated intake. Finally, these individuals now crave the drug when it is absent as the negative affect grows with time since (the impulsive condition), the drug itself is rewarding, gener- ating an effect preferred by the user (i.e., a rewarding effect). taking the drug. Intake is increased as well by neuroadapta- After the drug’seffects have subsided, there is no change in tions in yet other systems, e.g., orbitofrontal cortex, which the user’saffective state, i.e., the user is relatively neutral in normally mediates salience for traditional reinforcers such the drug’s absence. Finally, there is no true craving for the as food and sex, is now shifted toward the drug, and the sys- tems involved in executive function (prefrontal cortex; plan- drug in this group, but if such anticipation of the drug does occur, it is one of a desire to repeat its rewarding effects. ning, inhibition, memory, and attention) are downregulated. Importantly, the drug does initiate a compensatory response Consequently, these individuals have difficulty targeting rel- (allostasis) that generally is opposite in nature to that of its evant reinforcers and inhibiting further drug intake. The initial effect. If the user takes the drug relatively infrequently, cycle continues and spirals out of control with escalated intake, more frequent use, and high rates of relapse (poten- at low doses, and by routes of administration that have a slow onset and offset, this allostatic state subsides and there tiated by the presence of cues and stress that reactivate the is no appreciable change in the abovementioned characteri- mesolimbic and cortical areas via increased input from the zation. The drug maintains its reinforcing effects with little frontal cortex). change with its absence and no appreciable craving. However, if the pattern of drug use changes, e.g., 3. Role of Reward in Drug Use and Abuse increased frequency of use at higher doses and by routes of administration with more rapid onset (and offset), neuroad- The addiction cycle proposed by Koob and his colleagues [5, aptations occur that drive the transition from use to abuse 7] illustrates how drug-taking patterns transition from (involving roughly 10-15% of individual drug users). These impulsive (acute use) to compulsive (chronic use) as a func- neuroadaptations move impulsive use to compulsive use tion of neuroadaptations leading to the downregulation of where an individual loses control over abstaining from the dopamine pathways and processes, upregulation of stress drug, escalates drug intake, and relapses [5]. For this group systems, and the dysregulation of the prefrontal cortex (see of individuals, the drug may still have positively reinforcing above). Important to this analysis is that although the nature effects, although they are likely to be diminished as a result of reinforcement initiating and mediating these effects dif- of the drug-induced downregulation of mesolimbic and fers (positive vs. negative), the general role of reinforcement mesocortical pathways [7] that mediate these effects. This in drug intake (both acute and chronic) is well characterized tolerance induces escalation of drug intake. Further, because [9–12]. However, drugs have other stimulus properties that these systems are involved in regulating natural reward, their may be important as well in drug use and abuse. One such diminished state (a compensatory reaction to elevated drug property is a drug’s aversive effect that limits drug-taking intake) results in a negative affect (anhedonia-dysphoria, instead of initiating and maintaining it. The evidence for Behavioural Neurology 3 intake among those with the gene for this enzyme (see such effects comes from both clinical and preclinical research (for an excellent review of how initial responses to [22]; for evidence of acetaldehyde’s rewarding and motivat- a drug impact subsequent use in both clinical and preclinical ing effects, see [23]. The use of the drug disulfiram, a drug that blocks the metabolism of acetaldehyde, in the treatment populations, see [13]). of alcoholism is based on this same principle. In an assessment of patterns of alcohol intake in 4. Clinical Evidence of the Aversive Effects of humans, Baker and Cannon [24] noted that approximately Drugs of Abuse 45% of individuals hospitalized for the treatment of alcohol- ism reported aversions to the flavor of specific Clinical anecdotal reports note that drugs have both reward- alcohol prep- ing and aversive effects (with their use a function of the bal- arations most of which were acquired as a function of ance of these two properties; see [14] for a discussion; for overconsumption during early adolescence. That is, becom- factors impacting drug intake, see [9, 13, 15]). For example, ing sick with their initial alcohol experience limited subse- smokers often report the first exposure to nicotine as aver- quent consumption of those specific beverages. Similarly, sive (heart palpitations, feeling faint, dizziness, throat irrita- based on a survey of taste aversions in humans, Logue tion, coughing, and nausea) and adjust their intake to reduce et al. [25] reported upwards of 25% of 517 individuals who these effects or as tolerance develops allowing them to con- answered the survey indicated aversions to alcohol that were tinue to smoke. Interestingly, DiFranza and colleagues [16] associated with earlier patterns of alcohol consumption. It is noted that among first-time users (primarily young adoles- interesting in this context that one chemical treatment of cents), throat irritation with the first puff is a predictor of alcoholism utilizes aversion therapy in which alcohol con- reduced cigarette use whereas relaxation, dizziness, and nau- sumption is associated with an injection of a nauseant drug sea predict subsequent cigarette use disorder (see also [17, that induced aversions to the taste of alcohol ([26–28]; for 18]). In a self-report of the effects of mescaline, the user reviews, [29, 30]). Further (and along the lines noted above described vivid hallucinations but noted aversive side effects with genetic mutations), individuals appear to be differen- such as nausea and dizziness that led to speculation that the tially sensitive to these aversive effects of alcohol evidencing drug would not likely become popular given that such side another genetic vulnerability, in this case toward greater effects would spoil the generally positive effects of the drug consumption in those individuals less affected by alcohol’s [14]. One also sees these aversive effects with injected heroin aversive effects. Importantly, these vulnerabilities appear to as the drug has been reported to induce an orgasmic rush interact with experience as well given that individuals who that is often accompanied by nausea, retching, and vomiting. do not initially experience aversive effects seem to be pro- These aversive side effects diminish with repeated dosing tected from subsequent aversive reactions (either through [19]. Effects of caffeine have also been reported to reflect tolerance to alcohol or the added rewarding effects of alcohol the interaction of its rewarding and aversive effects, and this in ameliorating withdrawal symptoms; see [24]). interaction appears to be dose-dependent. For example, in These data from clinical populations illustrate that drugs an assessment of intake and reactions to varying doses of of abuse are complex pharmacological agents that possess caffeine, low doses (e.g., 100 mg) were found to be positively multiple stimulus effects, with the rewarding effects increas- rewarding to all subjects (with none reporting any negative ing vulnerability to initial use and subsequent abuse and the effects). With increases in dose, a general preference for aversive effects limiting intake. Such effects can occur at the the drug decreased as specific aversive or unwanted effects same dose; some are dose-dependent. Some effects appear to such as jitteriness and nervousness appeared [14]. Similar be impacted by genetic vulnerabilities; some are affected by dose-related effects have been reported with phencyclidine experience. Independent of the drug and the factors that (PCP). For example, at low doses, PCP produces a rewarding modulate its effects, what is clear is that individuals weigh effect that is often accompanied by a range of aversive the balance of these effects and intake is either adjusted or effects, e.g., thought disturbances, as well as violent behavior. continued with the anticipation that the aversive effects will With even greater doses, the aversive and unpleasant side be lessened with use (tolerance) or will become less salient as effects such as panic, fear paranoia, incoherent speech, and the rewarding effects increase (sensitization). bizarre behaviors become more intense that may dimmish the likelihood of further intake (see also [15, 20]). 5. Preclinical Evidence of the Aversive Effects of Work with alcohol further demonstrates the aversive Drugs of Abuse: Taste Aversions effects of drugs and how these effects modulate or impact drug intake. For example, the mutation in the gene coding Work with preclinical populations also reports evidence of for the enzyme aldehyde dehydrogenase (from the typical aversive effects of drugs of abuse. While there is considerable isozyme ACDH2 to the less efficient isozyme ACDH2*2; support for such effects in preclinical literature, the roots of found predominately in East Asian populations) results in this evidence are in toxicology [31]. In fact, work demon- the reduced ability to metabolize acetaldehyde, a metabolite strating such effects came from investigations related to mil- of alcohol [21]. Acetaldehyde has been reported to produce a itary applications during World War II, i.e., the effects of variety of adverse reactions, e.g., flushing of the face, head- toxins on rodent infestations (see [32]) and the effects of aches, and heart palpitations (with the severity of these reac- radiation exposure on biological systems (see [33]; for a tions greater in individuals homozygous for the ACDH2*2 review, see [34]). Initial field trials on rodent management gene), and appears to be protective against further alcohol with baits (i.e., a poison mixed with food base) presented a 4 Behavioural Neurology extended to the selective nature of CTA learning that pre- major difficulty, as rats exhibit a neophobic response toward novel foods and rarely sample enough of the bait to ingest a vents irrelevant stimuli (e.g., external cues) from interfering lethal amount of the poison. In early studies of this phenom- with the learning of a taste-illness association [38–40]. enon (bait-shyness), Rzóska [32] fed rats a food base laced with poison and noted that rats that had initially accepted 6. Taste Aversions as an Index of Toxicity the poisoned bait avoided the same bait in successive trials, but when a new base laced with the same poison was offered, Although the initial investigations into CTAs primarily they readily consumed the new bait. In speculating on these focused on their empirical assessments and theoretical empirical findings, i.e., refusal of identical poisoned bait and implications, subsequent research in this area shifted to acceptance of experienced poison in the new base, Rzóska explore the conditions under which CTA learning can be concluded that the rats associated the food base, rather than acquired, effects of various manipulations on its expression, the poison itself, with the illness experienced following and issues of mechanisms and applications. An important ingestion of the bait so they avoided the same food on sub- extension involved the use of CTA preparation as a tool to sequent trials. detect and characterize the behavioral and physiological In the early 1950s, this phenomenon of associative learn- effects of a toxin [31]. Empirically, the application of CTA ing between a novel taste and illness was further demon- as an index of toxicity is supported by the evidence that a strated with the effects of radiation by Garcia and his wide range of classical toxins that were characterized by colleagues who observed that rats given water in plastic bot- other behavioral and pharmacological tests could also condi- tles during radiation exposure subsequently avoided drink- tion taste aversions under various experimental conditions ing water from those plastic bottles. Importantly, the same (for a review, see [31]). For example, Nachman and Hartley rats would drink the water provided in glass bottles, suggest- [41] demonstrated that various rodenticides highly toxic to ing that the plastic bottle gave the water a unique taste that rats (i.e., copper sulfate, red squill, and sodium fluoroace- was associated with the effects of radiation (for a history of tate) produced strong taste aversions often with only a single Garcia’s early work with radiation, see [34]). In subsequent pairing of a novel taste with the compound. In addition to studies, Garcia and colleagues [33] tested the basis of these being rapidly learned, CTAs appeared relatively sensitive to aversions by giving rats a novel saccharin solution to drink detecting the aversive effects of drugs relative to other indi- during radiation exposure and reported that those rats ces of toxicity. For example, trimethyltin, a known neurotox- strongly suppressed consumption of the saccharin solution icant that causes specific damage to the hippocampus, after a single pairing of saccharin with radiation compared induces taste aversions [42, 43]. In more traditional behav- to the control group that was not exposed to radiation fol- ioral assays, a single administration of trimethyltin disrupts lowing intake of the saccharin. Garcia et al. concluded that hippocampus-dependent performance as measured in a the aversive effects of radiation conditioned an aversion to number of tasks, e.g., Hebb-Williams maze, radial-arm the radiation-paired flavor (see Figure 2). This initial report maze, and differential reinforcement of low rates of respond- demonstrated the fast and robust nature of conditioned taste ing (DRL). Interestingly, the dose of trimethyltin needed to aversions (CTAs) as a form of classical conditioning, condition a taste aversion is 500% less than that required wherein learning occurred with a single pairing; the aversion to produce effects in other behavioral indices of toxicity was dose-dependent (30 vs. 57 roentgen (r)) and evident for [42, 43]. These dose-response comparisons substantiate the over 30 days post conditioning despite the fact that animals taste aversion design as a sensitive index in detecting toxic- were given continuous access to the initially preferred sac- ity, as compounds that support taste aversions generally do charin solution and water during this period. Such aversions so at lower doses than are necessary to produce effects in have been reported to be maintained with a year (53 weeks) more traditional assessments of toxicity. From a theoretical intervening between its acquisition and eventual test [35]. perspective, the sensitivity of the taste aversion design Subsequently, Garcia et al. [36] demonstrated that an appears to be a natural extension of the concept of adaptive aversion to saccharin was acquired with an interstimulus specialization in normal consummatory behavior. An organ- interval as long as 75 min (i.e., when the delay between con- ism that can learn the toxic potential of its food source is sumption and radiation was 75 min). In a separate study likely to quickly avoid subsequent toxicosis and reduce the published the same year, taste aversion learning appeared possibility of ingesting the fatal dose of the toxin (see above). selective to gustatory stimuli, wherein rats selectively associ- Research investigating other compounds with toxic and ated saccharin with radiation but audiovisual cues with foot adverse effects within the CTA preparation steadily shock [37]. These unique conditions under which CTA was increased throughout the 1970s with several well-known acquired, that is, learning with one trial, over long delays and toxins such as barium sulfate, cyanide, red squill, strychnine relatively selective to tastes, led to the reconceptualization of sulfate, and sodium fluoride reportedly producing CTAs (for the role of evolution in shaping behavior and learning. It a more comprehensive list of compounds with toxic and seems plausible that natural selection favored organisms able adverse effects that induce CTAs, see Table 1). Although to quickly learn the taste-illness association. Given that aver- most classical toxins (and neurotoxins) reliably condition sive outcomes are likely to occur after some delay as the nat- taste aversion, several compounds with known toxicity have ural function of digestion, the ability to learn a taste-illness been reported to be ineffective. While such caveats clearly association over long delays prevents repeated consumption suggest a limitation of the CTA preparation as an index of of toxic foods. Such adaptive specialization for survival also toxicity, alternative interpretations have been raised in Behavioural Neurology 5 90 Preirradiation preference score 3 7 11 19 35 51 59 63 15 23 27 31 39 43 47 55 Days postirradiation Figure 2: Median saccharin preference scores for animals previously given saccharin access during radiation exposure. Redrawn from Garcia et al. [33]. relation to specific procedures in assaying taste aversions 7. Conditioned Taste Aversions Induced by that might account for these failures (see [31] for a discus- Drugs of Abuse sion of the basis for the failure of known toxins to condition taste aversions and procedural variations of the CTA prepa- Although the initial work on the conditions supporting taste ration that could increase the efficacy of those compounds to aversion learning assessed compounds with adverse or toxic induce CTA). effects as potential aversive stimuli, by the early 1970s, a host There are certainly other behavioral assays for the aver- of other compounds were being investigated, some of which sive effects of drugs than taste aversion learning, e.g., sup- included drugs of abuse. For example, Lester et al. [100] pression of normal regulatory behavior (food and water assessed taste aversion learning with ethanol in which male intake) and disruptions of scheduled-controlled responding, Wistar rats were given 10 min access to a saccharin solution activity, learning and memory, and hedonic shifts (see Riley that was then followed by administration of ethanol (at var- and Tuck, 1985 [31]). One assay very related procedurally to ious concentrations and doses and by different routes of conditioned taste aversions is the conditioned place aversion administration). Under these parametric conditions and (CPA) preparation in which specific environments (or con- with only a single conditioning trial, ethanol induced signif- textual cues) are associated with drug injection. In this prep- icant suppression of saccharin consumption, and as reported aration, animals avoid or spend less time in the drug-paired with work with known toxins [34], the degree of the aver- environment than in one that is paired with the drug vehicle. sions induced was dose-, concentration-, and route- Although this procedure is often used to assess the aversive dependent. Importantly, control subjects receiving the same effects of a drug, it should be noted that when direct compar- saccharin solution paired with injections of the ethanol vehi- isons have been made between the taste and place aversion cle readily consumed it, indicating that the suppression evi- designs, aversions are generally more rapidly acquired and dent in the ethanol-treated animals was a function of the more strongly evident in taste (than place) conditioning association of saccharin with ethanol. (for a direct comparison between LiCl-induced taste and The following year, Cappell and LeBlanc [101] assessed place aversions and a review of other drug comparisons in the aversive effects of several other drugs of abuse, specifi- these two designs, see [99]). These differences between the cally mescaline and d-amphetamine. In the assessment with taste and place conditioning procedures in such assessments mescaline, male Wistar rats were given access to a novel sac- are likely a function of the relatively greater associability of charin solution and injected intraperitoneally with 0 (vehi- taste (over place) in the conditioning of aversive effects cle), 20, 36, or 62.4 mg/kg mescaline hydrochloride, and (see [38–40]). It is important to note that the majority of after, only a single pairing saccharin consumption was sig- drugs of abuse that reliably induce taste aversions fail to nificantly suppressed in all groups injected with mescaline induce a place aversion (in fact, generally inducing a place (maximum suppression at 36 mg/kg). In other groups of preference; see below) or produce a CPA under specific rats, amphetamine (administered intraperitoneally at 0, 2, parametric conditions (high doses, without a drug history, 4, and 8 mg/kg) was given following saccharin consumption, and time of injection relative to placement in chamber) or and significant aversions were again evident at all doses with specific sex, age group, or species (for a discussion, (maximum suppression at 2 mg/kg). Control subjects con- see [99]). Given that taste aversion conditioning has been sumed at high levels following the saccharin-saline pairing. more extensively examined as a behavioral assay of the aver- Subsequent work by Cappell and his colleagues [102] repli- sive effects of drugs and does so with greater sensitivity and cated Lester et al. [100] by reporting dose-dependent generality, the present review focuses primarily on condi- ethanol-induced CTAs in male Wistar rats and extended tioned taste aversion learning in our analysis. the classes of drugs that were effective in inducing aversions 30r 57r Saccharin preference score 6 Behavioural Neurology Table 1: Compounds with adverse or toxic effects effective in producing CTAs. Compound Reference α-Naphthylthiourea (rodenticide) Rzóska, 1954a [32] 1,1,2-Trichloroethane (carcinogen) Kallman et al., 1983 [44] 1,2-Dicholoethane (probable carcinogen) Kallman et al., 1983 [44] 1,2-Dichloroethylene (health hazard) Kallman et al., 1983 [44] 2,3,5-Trimethylphenyl methyl carbamate (neurotoxin) Nicolaus, 1987 [45] 2,4,5-Trichlorophenoxyacetic acid (herbicide) Sjödén and Archer, 1977 [46] 6-Formylindolo (3,2-b) carbazole (FICZ) (carcinogen) Mahiout and Pohjanvirta, 2016 [47] Acetaldehyde (primary metabolite of ethanol) Brown et al., 1978 [48] Acetoxycycloheximide (protein synthesis inhibitor) Ungerer et al., 1975 [49] Acrylamide (neurotoxin) Anderson et al., 1982 [50] Adriamycin (gastrointestinal tract toxin) Bernstein et al., 1980 [51] Aflatoxin B1 (toxic to liver and kidney) Rappold et al., 1984 [52] Alloxan monohydrate (diabetogenic agent) Brookshire et al., 1972 [53] Arsenic (rodenticide) Rzóska, 1954a [32] Atrazine (chlorotriazine herbicide) Hotchkiss et al., 2012 [54] barium carbonate (rodenticide) Rzóska, 1954a [32] Baygon (insecticide) Ebeling, 1969 [55] Benzo[α]pyrene (BaP) (dioxins) Mahiout and Pohjanvirta, 2016 [47] Boric acid (pesticide) Ebeling, 1969 [55] Bufotoxin (neurotoxin) Ward-Fear et al., 2016 [56] Cadmium (toxic metal) Wellman et al., 1984 [57] Carbaryl (insecticide) MacPhail and Leander, 1980 [58] Chloral hydrate (potent sedative) Kallman et al., 1983 [44] Chlordimeform (insecticide) Landauer et al., 1984 [59] Cisplatin (cytotoxin) Revusky and Reilly, 1989 [60] Clorgyline (neurotoxin) Buresová and Bures, 1987 [61] Cobalt chloride (toxic to organs) Wellman et al., 1984 [57] Cobra venom (neurotoxin) Islam, 1980 [62] Copper sulfate (pesticide) Nachman and Hartley, 1975 [41] Cyanide (cytotoxin) O’Connor and Matthews, 1995 [63] Cycloheximide (protein synthesis inhibitor) Booth and Simson, 1973 [64] Cyclophosphamide (gastrointestinal tract toxin) Dragoin et al., 1971 [65] Cytoxan (cytotoxin) Bernstein et al., 1980 [51] Dactinomycin (cytotoxin) Revusky and Martin, 1988 [66] Denatonium benzoate (rodenticide) El Hani et al., 1998 [67] Doxorubicin (cytotoxin) Revusky and Martin, 1988 [66] Emetine hydrochloride (emetic) Cannon and Baker, 1981 [68] Ferric nitrilotriacetate (Fe-NTA) (renal carcinogen) Irie et al., 2000 [69] Formalin (systemic poison) Stricker and Wilson,1970 [70] Ipecacuanha (emetic) Rudd et al., 1998 [71] Krait venom (neurotoxin) Islam, 1980 [62] Lead (toxic metal) Leander and Gau, 1980 [72] Lipopolysaccharide (endotoxin) Exton et al., 1995 [73] Mechlorethamine (vesicant) Revusky and Martin, 1988 [66] Mercuric chloride (cumulative poison) Klein et al., 1974 [74] Methyl bromide vapor (cumulative poison) Miyagawa, 1982 [75] Methylmercury (neurotoxin) Levine, 1978 [76] Methiocarb (pesticide) Mason and Reidinger, 1982 [77] Behavioural Neurology 7 Table 1: Continued. Compound Reference Metrazol (convulsant) Millner and Palfai, 1975 [78] Mesurol (pesticide) Gustavson et al., 1982 [79] Sodium fluoroacetate (rodenticide) Nachman and Hartley, 1975 [41] n-Butyraldoxime (aldehyde dehydrogenase inhibitor) Nachman et al., 1970 [80] N-N-Ethyl-2-bromobenzylamine (neurotoxin) Archer et al., 1983 [81] Ochratoxin (mycotoxin) Clark and Wellman, 1989 [82] Ozone (toxic to lung) MacPhail and Peele, 1992 [83] Paraquat (herbicide) Dey et al., 1987 [84] p-Chlorophenylalanine (neurotoxin) Nachman et al., 1970 [80] Phenylthiocarbamide (neurotoxin) St. John et al., 2005 [85] Picrotoxin (GABA receptor inhibitor) Chester and Cunningham, 1999 [86] Red squill (rodenticide) Rzóska, 1954a [32] Sarin (neurotoxin) Landauer and Romano, 1984 [87] Scorpion venom (neurotoxin) Islam, 1980 [62] Sodium cyanide (rodenticide) Nachman and Hartley, 1975 [41] Soman (neurotoxin) Romano et al., 1985 [88] Staphylococcal enterotoxin B (exotoxin) Kusnecov et al., 1999 [89] Strychnine sulfate (rodenticide) Howard et al., 1968 [90] T-2 toxin (mycotoxin) Wellman et al., 1989 [91] Thallium sulfate (rodenticide) Nachman and Hartley, 1975 [41] Thiabendazole (pesticide) Gustavson et al., 1983 [92] Thiram (fungicide) Tobajas et al., 2019 [93] Tumour necrosis factor α (cytokines) Goehler et al., 1995 [94] Trichloroethylene (carcinogen) Kallman et al., 1983 [44] Trichloromethane (neurotoxin) Balster and Borsellca, 1982 [95] Triethyltin (neurotoxin) MacPhail, 1982 [42] Trimethyltin (neurotoxin) MacPhail, 1982 [42] Triphenyltin (fungicide) MacPhail and Peele, 1992 [83] Toluene (systemic toxin) Miyagawa et al., 1984 [96] Viper venom (hemotoxic) Islam et al., 1982 [62] Vomitoxin (mycotoxin) Clark et al., 1987 [97] Xylene (systemic toxin) MacPhail and Peele, 1992 [83] Ziram (fungicide) Baker et al., 2005 [98] to morphine and chlordiazepoxide (3, 6, and 9 mg/kg; intra- ulus effects seemed paradoxical. At the outset, it was recog- peritoneal). Importantly, this work revealed that while aver- nized that these two effects, i.e., rewarding and aversive, sions were dose-dependent, the strength of the aversions and were generally assessed via different procedures (and gener- the doses at which significant aversions were evident varied ally in different laboratories). As such, demonstrations of these multiple stimulus effects may be a function of the spe- across drugs, suggesting drug-specific aversive effects. Con- current with (and subsequent to) these initial investigations, cific procedure under which they were assessed and not nec- a wide range of drugs of abuse known for their ability to sup- essarily paradoxical. As examples of these differences, port self-administration [103] induced taste aversions as well Cappell and his colleagues [127] noted that with work asses- (see Table 2 for a comprehensive list of various drugs of sing the self-administration of drugs, the drug is generally administered intravenously and under the control of the abuse effective in inducing conditioned taste aversions), sug- gesting that such drugs produce a number of stimulus effects subject (for a discussion of alternatives, see [10, 129]), (both rewarding and aversive). whereas in typical taste aversion studies, subjects are given Almost immediately upon these various demonstrations, the drug intraperitoneally, subcutaneously, or orally ([34, a question was raised as to how drugs that were readily self- 130, 131]; though see [132–136] for evidence of taste aver- sions induced by intravenously delivered drug) and at the administered could also be aversive (as indexed by taste aversion learning; see [127, 128], i.e., the two opposing stim- control of the experimenter and not the subject (though 8 Behavioural Neurology Table 2: Drugs of abuse that are effective in producing a CTA. Each drug has the reference for one of the initial studies examining that specific drug. Compound Reference α-Pyrrolidinopentiophenone (α-PVP) (synthetic cathinone; CNS stimulant) Nelson et al., 2017 [104] 9 9 Δ -Tetrahydrocannabinol (Δ -THC) (cannabinoid) Elsmore and Fletcher, 1972 [105] 3,4-Methylenedioxymethamphetamine (MDMA) (hallucinogen) Lin et al., 1993 [106] 3,4-Methylenedioxypyrovalerone (MDPV) (synthetic cathinone; CNS stimulant) King et al., 2014 [107] Amobarbital (CNS depressant) Vogel and Nathan, 1975 [108] Amphetamine (CNS stimulant) Berger, 1972 [109] Barbital (CNS depressant) Jolicoeur et al., 1977 [110] Caffeine (CNS stimulant) Dickens and Trethowan, 1971 [111] Cathinone (CNS stimulant) Goudie and Newton, 1985 [112] Cannabidiol (CBD) (cannabinoid) Corcoran et al., 1974 [113] Cannabigerol (CBG) (cannabinoid) Corcoran et al., 1974 [113] Cocaine (CNS stimulant) Goudie et al., 1978 [114] CP 55,940 (synthetic cannabinoid) McGregor et al., 1996 [115] d-Amphetamine (CNS stimulant) Cappell and LeBlanc, 1971 [101] Diazepam (CNS depressant) Jolicoeur et al., 1977 [110] Ethanol (CNS depressant) Lester et al., 1970 [100] Ethanol (CNS depressant)+cocaine (CNS stimulant) Busse et al., 2005 [116] Flurazepam (CNS depressant) Vogel and Nathan, 1975 [108] Heroin (analgesic) Grigson et al., 2000 [117] Heroin (analgesic)+cocaine (CNS stimulant) Riley et al., 2019 [118] Hexobarbital (CNS depressant) Vogel and Nathan, 1975 [108] Ketamine (hallucinogen) Etscorn and Parson, 1979 [119] l-Amphetamine (CNS stimulant) Carey and Goodall, 1974 [120] Lysergic acid diethylamide (LSD) (hallucinogen) Parker, 1996 [121] Methamphetamine (CNS stimulant) Martin and Ellinwood, 1973 [122] Mescaline (hallucinogen) Cappell and LeBlanc, 1971 [101] Methaqualone (sedative hypnotic) Vogel and Nathan, 1975 [108] Methyprylon (sedative hypnotic) Jolicoeur et al., 1977 [110] Methylone (synthetic cathinone; CNS stimulant) Manke et al., 2021 [123] Methylphenidate (CNS stimulant) Riley and Zellner, 1978 [124] Morphine (analgesic) Cappell et al., 1973 [102] Nicotine (CNS stimulant) Etscorn, 1980 [125] Pentobarbital (CNS depressant) Buresova and Bures, 1980 [126] Phencyclidine (PCP) (hallucinogen) Etscorn and Parson, 1979 [119] Phenobarbital (CNS depressant) Vogel and Nathan, 1975 [108] see [117, 137–139] for demonstrations of aversions induced effects of many drugs of abuse could be seen in a design that when the drug was self-administered and/or under the con- concurrently assessed these effects which assured that the trol of the subject). parametric conditions under which any effects were tested In addition to these basic procedural differences in drug were identical. For example, Wise et al. [137] gave rats access self-administration vs. taste aversion learning, such demon- to saccharin and then immediately allowed them to self- strations of the rewarding and aversive effects were often administer apomorphine (0.5 mg/kg per infusion; all sub- assessed under different parametric conditions, e.g., with dif- jects had previous experience with the intravenous self- ferent sexes, at different ages, in different strains, at different administration of amphetamine). On the subsequent expo- doses, and under different deprivation schedules, following sure to saccharin, 10 of the 11 subjects trained and tested acute and chronic exposure. The possibility that demonstra- displayed aversions to the apomorphine-associated saccha- tions of reward and aversion were a function of simple para- rin solution with the degree of the aversion directly related metric differences between such demonstrations was soon to the amount of apomorphine self-administered during dismissed with reports that the aversive and rewarding the initial training session. Thus, both the rewarding (self- Behavioural Neurology 9 administration) and aversive (CTA) effects of apomorphine aversions were reported with the combined design (for were evident under the same parametric conditions (and at reviews, see [166, 167]). comparable doses), suggesting multiple (and opposing) The advantage of using a combined procedure to exam- stimulus effects of the drug. In a related study, White et al. ine a drug’s aversive and rewarding effects in the same ani- [140] reported that rats injected with morphine after run- mal is that it addresses the concern that the two effects are ning down a straight alley to obtain food ran faster to obtain simply a function of different experimental conditions under the food (reward) but failed to consume it (aversion), again which they are tested (see above). While this is true, the revealing dual (and concurrent) effects of a drug, in this case combined procedure as generally used does train the animal morphine. Interestingly, animals given the emetic LiCl in a serial manner, i.e., the animal is given access to some under the same conditions displayed reduced running speed novel solution, e.g., saccharin, injected with the drug and to obtain the food and failed to eat the food, as well. In then put on one side of the place preference apparatus. related work, Ettenberg and Geist [138, 139] have reported Under such conditions, one could argue that acquisition of both positive and negative effects of cocaine in a runway the CTA itself or the conditions under which the CTA is model. In this design, animals are allowed to run down a generally trained and tested, i.e., water deprivation, could straight alley for an intravenous injection of cocaine. After impact the acquisition (or display) of the place preference. several such trials, the latency to leave the start box As such, the measure of reward in terms of place preference decreased (indicative of cocaine’s rewarding effects) and conditioning within the combined design might differ from the running time to enter the goal box increased as animals what one would see if place preferences were assessed began to retreat from the goal box with further training separately. (indicative of cocaine’s aversive effects). Ettenberg et al. sug- Although there are many studies using the combined gested that the immediate actions of cocaine were rewarding design (see above), there are only a few that have addressed (decreasing response latencies) that were quickly followed by this potential confound. For example, in one such study, ani- an opponent process crash that resulted in an approach/ mals were given morphine-induced taste aversion training, avoidance reaction and increased running time as animals and once aversions were established, the same animals were retreated from (avoided) the goal box that was associated assessed for place preference conditioning with morphine. with cocaine (see also [141]; for evidence of this time- Place preferences were then compared between groups that dependent opponent process of reward/aversions, see [142]). had the aversion history vs. those that had been given con- trol injections during the taste aversion training, i.e., control subjects with no pairings of the taste with morphine. Under 8. Combined Taste Aversion/Place these conditions, there were no differences between animals with or without the taste aversion history, as morphine- Preference Procedure induced place preferences were similar for both groups Shortly after the demonstrations by Wise et al. [137] and [153]. These results suggest that having a history in which White et al. [140], Reicher and Holman [143] used a differ- a specific drug induced an aversion had no effect on its abil- ent procedure to assess the aversive and rewarding effects of ity to induce a place preference for that same drug. While this addresses the effects of an aversion history on place pref- amphetamine. Specifically, this group used a combined con- ditioned taste aversion and conditioned place preference erence conditioning, it does not address the possibility that (CTA/CPP) design in which they gave female Sprague- the procedures used in the combined design to induce an Dawley rats an intraperitoneal injection of amphetamine aversion might impact the acquisition of the place prefer- (1.43 mg/kg) and placed them on one side of a two- ence. One factor that might impact such learning would be compartment shuttle box during which they had access to water deprivation (or its associated stress). In the combined a novel-flavored solution (banana or almond). On the next design, animals are generally water deprived to encourage day, the animals were injected with the amphetamine vehicle consumption, but it is present as well during the place pref- erence assessment, a condition not typically used in inde- and placed on the opposite side of the shuttle box with access to the other novel solution (almond or banana). Six pendent assessments of place preference conditioning. In a such alternating trials were given followed by tests for side recent study, Dannenhoffer and Spear [147] examined the and flavor preferences. Under these conditions, amphet- combined CTA/CPP procedure with nicotine in nonde- amine induced significant taste aversions and place prefer- prived adolescent and adult rats. To induce drinking in these nondeprived animals, a highly palatable sucrose/saccharin ences, again demonstrating both aversive and rewarding effects of the same drug and under identical parametric solution was given after which the animals were injected conditions. Subsequent to the initial work by Reicher and with nicotine and placed on one side of a place preference Holman, a variety of drugs have now been shown to sup- chamber. As expected, nicotine induced significant taste port both effects in the combined CTA/CPP procedure aversions and place preferences, and importantly, place pref- erences (and taste aversions) were similar to those reported including 3,4-methylenedioxypyrovalerone (MDPV) [144], α-pyrrolidinopentiophenone (α-PVP) [104, 145, 146], nic- in independent assessments of each. Further, adolescents otine [147], amphetamine [148–150], morphine were more sensitive to the rewarding effects of nicotine [150–157], cocaine [158–160], alcohol [161], and caffeine (and less sensitive to its aversive effects) relative to adults [162]; for several drugs, e.g., ethanol [163] and Δ -tetrahy- (for comparison, see [168] who reported these same relative sensitivities of CPP and CTA when separately assessed). drocannabinol (THC) ([164, 165], both taste and place Affective Value 10 Behavioural Neurology Rewarding Other comparisons across studies have shown that place preference conditioning is comparable when assessed in a combined CTA/CPP design or as an independent CPP and that manipulations in either design impact place preference conditioning similarly (see [152, 157] for assessments of the combined CTA/CPP assay with morphine compared to [169, 170] for assessments of morphine using only CPP; for a similar comparison with MDPV, see [171] compared to [172]; for α-PVP, see [104] compared to [173, 174]; and for caffeine, see [162] compared to [175]). 9. Implications of the Aversive and Rewarding Effects of Drugs Aversive The fact that drugs have both rewarding and aversive effects Drug Dose raises an interesting issue regarding their possible role in drug intake. Specifically, the balance of these two effects Figure 3: A hypothetical model of the aversive and rewarding may be important in the likelihood of a drug’s initial use effects of a drug and their potential interaction to impact its self- administration (which is a function of the overall affective and its continued (regulated) intake (see Figure 3). Further, response to the drug). The drug produces both aversive and we are suggesting that it is this very balance that predicts rewarding effects in a dose-dependent manner. As illustrated in the abuse vulnerability of a specific drug [20, 137, 141, 166, this specific example, the drug’s rewarding effects are produced at 176–179]. If the rewarding effects of the drug (at any given lower doses that increase the drug’s overall affective property that, dose) are greater than its aversive effects at that same dose, in turn, drives the drug’s intake. With increases in the dose, the the abuse vulnerability of this drug might be predicted to drug’s rewarding effects asymptote while the drug’s aversive be high as intake may increase with its overall greater affec- effects increase, reducing the overall affective value of the drug tive value. If at the outset the drug’s aversive effects (at any and decreasing the drug’s self-administration. In this model, the given dose) exceed its rewarding effects at that same dose, drug’s rewarding effects are assumed to initiate and maintain it might be expected that drug intake would not continue drug intake (at least under acute conditions) while its aversive and the drug would have limited abuse potential. It is impor- effects limit it. The nature of such an interaction is not static and tant to note that this balance is not fixed for any specific depends upon a host of factors (see Sections 11 and 12). Further, drug as a wide range of factors have been reported to affect the relative contributions of the aversive effects in limiting intake change as drug intake go from regulated to dysregulated given the both its rewarding and aversive effects (see below) which, change in the reward valence from positive to negative. Created in turn, can shift the affective balance. It is also important with BioRender.com. to note that the nature of the drug’s rewarding effects changes with more frequent and chronic use (from positive associated with acute and regulated intake to negative asso- Interestingly, animals that acquired strong morphine- ciated with dysregulated intake and the onset of dependence, induced taste aversions were just as likely to display weak anhedonia, and withdrawal (see [4–7]). Although under or strong morphine-induced place preferences. Similarly, these latter conditions, drug intake may still be a function animals that acquired weak morphine-induced taste aver- of the balance of reward and aversion; the very nature of sions were just as likely to display weak or strong place pref- anhedonia may weaken the relative contribution of the erences (for related findings with serial conditioning of drug’s aversive effects as individuals use the drug for relief CTAs and CPPs, see [180]). That is, there was no relation from withdrawal despite their aversive effects which would between the two measures. The same pattern emerged with normally limit intake. amphetamine. King et al. [171] have also reported similar independence with the synthetic cathinone, MDPV. In this report, males and females both acquired dose-dependent 10. Dissociation between the Aversive and taste aversions with males displaying greater aversions than Rewarding Effects of Drugs females. On the other hand, while both sexes acquired The fact that these two stimulus effects are evident in the MDPV-induced place preferences, these were independent same animals and often under similar parametric conditions of sex and correlational analysis between the degree of taste aversions and place preferences did not reveal a consistent supports the position that a drug has multiple affective prop- erties. Interestingly, it appears that these two effects can be relationship between the two measures (see [145] for related dissociated. For example, Verendeev and Riley [150] (see findings with the synthetic cathinone a-PVP in which both also [180]) have reported that animals trained in a combined males and females displayed significant and dose- CTA/CPP procedure with morphine (5 or 10 mg/kg, intra- dependent CTAs (M> F), but only males displayed signifi- cant place preferences). peritoneal) or amphetamine (3 or 5 mg/kg, intraperitoneal) acquired taste aversions as well as place preferences; how- The apparent dissociation of taste aversions and place ever, there was no relationship between the strength of taste preferences as measured in the combined CTA/CPP design aversion and place preference conditioning for either drug. argues that these two effects occur concurrently but are not (- ) Affective Properties (+) Behavioural Neurology 11 aversions based on studies for which the doses supporting related. The fact that the aversive effects of the drug are asso- ciated with taste (CTA) while the rewarding effects are asso- the two effects differ (see [161, 162, 164, 165, 195]), it is ciated with a specific place (CPP) is likely a function of the important to note that under most of the assessments cited relative selectivity of taste and environment conditioning above reporting the dissociation of CTAs and CPPs, compa- with these specificaffective properties (see [33, 38, 40]; for rable doses were administered, yet the two indices of the a review, see [34]). Although apparently dissociable, any drug’saffective properties were still differentially affected attempt to relate these behaviors in a correlational analysis by various manipulations [116, 145–147, 152, 159, 168, should be made cautiously, given that CTA and CPP proce- 181, 182, 188, 191], i.e., the different effects reported for dures may differ in their relative sensitivity as measures of CTA and CPP were not simply due to animals being tested the aversive and rewarding effects of drugs, respectively. under different doses in the two designs. For example, CTA may be less sensitive as a measure of the aversive effects of a drug than CPP is as a measure of 11. Nature of the Aversive Effects of Drugs its rewarding effects, and the drug’s aversive effects may not be accurately reflected in the expression of taste aver- The present review has discussed conditioned taste aversions sions. Conversely, CPP may be less sensitive as a measure in the context of their origins and extensions. As such, it has of the rewarding effects of a drug than CTA is as a measure used the animal’s suppression of consumption of a specific of its aversive effects. That is, the drug’s rewarding effects taste following its pairing with either a toxin or drug of abuse may not be accurately reflected in the expression of place to be a function of the compound’s aversive effects that preferences. As such, any attempt to relate these behaviors become conditioned to the taste itself. Noting that drugs of in a correlational analysis should be made cautiously. Inter- abuse have aversive effects that may limit (or modify) their estingly, under conditions where taste aversions and place intake suggests that these effects may be important in regu- preferences have been analyzed in individual subjects most lated drug intake; however, such a position does not indicate sensitive to either aversive (high CTA) or rewarding (high their nature which has been somewhat elusive over the his- CPP) effects of drugs, there still is no consistent relationship tory of the phenomenon of taste aversion learning [34]. between the ability of either drug to produce these effects The present review is somewhat neutral on this issue, but (see [144, 150]), supporting the ability of the aversive and suffice it to say, the literature has had much to discuss rewarding effects to cooccur and at the same time being dis- (and debate) regarding the basis of taste aversion condition- sociable—a position consistent with the drugs having cooc- ing. At the outset of work on this phenomenon [33, 196], the curring, but unrelated, effects. avoidance was thought to be a function of conditioning of Such a position is supported by other assessments of the radiation-induced gastrointestinal effects, e.g., sickness. drug-induced taste aversions and place preferences that have The resulting avoidance was a reflection of conditioned sick- found similar dissociations between the two effects in a ness/malaise itself, i.e., a conditioned aversion to that taste number of studies evaluating the impact of a variety of [38]. As reported by Garcia and Kimeldorf [197], radiation manipulations on their acquisition and display, e.g., age localized to the abdomen induced significant taste aversions [147, 168, 181], sex [145], strain [181–183], drug history at doses that had no effect when targeted to other areas [146, 152, 182, 184], drug interactions [116], genetic knock- (including the head; higher doses localized to the head, pel- outs/knockins [185, 186], lesions [133, 187], state depen- vis, or thorax did produce aversions, but even here, they did dency [188], role of DARRP-32 [189], effects of LPS [190], not approximate those targeting the abdomen). Garcia and effects of Fe particles [191], neuroanatomical and neuro- Kimeldorf noted that abdomen radiation induced aversions chemical mediation [157, 192, 193], and receptor subtype at the same dose that decreased gastric distension and tran- [186, 194]. For these assessments, CTA and CPP were differ- sit, leading them to conclude that gastric disruption is the entially affected, suggesting that the two were unrelated, i.e., stimulus likely necessary to condition aversions. As other if related one would expect that the two effects would be agents (mostly toxins) were reported to induce aversions, it similarly impacted. In the above evaluations, CPP could be was assumed that these compounds also produced sickness seen with no evidence of a CTA (and vice versa) or CPP or malaise, but these conclusions were generally made in the absence of direct corroborative evidence of such effects could be increased and CTA decreased (or vice versa) by chemical and neuroanatomical challenges. Although these (and often in the context of contrary evidence, e.g., the gen- demonstrations were generally made with separate analyses eral inability of antiemetic drugs to affect CTAs [198, 199], of reward and aversion, i.e., using the CTA (or conditioned the ability of antiemetics to induce CTAs themselves [109, place aversion) design to assess the drug’s aversive effect 200], and the absence of a relationship between the degree and the CPP design to assess reward, some were made with of sickness and CTAs [201]. the combined design demonstrating again that the dissocia- A similar explanation was used by many to account for tions were not a simple function of parametric conditions. the avoidance of taste paired with drugs of abuse which, in One specific manipulation that deserves special attention part, created the initial paradox of how drugs of abuse could is that of dose. As noted in the clinical literature (see above), be both aversive (via sickness) and rewarding at the same the rewarding and aversive effects of some drugs were time. While conditioned aversions (sickness) were often reported to be dose-dependent, specifically rewarding at applied to the suppression of consumption of tastes paired low doses and aversive at higher ones. While there is evi- with drugs of abuse, others challenged this position. For dence of dissociations between place preferences and taste example, in an elegant series of studies, Parker assessed taste 12 Behavioural Neurology from use to abuse, see [5]); any disruption in this state is per- reactivity as an index of the sickness-inducing effects of drugs and found that although most drugs of abuse resulted ceived as dangerous and defended. In one of the first reports in the suppression of consumption of solutions paired with on this possibility, Gamzu [128] discussed drug novelty itself as being the necessary condition for disruptions of homeo- the drug (see [202]; see also above; Table 2), these same drugs did not produce signs of sickness in the taste reactivity stasis and in conditioning taste aversions (see [218] for a assessments ([203]; for recent work with LiCl vs. lactose, see related position that argued that the actual rewarding effects [204]). In assessments of taste reactivity, a taste previously of drugs were the novel stimulus that induced taste aver- associated with some drug, e.g., LiCl, amphetamine, and sions). Although drug novelty is important in the condition- ing of taste aversions (as exposure to the drug prior to cocaine, is infused into the animal’s mouth via an indwelling cannula and both aversive and positive taste reactions to the conditioning weakens the acquisition of taste aversions), infused solution are recorded. If the taste has been paired several arguments challenged this specific account. For with LiCl (and other emetics), a host of aversive taste reac- example, as noted above, a number of classic toxins such tions are increased, e.g., gaping, chin wipes, and paw tread- as strychnine and cyanide as well as convulsants fail to induce CTAs (see [41]). It is difficult to explain how drugs ing, which are used as an index of sickness/malaise induced by the conditioned taste (via its pairing with a drug with clear toxicity fail to induce a novel state. More impor- that induced such effects unconditionally; see [205, 206]). As tantly, although drug history weakens taste aversion acquisi- noted, tastes paired with drugs of abuse generally do not tion, with repeated conditioning trials (where the taste and induce aversive taste reactivity (for reviews, see [207–209]). familiar drug are repeatedly paired), aversions do develop despite the fact that the drug is no longer novel (for a review, Parker and her colleagues concluded from these analyses that drugs of abuse do not induce sickness (as indexed by see [219]). the taste reactivity test), and thus, the suppression of con- Disruptions in homeostasis can be produced by toxins, sumption of the taste associated with such drugs is not a chemicals with adverse effects, and drugs of abuse, and function of a conditioned aversion to the taste itself. Impor- according to the evolutionary importance of recognizing such disruptions as potentially dangerous, all such com- tantly, Parker has shown that even drugs such as LiCl which do induce aversive taste reactivity (reflective of conditioned pounds should be effective in inducing taste aversions (and sickness) do not suppress the intake of LiCl-associated solu- for the most part they are). However, stating that such dis- ruptions are important in inducing aversions does not sug- tions through this mechanism in that antiemetics can atten- uate aversive taste reactivity while leaving LiCl-taste gest that there is a common mechanism mediating all of these compounds. For example, even though drugs of abuse aversions intact [210] (for a review, see [199]). From her analysis of the basis of the suppressed consumption of solu- are rewarding as assessed in standard operant and Pavlovian tions induced by drugs of abuse, Parker suggests that sick- designs that index these effects, collateral effects such as sick- ness (morphine), hyperthermia (synthetic cathinones [145]), ness plays no role and even questions the role of sickness in suppression induced by emetics such as LiCl (for evidence anxiety (cocaine and amphetamine [138, 139]), sedation (barbiturates), hypothermia (alcohol [220]), and opponent critical of Parker’s position of the importance of sickness in taste aversion learning using measures other than taste reac- process-related withdrawal (cocaine and morphine [136, tivity, i.e., lick pattern and rate, to assess sickness and palat- 183, 221–223]), may be the stimuli important in inducing aversions by virtue of their ability to disrupt homeostasis. ability shifts, see [211–215]; see also [216, 217]). Given the diminishing role of sickness as the common What is critical about this explanation of homeostasis is that the aversive effects of drugs that condition aversions are mediator of the effects induced by various agents to induce taste aversions, others turned to different mediators of such drug (and parameter)-specific (and not due to a general effects. In this context, it was generally stated that issue of malaise or stress; for a discussion of a potential com- mon mediator, i.e., fear, see [224]). It is important to note aversion-inducing agents had toxic (adverse) effects (but not necessarily sickness or malaise) that were responsible here that few of the proposed mediating stimulus effects for taste aversion conditioning [31]. As such, interpretations have been directly tested and the failure of specific toxins became couched not in sickness but in rather general terms to induce aversions still needs to be explained (see [31] for of toxicity. Such a general term conveyed no clear mecha- an explanation of failure of several rodenticides and toxins). Further, over the past 20 years, a wide range of neuroactive nisms of the toxicity, and, further, drugs with reported tox- icity in other behavioral toxicological screens did not compounds as well as neurochemicals involved in the mod- always induce aversions [41] (for a discussion, see [31]). ulation of normal neuronal function (and behaviorally Also, when drugs of abuse were reported to induce taste active) are not effective in inducing CTAs, failures that chal- aversions (see above), the explanations were even more dif- lenge a simple homeostatic disruption as mediating aversion learning, e.g., interleukin-1B [225], interleukin-6 [226], lep- ficult in the context of general toxicity as such drugs in addi- tion to being rewarding in other preparations produced no tin [227], GHR-R antagonist JMV 2959 [228, 229], L- obvious toxic effects at the doses tested [128] (see [20]). To tryptophan [230], N-acylphosphatidylethanolamine [231], address this issue, a number of individuals noted that such and oleoylethanolamide [232]. drugs of abuse were aversive by disrupting normal homeo- Although each of these mechanistic accounts has been offered stasis [31, 127, 128, 207, 214]. That is, given that general as a basis for taste aversion learning and most papers homeostasis is a well-defended state (see [128]; for related refer to one of these interpretations in their analysis of discussion on drugs of abuse in terms of their transition CTAs, no individual perspective is generally accepted. Behavioural Neurology 13 and marijuana) whether the initial response to these com- Independent of which interpretation eventually garners con- sensus, all argue that the drug (whether a toxin, exogenous pounds is associated with subsequent use and/or abuse. As chemical agent, peptide, neurochemical, or drug of abuse) they describe, individuals differ significantly in their initial response to these drugs (as a function of environmental has some adverse effect that induces aversions (for an alter- native interpretation that argues that the avoidance of drug- and genetic influences) and that for several drugs the initial paired tastes is a function of a reward comparison in which responses (either positive or negative) are correlated with the taste is devalued relative to the injected drug, i.e., antic- subsequent use (and in some instances substance use disor- ipatory contrast, see [155–157, 233–235]; see [20] for a der). For example, with alcohol, individuals who initially dis- play greater stimulant-like effects as breath alcohol review of the reward comparison hypothesis). concentrations are rising (see [237]) and feel fewer depres- sant effects as these levels decrease [238] are more likely to 12. Implications for the Aversive and use and abuse alcohol. Conversely, those individuals that experience unpleasant effects are less likely to subsequently Rewarding Effects of Drugs to Use consume alcohol, effects and outcomes similar to what was and Abuse previously described for individuals with metabolic differ- ences in the ability to metabolize the alcohol metabolite acet- The fact that drugs of abuse have both aversive and reward- ing effects is now well characterized by a wide range of such aldehyde (see above; see also [22, 239]). compounds. The fact that the two effects are also dissociable For other drugs (e.g., nicotine), the initial positive response was a better predictor of use and abuse (although is important given that they can be differentially impacted by a host of parametric, experiential, and subject factors (see negative responses limited intake under some conditions). For others (e.g., marijuana), only initial positive responses above). That is, the balance between these two affective properties can be differentially impacted by these factors were associated with later use that, in turn, had little associ- and, in turn, can change abuse vulnerability. In this context, ation with initial negative reactivity. For caffeine, unpleasant effects or negative subjective responses predicted lower con- the hypothetical interaction of aversion and reward as illus- trated in Figure 3 is not static but is one that will differ sumption. Finally, for heroin, individuals having greater depending upon the drug examined (including its dose, positive experience were more associated with later abuse route of administration, and frequency of use) and the myr- (although no data have been reported on the relative associ- iad of subject (sex, age, and genetics) and experiential (drug ation with any negative effects, e.g., nausea). In a summary of their work, De Wit and Phillips [13] cautioned that an interactions, drug history, drug expectancy, and condition- ing history) factors that can modulate each affective understanding of the contribution of the initial affective response (for a discussion, see [166, 176, 236]). Knowing response to a drug to its later use and/or abuse must be the impact of these factors on drug aversion and reward assessed in the context of many other factors such as expec- and their balance should provide insight into the drug’s tancies, cognitive control, drug history, learning, and physi- use and its abuse vulnerability. cal dependence, all of which clearly impact the likelihood of The questions then become how this impact occurs and continued drug use and its escalation (e.g., the fact that indi- under what conditions. The complexity of these questions viduals adjust doses of heroin or become tolerant to its aver- becomes clear when one examines facets of drug-taking sive effects may limit generalization about the relative role of (see [4]) that range from controlled to dysregulated use initial positive and negative effects to its continued use). (abuse). In this context, aversion and reward (and their bal- Interestingly, De Wit and Phillips [13] also assessed ance) could impact the likelihood of initial drug intake and related work on positive and negative drug effects in animal its maintenance as well as the dysregulation of drug intake models and noted the relative paucity of data assessing affec- that may escalate to abuse. Although each of these is impor- tive valence in nonhuman subjects and its relationship to tant in assessing how drug use and abuse may be impacted drug intake in animals. The one area for which considerable by the affective properties of drugs, relatively little has data have been reported has used selectively bred animals addressed these specific issues. This review will highlight (lines selectively bred for specific phenotypes) and inbred some of the work in these areas and what could be done. animal strains (derived from full-sibling mating that maxi- These issues have recently been addressed by De Wit and mize genetic homogeneity) as their focus (for reviews, see Phillips [13] in their review “Do initial responses to drugs [176, 236, 240]). The creation of selectively bred lines that predict future drug use?.” In this review, they raise the point are differentially sensitive to the aversive effects of drugs that drugs can vary on a number of characteristics, including has been reported for many years (see [241, 242]). Such ani- the magnitude, quality, and duration of their effects, all of mals (taste aversion prone and taste aversion resistant, TAP which may impact subsequent use. One characteristic which and TAR, respectively) display significant differences in their is highlighted in their review is the affective valence of a ability to acquire aversions induced by a variety of drugs, drug’seffects, i.e., the positive and negative effects that may e.g., cyclophosphamide, LiCl, and emetine hydrochloride facilitate and discourage use, respectively (similar to the [241, 242], and importantly by drugs of abuse, e.g., alcohol affective properties noted in the present review). Using both ([243]; see also [244]), with the TAP animals displaying retrospective and prospective assessments (along with aversions at lower doses and acquiring aversions at a faster human laboratory studies), they then assess for a variety of rate than the TAR animals. These differences in aversion drugs (alcohol, nicotine, caffeine, psychostimulants, heroin, learning do not reflect differential abilities to learn in general 14 Behavioural Neurology methamphetamine displayed no differential aversive (as as TAP and TAR rats are similar in other learning prepara- tions that do not utilize aversion conditioning (see [245, measured by CTA) or rewarding (as measured by CPP) 246]). effects of cocaine, showing that the genetic sensitivity to the aversive and rewarding effects of methamphetamine Although Elkins and his group did not assess the poten- tial contribution of these differential sensitivities of the aver- does not impact cocaine susceptibility [195]. Such findings sive effects of alcohol (and cocaine) to drug intake in these of the inverse relationship between the aversive effects of a same animals, others have done related work and have drug and its tendency to be self-administered in selectively shown in both inbred strains and other selected lines that bred strains are not limited to methamphetamine and the low and high drinking mice. For example, our laboratory animals that show greater drug-induced taste aversions induced by specific compounds such as alcohol, metham- has also focused on this issue in selectively bred rat strains, phetamine, and heroin are less likely to self-administer those specifically the Lewis (LEW) and Fischer (F344) strains that same compounds (orally or intravenously) (see [166, 176, are well characterized for their differences in intravenous 236]). For example, the Wistar Kyoto (WKY) rat strain that self-administration of a variety of drugs. These two strains were originally selectively bred for cancer susceptibility and generally displays low consumption of alcohol in free-choice assessments displays strong taste aversions to novel solu- tissue inflammation (for discussion of the origins of these tions paired with exogenously administered ethanol (and lines, see [176]) but subsequently were shown to differ for differ significantly in both measures relative to the Marshal a myriad of other behaviors, including stress reactivity and strain (M520) that generally consumes high levels of alcohol drug intake, although the two strains were not selectively bre and only weak aversions to ethanol-paired solutions). In d for differences in these latter two effects. In relation to other words, there is an inverse relationship between alcohol drug intake, the LEW and F344 rat strains are well charac- consumption and its aversive effects (see [247, 248] for sim- terized for their differences in the self-administration of a ilar comparisons between the high alcohol-consuming Wis- variety of drugs of abuse, including alcohol (oral), morphine, tar Kyoto hyperactive rat (WKHA) and the WKY and etonitazene, methamphetamine, cocaine, and nicotine, and spontaneously hypertensive rat strains). under most comparisons, LEW rats self-administer greater The vast majority of work assessing the relationship amounts of drugs than does the F344 strain (for a review, between the aversive effects of drugs and drug intake has see [176]). The general conclusion regarding these genetic been with inbred strains of mice, specifically the C57BL/6J differences in drug intake is that the two strains differ signif- and DBA/2J strains. These two strains have been examined icantly in their sensitivity to the drugs’ rewarding effects, a for alcohol preference and ethanol-induced taste aversions conclusion supported by the fact that for a variety of drugs in a number of contexts and have consistently been shown the LEW strain displays conditioned place preferences at to display an inverse relationship between alcohol intake lower doses than the F344 strain (see [176]). Interestingly, and ethanol-induced taste aversions. Specifically, DBA mice however, these strains also differ significantly in the aversive (alcohol avoiding) acquire ethanol-induced taste aversions at effects of the same drugs. For example, we have demon- a lower dose/concentration and at a faster rate relative to strated for morphine [254–256], alcohol [163], and nicotine alcohol-preferring C57 mice. In a comprehensive analysis [257] that the F344 strain acquires morphine-, alcohol-, and of 15 inbred mouse strains, Broadbent et al. [249] reported nicotine-induced taste aversions at lower doses than the a significant inverse relationship between alcohol consump- LEW strain. Such differences in sensitivity to the aversive tion and ethanol-induced taste aversions, suggesting that the effects of these drugs are not a general function of learning sensitivity to the aversive effects of alcohol may serve as a as these strains differ in the opposite direction for the drugs’ protection against elevated alcohol intake (see [250] for a rewarding effects as indexed by place preference condition- similar inverse relationship between oral alcohol intake ing (L>F). Further, the two strains do not differ in aversions and ethanol-induced place aversion conditioning, another induced by compounds with no abuse potential, e.g., the index of the aversive effects of drugs; see [251] for related emetic LiCl [258], the kappa opiate receptor agonist work showing that ethanol-induced place preference condi- U50,488H [255], the delta opiate receptor agonist SNC80 tioning was not significantly correlated with alcohol con- [255], and the peripherally acting mu opiate receptor agonist sumption, suggesting a greater role for the aversive effects loperamide [256]. of alcohol in strain differences in alcohol acceptability). Thus, similar to work with inbred strains, we see an Other work has focused on selective breeding to assess inverse relationship between drug intake and the relative the relationships between the aversive effects of drugs and sensitivity to taste aversion conditioning, i.e., animals readily their self-administration. For example, Phillips and her col- self-administering the drug display weaker taste aversions leagues have reported similar findings with methamphet- (and vice versa), again substantiating a genetic component amine. Specifically, rats that are selectively bred for high mediating the basis for drug use. In that context, there are oral self-administration of methamphetamine were less several important caveats. First, when cocaine is used as likely to display methamphetamine-taste aversion (an index the aversion-inducing agent, the LEW strain displays greater of its aversive effects) and more likely to display aversions, i.e., the LEW strain self-administers cocaine at methamphetamine-place preferences (an index of its higher rates than the F344 strain and displays greater rewarding effects) than rats selectively bred for low metham- cocaine-induced taste aversions [259] (see [260] for related phetamine intake (see [183]; see also [252, 253]). Interest- findings with caffeine). While this challenges the inverse ingly, rats selectively bred for low and high drinking of relationship reported with alcohol, morphine, and nicotine, Behavioural Neurology 15 overconsumption followed by a reduced ability to control it should be noted that such a finding is not necessarily inconsistent with the position that drug intake is a balance the desire to obtain drugs regardless of the risks involved, of reward and aversion. In the case of cocaine, the LEW ultimately resulting in compulsive drug seeking [7]. The pos- strain is more sensitive to both affective properties, but the sibility that environmental stimuli associated with the post- balance may nonetheless be shifted toward reward, support- ingestive rewarding effects of drugs strongly motivate ing greater self-administration (see above discussion on the consumption has guided much of the research exploring balance of reward and aversion). A second caveat concerns the role of neuroadaptations in the mesolimbic and meso- the implications of the findings in general for a genetic cortical dopamine systems as well as in the prefrontal and mediation of the aversive and rewarding effects of drugs orbitofrontal cortices mediating responses to drug rewards based on the selective breeding model. While the difference [5, 274]. There is little doubt that the memory of highly between the LEW and F344 rat strains clearly represents rewarding postingestive drug effects can strongly influence effects that have genetic influence, it does not mean that expectations about the outcomes a particular drug will pro- these differences cannot be impacted by environmental fac- duce. The strength to which drug-related contexts (e.g., time tors. Support for this position comes from work on cross- and space) can excite retrieval of those memories is a key fostering in the strains. For example, we have reported that determinant of current and future consummatory behavior while LEW and F344 stains differ in their sensitivity to the [275, 276]. aversive effects of morphine (F>L; see [254]), these differ- However, the response to drug-related cues involves ential sensitivities are partially reversed with cross- more than excitatory associations that predict rewarding fostering. That is, F344 animals that normally display robust postingestive outcomes that, in turn, generate drug-taking. morphine-induced aversions resemble pups for the LEW As demonstrated by the majority of individuals consuming strain that are relatively insensitive to morphine if they are drugs, the patterns of drug intake are generally well regu- reared by a LEW dam; conversely, LEW animals that gener- lated, indicating that the capacity for drug-related cues to ally show weak morphine-induced aversions acquire strong evoke intake is not without limits [277, 278]. That is, bouts aversions (similar to the F344 strain) if reared by a F344 of drug intake stop even when environmental cues (and dam [261]. Partial reversals were also seen when cocaine the drug itself) that have gained the power to initiate intake was used as the aversion-inducing drug, i.e., the F344 strain are still present. Such regulatory control involves higher- that normally displays weak cocaine-induced taste aversion level learning and memory processes that counter the power display strong aversion characteristics of the LEW strain if of palatable drugs (and drug-related stimuli) to inhibit fur- reared by a LEW dam (see [176]; for reports of reversals of ther intake [271, 279–281]. The same environmental stimuli other behavioral effects by cross-fostering, see [262, 263]). associated with the rewarding consequences on some occa- The major work showing how the aversive (and reward- sions, e.g., at the outset of consumption, can also predict ing) effects of drugs may impact drug intake has primarily nonrewarding or even aversive consequences on other occa- been within various genetic models (see above; for related sions, e.g., toward the end of a bout of drug use. Thus, both work with KO mice, see also [186, 189, 264–266]; see also excitatory and inhibitory associations are formed between [267, 268] for effects of aldehyde dehydrogenase type 2 KO drug cues and positive and negative postingestive outcomes, and alcohol consumption and acetaldehyde brain, blood, respectively, depending on the context. The ambiguous and liver levels). It is important to note here that the aversive nature of the associations between drug-related cues and effects of drugs are impacted by a variety of other factors these consequences suggests that additional signals must be used to predict when taking the drug will produce rewarding such as sex [177], drug history [219], and age [269, 270], and the impact of these factors on drug use and abuse has outcomes and when the drug will produce nonrewarding or only recently been explored in this context. It will be critical even aversive effects, leading to an end in the bout of drug in such analyses that the impact of their effects be explored intake. We are suggesting that regulatory control of drug not only on the initial use of various drugs of abuse (i.e., intake is dependent in part on the ability of contextual drug reflecting the drug’s initial acceptability) but also on how states to disambiguate conflicting associations between drug these factors impact the likelihood of drug escalation and cues and postingestion outcomes. In this framework, choice as well as relapse of extinguished drug response (rein- although the initiation of drug-taking depends on the activa- statement) (for an example of such assessments on the com- tion of excitatory associations that predict rewarding effects, plexity of drug-taking, see [271]). contextual stimuli suppress intake by activating the inhibi- tory associations between the same drug cues associated with nonrewarding or aversive postingestive outcomes. Dysregu- 13. Drug Regulation lated intake, in turn, may be a function of poor control by Although the aversive effects of a drug on its subsequent these drug state cues that would produce an imbalance that intake have primarily been discussed as a limiting or protect- favors the excitatory associations, leading to overconsump- tion (see evidence by [282–284] for the role of similar pro- ing factor (see [20, 141, 236]), these effects may also be important to the regulation of normal intake or dysregula- cesses involved in the regulation/dysregulation of food intake). tion of intake that transitions drug use to drug abuse. This possibility has recently been suggested by our laboratory in Although the processes of cognitive inhibition described discussions on the role of drug states in regulated drug above have primarily been implicated in the regulation of food intake, the imbalance between inhibitory and excitatory intake [272, 273]. A principal feature of drug addiction is 16 Behavioural Neurology suppress the retrieval of memories of rewarding outcomes control mechanisms may also explain why some people progress from regulated to dysregulated drug use. Given free [298–300]. Hippocampal damage has been shown to impair drug access, animals learn to regulate drug intake to achieve the ability of humans [301–303] and rats [304, 305] to dis- criminate interoceptive satiety cues from hunger and to sup- a particular level of intoxication by titrating drug levels within the brain and bloodstream [15]. Characteristics of press food-reinforced conditioned response maintained drug self-administration indicate that drug or overconsumption. Rats with impaired hippocampal- drug-associated stimuli encountered by an animal in a dependent inhibitory control showed greater intake and drug-free state will initiate drug intake, but when the drug meal frequency within a shorter interval [306–308] and greater weight gain within weeks [309] or months [310]. level reaches above a satiety threshold, i.e., the minimal drug level at which self-administration is maintained, animals Specific to the issue of drug intake, we suggest that neu- temporarily suspend drug seeking [15, 280]. Consistent with roadaptations resulting from chronic drug use disrupt the this position, the presence or absence of a drug in the biolog- ability of the hippocampus to mediate inhibitory control ical system has been demonstrated to serve discriminative over responses to drug-related cues. In this context, hippo- campal impairments have been implicated to modulate the functions that signal the availability of certain reinforcers, e.g., food and water [285–288]. Not only can drugs serve as transition from regulated to dysregulated drug intake. In discriminative stimuli in general but also the discriminative chronic drug users, various drugs of abuse have been control of the training drug can also be generalized to drugs reported to impair the functional integrity of the hippocam- with comparable mechanisms of action [289–292]. pus and interfere with learning and memory [311, 312]. Hip- pocampal lesions have also been demonstrated to increase We [293] and others [294–297] have extended the anal- ysis on drug discrimination learning to show that interocep- the oral consumption of alcohol and the intravenous self- tive drug cues can also signal the presence and absence of an administration of cocaine, methamphetamine, morphine, aversive outcome using a modified conditioned taste aver- and nicotine in rodents [313–316]. Furthermore, we have sion design (for a review of the conditioned taste aversion recently reported that chronic administration of cocaine interfered with the ability of rats to solve a hippocampal- baseline of drug discrimination learning, see [272]). In one demonstration, rats received PCP followed by a pairing of dependent discriminative task known as the serial feature saccharin with the emetic LiCl on the conditioning day, negative (sFN) discrimination that requires the animals to use contextual signals to disambiguate postingestive out- and on the subsequent 3 days, the same animals received the PCP vehicle followed by paring of saccharin with the comes [317]. Interestingly, chronic administration of cocaine in the same animals had no effect on simple discrim- LiCl vehicle. Over multiple trials, animals avoided consum- ing saccharin when it was preceded by PCP and consumed ination problem that does not require a functional hippo- saccharin when it was preceded by the PCP vehicle. The campus, indicating that the type of learning and memory processes required to resolve approach-avoidance conflict control group that received the same PCP/vehicle injections prior to saccharin, but never the postsaccharin injection of in the sFN discrimination task does not rely on nonspecific factors (e.g., motivation and attention) but a higher-level LiCl, consumed high levels of saccharin throughout the study, indicating that the suppressed saccharin consumption regulatory mechanism dependent on the hippocampus to in the LiCl-treated group was a function of PCP signalling disambiguate conflicting associations. Taken together, these data highlight the fact that the hip- the saccharin-LiCl contingency rather than an uncondi- tioned suppression on saccharin consumption [293] (for pocampus is critically involved in regulating consummatory behaviors and that chronic drug use uniquely targets related work with morphine, see [295, 297]). To date, accumulating evidence that a wide range of hippocampal-dependent forms of learning and memories. drugs can serve such a discriminative function provides clear If chronic drug use disrupts the hippocampal function to modulate the ability of interoceptive cues of drug satiety to support for the ability of drug stimuli to modulate consum- matory behavior by signalling postingestive outcomes. Simi- engage inhibitory associations, then chronic drug exposure lar to the function of satiety cues in food intake regulation, might reduce the power of drug satiety cues to inhibit intake. discriminative learning may be important in regulating drug In support of this idea, future studies in drug addiction intake. Humans and other animals might use interoceptive should not be limited to reward- and motivation-based models; rather, future research should also explore a model drug signals to determine when a sufficient drug level has been achieved and whether to continue or refrain from con- predicated upon hippocampal functioning underlying regu- tinued or elevated consumption (see [13] for a discussion of lated drug use that could potentially contribute to prevent- the possible role of the inability to detect such stimulus ing the transition to dysregulated drug use and effects in alcoholics). Such an evaluation of drugs and conse- pathological state of drug abuse. quences of intake is governed by prior learning of various consequences of drug use. Further, memory processes repre- 14. Conclusions sent associations between drug-taking contexts, drug cues, and the consequences of drug-taking acquired over a In this review, we have discussed drug use and abuse in the repeated experience that strongly influence the cognitive context of a reward model and have qualified this analysis by inhibition of drug intake. A rich literature has demonstrated arguing that drugs of abuse have multiple stimulus proper- that the hippocampus modulates the capacity of any contex- ties (both rewarding and aversive) that need to be considered tual or discrete cues to activate inhibitory associations to in any account of drug-taking behavior. We provided Behavioural Neurology 17 [6] G. F. Koob, “The dark side of emotion: the addiction perspec- evidence that drugs have aversive effects (from both clinical tive,” European Journal of Pharmacology, vol. 753, pp. 73–87, and preclinical populations) and have introduced and dis- cussed these effects in their historical context (generated by [7] G. F. Koob and N. D. Volkow, “Neurobiology of addiction: a work on conditioned taste aversions). We indicate that the neurocircuitry analysis,” The Lancet Psychiatry, vol. 3, aversive effects can occur concurrent with rewarding ones pp. 760–773, 2016. in the same subject trained and tested under identical condi- [8] J. S. Meyer and L. F. Quenzer, Psychopharmacology: Drugs, tions and that their relative balance is important to the use the Brain, and Behavior, Sinauer Associates, Inc, Sunderland, and/or abuse of the drug. While both rewarding and aversive MA, 2nd edition, 2018. effects occur, we describe reports indicating that these effects [9] E. C. O’Connor, K. Chapman, P. Butler, and A. N. Mead, appear dissociable, suggesting that manipulations can “The predictive validity of the rat self-administration model impact them differently. We further suggest that an aware- for abuse liability,” Neuroscience & Biobehavioral Reviews, ness of each affective property and the multiple parametric, vol. 35, pp. 912–938, 2011. experiential, and subject factors that impact them and their [10] B. Kuhn, P. Kalivas, and A. C. Bobadilla, “Understanding relative balance will give insight into use and abuse vulnera- addiction using animal models,” Frontiers in Behavioral Neu- bility (for example, see [177]). Data supporting such a posi- roscience, vol. 13, pp. 1–24, 2019. tion were provided by an overview of the relationship [11] M. A. Smith, “Nonhuman animal models of substance use between initial and subsequent drug use (in humans) and a disorders: translational value and utility to basic science,” more detailed analysis of the inverse relationship between Drug and Alcohol Dependence, vol. 206, article 107733, 2020. perceived aversive effects of drugs and their intake. We close [12] Y. Swain, J. C. Gewirtz, and A. C. Harris, “Behavioral predic- our review by noting that the interaction of reward and aver- tors of individual differences in opioid addiction vulnerability sion may also be involved within bouts of drug intake as the as measures using i.v. self-administration in rats,” Drug and ability to use the drug state itself to set the occasion for aver- Alcohol Dependence, vol. 221, article 108561, 2021. sive effects that may accompany elevated use. We conclude [13] H. De Wit and T. J. Phillips, “Do initial responses to drugs from these issues that examining a drug’s aversive effects predict future use or abuse?,” Neuroscience & Biobehavioral (in addition to the myriad of other stimulus effects pro- Reviews, vol. 36, pp. 1565–1576, 2012. duced) is critical to understanding drug intake and develop- [14] A. Goldstein, Addiction: From Biology to Drug Policy, Oxford ing prevention and treatment strategies associated with the University Press, Inc, New York, NY, 2nd edition, 2001. transition from use to abuse. [15] W. J. Lynch and M. E. Carroll, “Regulation of drug intake,” Experimental and Clinical Psychopharmacology, vol. 9, pp. 131–143, 2001. Conflicts of Interest [16] J. R. DiFranza, J. A. Savageau, K. Fletcher et al., “Susceptibility to nicotine dependence: the development and assessment of The authors declare that they have no conflicts of interest. nicotine dependence in youth 2 study,” Pediatrics, vol. 120, pp. e974–e983, 2007. Acknowledgments [17] J. R. DiFranza, J. A. Savageau, K. Fletcher, J. K. Ockene, and N. A. Rigott, “Recollections and repercussions of the first The present work described was funded by grants from the inhaled cigarette,” Addictive Behaviors, vol. 29, no. 2, Mellon Foundation (ALR). pp. 261–272, 2004. [18] J. R. DiFranza, J. A. Savageau, N. A. Rigotti et al., “Trait anx- iety and nicotine dependence in adolescents: a report from References the DANDY study,” Addictive Behaviors, vol. 29, pp. 911– 919, 2004. [1] L. D. Johnston, R. A. Miech, P. M. O’Malley, J. G. Bachman, [19] L. Lasagna, J. M. von Felsinger, and H. K. Beecher, “Drug- J. E. Schulenberg, and M. E. Patrick, Monitoring the Future induced mood changes in man. I. Observations on healthy National Survey Results on Drug Use, 1975-2020, Institute subjects, chronically ill patients, and postaddicts,” Journal of for Social Research, The University of Michigan, Michigan, the American Medical Association, vol. 157, pp. 1006–1020, USA, 2021. [2] Substance Abuse and Mental Health Services Administration [20] A. Verendeev and A. L. Riley, “Conditioned taste aversion [SAMHSA], Key substance use and mental health indicators and drugs of abuse: history and interpretation,” Neuroscience in the United States: results from the 2020 National Survey & Biobehavioral Reviews, vol. 36, pp. 2193–2205, 2012. on Drug Use and Health, Center for Behavioral Health Statis- tics and Quality, Substance Abuse and Mental Health Ser- [21] S. J. Kohut and A. L. Riley, “Conditioned taste aversions and the vices Administration, Rockville, MD, 2021. assessment of the aversive effects of drugs: implications for drug [3] United Nations Office on Drugs and Crime (UNODC), use and abuse,” in Encyclopedia of Psychopharmacology,I. P. Stolerman, Ed., Springer Verlag, Berlin, Germany, 2010. World Drug Report 2021, United Nations Publication, 2021, Sales No. E.21.XI.8. [22] R. F. Suddendorf, “Research on alcohol metabolism among [4] N. D. Volkow, G. F. Koob, and A. T. McLellan, “Neurobiolo- Asians and its implications for understanding causes of alco- holism,” Public Health Reports, vol. 104, pp. 615–620, 1989. gic advances from the brain disease model of addiction,” New England Journal of Medicine, vol. 374, pp. 363–371, 2016. [23] C. Cannizzaro, F. Plescia, and S. Cacace, “Role of acetalde- [5] G. F. Koob, M. A. Arends, and M. Le Moal, Drugs, Addiction hyde in alcohol addiction: current evidence and future per- and the Brain, Academic Press, Waltham, MA, 2014. spectives,” Malta Medical Journal, vol. 23, pp. 27–31, 2011. 18 Behavioural Neurology [42] R. C. MacPhail, “Studies on the flavor aversions induced by [24] T. B. Baker and D. S. Cannon, “Alcohol and taste-mediated learning,” Addictive Behaviors, vol. 7, pp. 211–230, 1982. trialkyltin compounds,” Neurobehavioral Toxicology & Tera- tology, vol. 4, pp. 225–230, 1982. [25] A. W. Logue, K. R. Logue, and K. E. Strauss, “The acquisition of taste aversions in humans with eating and drinking disor- [43] A. L. Riley, R. J. Dacanay, and J. P. Mastropaolo, “The effects ders,” Behaviour Research and Therapy, vol. 21, pp. 275–289, of trimethyltin chloride on the acquisition of long delay con- 1983. ditioned taste aversion learning in the rats,” Neurotoxicology, vol. 5, pp. 291–295, 1984. [26] F. Lemere and W. L. Voegtlin, “Conditioned reflex therapy of alcoholic addiction: specificity of conditioning against [44] M. J. Kallman, M. R. Lynch, and M. R. Landauer, “Taste aver- chronic alcoholism,” California and Western Medicine, sions to several halogenated hydrocarbons,” Neurobehavioral vol. 53, pp. 268-269, 1940. Toxicology and Teratology, vol. 5, pp. 23–27, 1983. [27] W. L. Voegtlin, “The treatment of alcoholism by establishing [45] L. K. Nicolaus, “Conditioned aversions in a guild of egg preda- a conditioned reflex,” American Journal of the Medical Sci- tors: implications for aposematism and prey defense mimicry,” ences, vol. 199, pp. 802–809, 1940. American Midland Naturalist, vol. 117, pp. 405–419, 1987. [28] W. L. Voegtlin, F. Lemere, W. R. Broz, and P. O’Hollaren, [46] P. O. Sjödén and T. Archer, “Conditioned taste aversion to “Conditioned reflex therapy of chronic alcoholism; IV. A pre- saccharin induced by 2,4,5-trichlorophenoxyacetic acid in liminary report on the value of reinforcement,” Quarterly albino rats,” Physiology & Behavior, vol. 19, no. 1, pp. 159– Journal of Studies on Alcohol, vol. 2, pp. 505–511, 1941. 161, 1977. [29] R. L. Elkins, “An appraisal of chemical aversion (emetic ther- [47] S. Mahiout and R. Pohjanvirta, “Aryl hydrocarbon receptor apy) approaches to alcoholism treatment,” Behaviour agonists trigger avoidance of novel food in rats,” Physiology Research and Therapy, vol. 29, pp. 387–413, 1991. & Behavior, vol. 167, pp. 49–59, 2016. [30] S. H. Revusky, “Chemical aversion treatment of alcoholism,” [48] Z. W. Brown, Z. Amit, B. Smith, and G. E. Rockman, “Differ- in Conditioned Taste Aversion: Behavioral and Neural Pro- ential effects on conditioned taste aversion learning with cesses, S. Reilly and T. R. Schactman, Eds., pp. 445–472, peripherally and centrally administered acetaldehyde,” Neu- Oxford University Press, New York, NY, 2009. ropharmacology, vol. 17, pp. 931–935, 1978. [31] A. L. Riley and D. L. Tuck, “Conditioned taste aversions: a [49] A. Ungerer, D. Marchi, P. Ropartz, and J.-H. Weil, “Aversive behavioral index of toxicity,” Annals of the New York Acad- effects and retention impairment induced by acetoxycyclo- emy of Sciences, vol. 5, pp. 272–292, 1985. heximide in an instrumental task,” Physiology & Behavior, vol. 15, pp. 55–62, 1975. [32] J. Rzóska, “Bait shyness, a study in rat behavior,” The British Journal of Animal Behaviour, vol. 1, pp. 128–135, 1954. [50] C. E. Anderson, H. A. Tilson, and C. L. Mitchell, “Condi- [33] J. Garcia, D. J. Kimeldorf, and R. A. Koelling, “Conditioned tioned taste aversion following acutely administered acrylam- ide,” Neurobehavioral Toxicology & Teratology, vol. 4, aversion to saccharin resulting from exposure to gamma radi- pp. 497–499, 1982. ation,” Science, vol. 122, pp. 157-158, 1955. [51] I. L. Bernstein, M. V. Vitiello, and R. A. Sigmundi, “Effects of [34] K. B. Freeman and A. Riley, “The origins of conditioned taste tumor growth on taste-aversion learning produced by antitu- aversion learning: a historical analysis,” in Conditioned Taste mor drugs in the rat,” Physiological Psychology, vol. 8, pp. 51– Aversion: Behavioral and Neural Processes, S. Reilly and T. R. Schactman, Eds., pp. 9–33, Oxford University Press, New 55, 1980. York, NY, 2009. [52] V. A. Rappold, J. H. Porter, and G. C. Llewellyn, “Evaluation [35] J. Rzóska, “Stomach analysis of brown rats poisoned in the of the toxic effects of aflatoxin B with a taste aversion para- digm in rats,” Neurobehavioral Toxicology and Teratology, field,” in Control of Rats and Mice, D. Chitty, Ed., pp. 395– 413, Clarendon Press, Oxford, England, 1954. vol. 6, pp. 51–58, 1984. [53] K. H. Brookshire, C. N. Stewart, and H. N. Bhagavan, “Sac- [36] J. Garcia, F. R. Ervin, and R. A. Koelling, “Learning with pro- charin aversion in alloxan-diabetic rats,” Journal of Compar- longed delay of reinforcement,” Psychonomic Science, vol. 5, ative and Physiological Psychology, vol. 79, pp. 385–393, 1972. pp. 121-122, 1966. [54] M. G. Hotchkiss, D. S. Best, R. L. Cooper, and S. C. Laws, [37] J. Garcia and R. A. Koelling, “Relation of cue to consequence in avoidance learning,” Psychonomic Science, vol. 4, pp. 123- “Atrazine does not induce pica behavior at doses that increase hypothalamic–pituitary–adrenal axis activation and cause 124, 1966. conditioned taste avoidance,” Neurotoxicology and Teratol- [38] J. Garcia and F. R. Ervin, “Gustatory-visceral and ogy, vol. 34, pp. 295–302, 2012. telereceptor-cutaneous conditioning—adaptation in internal and external milieus,” Communications in Behavioral Biol- [55] W. Ebeling, “The cockroach learns to avoid insecticides,” Cal- ifornia Agriculture, vol. 23, pp. 12–15, 1969. ogy, vol. 1, pp. 389–415, 1968. [39] S. Revusky and J. Garcia, “Learned associations over long [56] G. Ward-Fear, D. J. Pearson, G. P. Brown, B. Rangers, and delays,” in Psychology of Learning and Motivation: Advances R. Shine, “Ecological immunization: in situ training of free- in Research and Theory, G. H. Bower and J. T. Spence, Eds., ranging predatory lizards reduces their vulnerability to inva- sive toxic prey,” Biology Letters, vol. 12, 2017. pp. 1–84, Academic Press, Cambridge, MA, 1970. [40] P. Rozin and J. W. Kalat, “Specific hungers and poison avoid- [57] P. J. Wellman, P. A. Watkins, J. R. Nation, and D. E. Clark, ance as adaptive specializations of learning,” Psychological “Conditioned taste aversion in the adult rat induced by die- Review, vol. 78, pp. 459–486, 1971. tary ingestion of cadmium or cobalt,” Neurotoxicology, vol. 5, pp. 81–90, 1984. [41] M. Nachman and P. L. Hartley, “Role of illness in producing learned taste aversions in rats: a comparison of several roden- [58] R. C. MacPhail and D. J. Leander, “Flavor aversion induced ticides,” Journal of Comparative and Physiological Psychology, by chlordimeform,” Neurobehavioral Toxicology, vol. 2, vol. 89, pp. 1010–1018, 1975. pp. 363–365, 1980. Behavioural Neurology 19 [76] T. E. Levine, “Conditioned aversion following ingestion of [59] M. R. Landauer, T. W. Tomlinson, R. L. Balster, and R. C. MacPhail, “Some effects of the formamidine pesticide chlor- methylmercury in rats and mice,” Behavioral Biology, dimeform on the behavior of mice,” Neurotoxicology, vol. 5, vol. 22, pp. 489–496, 1978. pp. 91–100, 1984. [77] R. J. Mason and R. F. Reidinger, “Observational learning of food aversions in red-winged blackbirds (Agelaius phoeni- [60] S. Revusky and S. Reilly, “Attenuation of conditioned taste ceus),” The Auk, vol. 99, pp. 548–554, 1982. aversions by external stressors,” Pharmacology Biochemistry and Behavior, vol. 33, pp. 219–226, 1989. [78] J. R. Millner and T. Palfai, “Metrazol impairs conditioned aversion produced by LiCl: a time dependent effect,” Phar- [61] O. Buresová and J. Bures, “Conditioned taste aversion macology Biochemistry and Behavior, vol. 3, pp. 201–204, induced in rats by intracerebral or systemic administration of monoamine oxidase inhibitors,” Psychopharmacology, vol. 91, pp. 209–212, 1987. [79] C. R. Gustavson, G. A. Holzer, J. C. Gustavson, and D. L. Vakoch, “An evaluation of phenol methylcarbamates as taste [62] S. Islam, “Snake neurotoxins and conditioned taste aversion aversion producing agents in caged blackbirds,” Applied Ani- in mice,” International Journal of Neuroscience, vol. 11, mal Ethology, vol. 8, pp. 551–559, 1982. pp. 41–43, 1980. [80] M. Nachman, D. Lester, and J. L. Magnen, “Alcohol aversion [63] C. E. O’Connor and L. R. Matthews, “Cyanide induced aver- in the rat: behavioral assessment of noxious drug effects,” Sci- sions in the possum (Trichosurus vulpecula): effect of route of ence, vol. 168, pp. 1244–1246, 1970. administration, dose, and formulation,” Physiology & Behav- ior, vol. 58, pp. 265–271, 1995. [81] T. Archer, A. K. Mohammed, and T. U. C. Jarbe, “Latent inhi- bition following systemic DSP4: effects due to presence and [64] D. A. Booth and P. C. Simson, “Aversion to a cue acquired by absence of contextual cues in taste-aversion learning,” Behav- its association with effects of an antibiotic in the rat,” Journal ioral and Neural Biology, vol. 38, pp. 287–306, 1983. of Comparative and Physiological Psychology, vol. 2, pp. 319– 323, 1973. [82] D. E. Clark and P. J. Wellman, “Conditioned saccharin taste aversion induced by mycotoxins in rats: lack of effect of och- [65] W. Dragoin, G. E. McCleary, and P. McCleary, “A compari- ratoxin A,” Pharmacology Biochemistry and Behavior, vol. 32, son of two methods of measuring conditioned taste aver- pp. 819–821, 1989. sions,” Behavior Research Methods & Instrumentation, [83] R. C. MacPhail and D. B. Peele, “Animal models for assessing vol. 3, pp. 309-310, 1971. the neurobehavioral impact of airborne pollutants,” Annals of [66] S. Revusky and G. M. Martin, “Glucocorticoids attenuate the New York Academy of Sciences, vol. 30, pp. 294–303, 1992. taste aversions produced by toxins in rats,” Psychopharmacol- [84] M. S. Dey, R. I. Krieger, and R. C. Ritter, “Paraquat-induced, ogy, vol. 96, pp. 400–407, 1988. dose-dependent conditioned taste aversions and weight loss [67] A. El Hani, R. J. Mason, D. L. Nolte, and R. H. Schmidt, “Fla- mediated by the area postrema,” Toxicology and Applied vor avoidance learning and its implications in reducing Pharmacology, vol. 87, pp. 212–221, 1987. strychnine baiting hazards to nontarget animals,” Physiology [85] S. J. St. John, L. Pour, and J. D. Boughter, “Phenylthiocarba- & Behavior, vol. 64, pp. 585–589, 1998. mide produces conditioned taste aversions in mice,” Chemi- [68] D. S. Cannon and T. B. Baker, “Emetic and electric shock cal Senses, vol. 30, pp. 377–382, 2005. alcohol aversion therapy: assessment of conditioning,” Jour- [86] J. A. Chester and C. L. Cunningham, “Baclofen alters ethanol- nal of Consulting and Clinical Psychology, vol. 49, pp. 20– stimulated activity but not conditioned place preference or 33, 1981. taste aversion in mice,” Pharmacology Biochemistry and [69] M. Irie, S. Asami, S. Nagata, M. Miyata, and H. Kasai, “Clas- Behavior, vol. 63, pp. 325–331, 1999. sical conditioning of oxidative DNA damage in rats,” Neuro- [87] M. R. Landauer and J. A. Romano, “Acute behavioral toxicity science Letters, vol. 288, pp. 13–16, 2000. of the organophosphate sarin in rats,” Neurobehavioral Tox- [70] E. M. Stricker and N. E. Wilson, “Salt-seeking behavior in rats icology & Teratology, vol. 6, pp. 239–243, 1984. following acute sodium deficiency,” Journal of Comparative [88] J. A. Romano, J. M. King, and D. M. Penetar, “A comparison and Physiological Psychology, vol. 72, pp. 416–420, 1970. of physostigmine and soman using taste aversion and noci- [71] J. A. Rudd, M. P. Ngan, and M. K. Wai, “5-HT receptors are ception,” Neurobehavioral Toxicology & Teratology, vol. 7, not involved in conditioned taste aversions induced by 5- pp. 243–249, 1985. hydroxytryptamine, ipecacuanha or cisplatin,” European [89] A. W. Kusnecov, R. Liang, and G. Shurin, “T-lymphocyte Journal of Pharmacology, vol. 352, pp. 143–149, 1998. activation increases hypothalamic and amygdaloid expres- [72] J. D. Leander and B. A. Gau, “Flavor aversions rapidly pro- sion of CRH mRNA and emotional reactivity to novelty,” duced by inorganic lead and triethyltin,” Neurotoxicology, Journal of Neuroscience, vol. 11, pp. 4533–4543, 1999. vol. 1, pp. 635–642, 1980. [90] W. E. Howard, S. D. Palmateer, and M. Nachman, “Aversion [73] M. S. Exton, D. F. Bull, M. G. King, and A. J. Husband, “Par- to strychnine sulfate by Norway rats, roof rats, and pocket adoxical conditioning of the plasma copper and corticoste- gophers,” Toxicology and Applied Pharmacology, vol. 12, rone responses to bacterial endotoxin,” Pharmacology pp. 229–241, 1968. Biochemistry and Behavior, vol. 52, pp. 347–354, 1995. [91] P. J. Wellman, L. D. Rowe, D. E. Clark, and R. D. Cockroft, [74] S. B. Klein, M. J. Barter, A. L. Murphy, and J. H. Richardson, “Effects of T-2 toxin on saccharin aversion and food con- “Aversion to low doses of mercuric chloride in rats,” Physio- sumption in adult rats,” Physiology & Behavior, vol. 45, logical Psychology, vol. 2, pp. 397–400, 1974. pp. 501–506, 1989. [75] M. Miyagawa, “Conditioned taste aversion induced by inha- [92] C. R. Gustavson, J. C. Gustavson, and G. A. Holzer, “Thiaben- lation exposure to methyl bromide in rats,” Toxicology Let- dazole-based taste aversions in dingoes (Canis familiaris ters, vol. 10, no. 4, pp. 411–416, 1982. dingo) and new guinea wild dogs (Canis familiaris 20 Behavioural Neurology [108] J. R. Vogel and B. A. Nathan, “Learned taste aversions hallstromi),” Applied Animal Ethology, vol. 10, pp. 385–388, 1983. induced by hypnotic drugs,” Pharmacology Biochemistry and Behavior, vol. 3, pp. 189–194, 1975. [93] J. Tobajas, P. Gómez-Ramírez, P. María-Mojica et al., “Selec- tion of new chemicals to be used in conditioned aversion for [109] B. D. Berger, “Conditioning of food aversions by injections of non-lethal predation control,” Behavioural Processes, psychoactive drugs,” Journal of Comparative and Physiologi- vol. 166, article 103905, 2019. cal Psychology, vol. 81, pp. 21–26, 1972. [94] L. E. Goehler, C. R. Busch, N. Tartaglia et al., “Blockade of [110] F. B. Jolicoeur, D. B. Rondeau, M. J. Wayner, R. B. Mintz, and cytokine induced conditioned taste aversion by subdiaphrag- A. D. Merkel, “Barbiturates and alcohol consumption,” Bio- matic vagotomy: further evidence for vagal mediation of behavioral Reviews, vol. 1, pp. 177–196, 1977. immune-brain communication,” Neuroscience Letters, [111] G. Dickens and W. H. Trethowan, “Cravings and aversions vol. 185, no. 163, p. 166, 1995. during pregnancy,” Journal of Psychosomatic Research, [95] R. L. Balster and J. F. Borzelleca, “Behavioral toxicity of tri- vol. 15, pp. 259–268, 1971. halomethane contaminants of drinking water in mice,” Envi- [112] A. J. Goudie and T. Newton, “The puzzle of drug-induced ronmental Health Perspectives, vol. 46, pp. 127–136, 1982. conditioned taste aversion: comparative studies with cathi- [96] M. Miyagawa, T. Honma, M. Sato, and H. Hasegawa, “Condi- none and amphetamine,” Psychopharmacology, vol. 87, tioned taste aversion induced by toluene administration in pp. 328–333, 1985. rats,” Neurobehavioral Toxicology and Teratology, vol. 6, [113] M. E. Corcoran, I. Bolotow, Z. Amit, and J. A. McCaughran pp. 33–37, 1984. Jr., “Conditioned taste aversions produced by active and inac- [97] D. E. Clark, P. J. Wellman, R. B. Harvey, and M. S. Lerma, tive cannabinoids,” Pharmacology Biochemistry and Behav- “Effects of vomitoxin (deoxynivalenol) on conditioned saccha- ior, vol. 2, pp. 725–728, 1974. rin aversion and food consumption in adult rats,” Pharmacol- [114] A. J. Goudie, D. W. Dickins, and E. W. Thornton, “Cocaine- ogy Biochemistry and Behavior,vol. 27,pp.247–252, 1987. induced conditioned taste aversions in rats,” Pharmacology [98] S. E. Baker, S. A. Ellwood, R. W. Watkins, and D. W. Mac- Biochemistry and Behavior, vol. 8, pp. 757–761, 1978. donald, “A dose-response trial with ziram-treated maize [115] I. S. McGregor, C. N. Issakidis, and G. Prior, “Aversive effects and free-ranging European badgers Meles meles,” Applied of the synthetic cannabinoid CP 55,940 in rats,” Pharmacol- Animal Behaviour Science, vol. 93, pp. 309–321, 2005. ogy Biochemistry and Behavior, vol. 53, pp. 657–664, 1996. [99] J. K. Gore-Langton, S. M. Flax, R. L. Pomfrey, B. B. Wetzell, [116] G. D. Busse, A. Verendeev, J. Jones, and A. L. Riley, “The and A. L. Riley, “Measures of the aversive effects of drugs: a effects of cocaine, alcohol and cocaine/alcohol combinations comparison of conditioned taste and place aversions,” Phar- in conditioned taste aversion learning,” Pharmacology Bio- macology Biochemistry and Behavior, vol. 134, pp. 99–105, chemistry and Behavior, vol. 82, pp. 207–214, 2005. [117] P. S. Grigson, R. C. Twining, and R. M. Carelli, “Heroin- [100] D. Lester, M. Nachman, and J. Le Magnen, “Aversive condi- induced suppression of saccharin intake in water-deprived tioning by ethanol in the rat,” Quarterly Journal of Studies and water-replete rats,” Pharmacology Biochemistry and on Alcohol, vol. 31, pp. 578–586, 1970. Behavior, vol. 66, pp. 603–608, 2000. [101] H. Cappell and A. E. LeBlanc, “Conditioned aversion to sac- [118] A. L. Riley, K. H. Nelson, M. E. Crissman, and K. A. Pesca- charin by single administrations of mescaline and d-amphet- tore, “Conditioned taste avoidance induced by the combina- amine,” Psychopharmacologia, vol. 22, pp. 352–356, 1971. tion of heroin and cocaine: implications for the use of [102] H. Cappell, A. E. LeBlanc, and L. Endrenyi, “Aversive condi- speedball,” Pharmacology Biochemistry and Behavior, tioning by psychoactive drugs: effects of morphine, alcohol vol. 187, article 172801, 2019. and chlordiazepoxide,” Psychopharmacologia, vol. 29, [119] F. Etscorn and P. Parson, “Taste aversion in mice using phen- pp. 239–246, 1973. cyclidine and ketamine as the aversive agents,” Bulletin of the [103] M. A. Bozarth, Methods of Assessing the Reinforcing Proper- Psychonomic Society, vol. 14, pp. 19–21, 1979. ties of Abused Drugs, Springer-Verlag, New York, NY, 1987. [120] R. J. Carey and E. B. Goodall, “Amphetamine-induced taste [104] K. H. Nelson, B. J. Hempel, M. M. Clasen, K. C. Rice, and aversion: a comparison of d-versus l-amphetamine,” Phar- A. L. Riley, “Conditioned taste avoidance, conditioned place macology Biochemistry and Behavior, vol. 2, pp. 325–330, preference and hyperthermia induced by the second genera- tion ‘bath salt’ α-pyrrolidinopentiophenone (α-PVP),” Phar- [121] L. A. Parker, “LSD produces place preference and flavor macology Biochemistry and Behavior, vol. 156, pp. 48–55, avoidance but does not produce flavor aversion in rats,” Behavioral Neuroscience, vol. 110, pp. 503–508, 1996. [105] T. F. Elsmore and G. V. Fletcher, “Δ -Tetrahydrocannabinol: [122] J. C. Martin and E. H. Ellinwood, “Conditioned aversion to a aversive effects in rat at high doses,” Science, vol. 175, pp. 911- preferred solution following methamphetamine injections,” 912, 1972. Psychopharmacologia, vol. 29, pp. 253–261, 1973. [106] H. Q. Lin, D. M. Atrens, M. J. Christie, D. M. Jackson, and [123] H. N. Manke, K. H. Nelson, A. Vlachos et al., “Assessment of I. S. McGregor, “Comparison of conditioned taste aversions aversive effects of methylone in male and female Sprague- produced by MDMA and d-amphetamine,” Pharmacology Dawley rats: conditioned taste avoidance, body temperature Biochemistry and Behavior, vol. 46, pp. 153–156, 1993. and activity/stereotypies,” Neurotoxicology and Teratology, [107] H. E. King, B. Wetzell, K. C. Rice, and A. L. Riley, “3, 4- vol. 86, article 106977, 2021. Methylenedioxypyrovalerone (MDPV)-induced conditioned [124] A. L. Riley and D. A. Zellner, “Methylphenidate-induced con- taste avoidance in the F344/N and LEW rat strains,” Pharma- ditioned taste aversions: an index of toxicity,” Physiological cology Biochemistry and Behavior, vol. 126, pp. 163–169, Psychology, vol. 6, pp. 354–358, 1978. 2014. Behavioural Neurology 21 administration in rats,” Psychopharmacology, vol. 232, [125] F. Etscorn, “Sucrose aversions in mice as a result of injected nicotine or passive tobacco smoke inhalation,” Bulletin of pp. 2363–2375, 2015. the Psychonomic Society, vol. 15, pp. 54–56, 1980. [142] A. Ettenberg, M. A. Raven, D. A. Danluck, and B. D. Neces- [126] O. Burešová and J. Bureš, “Post-ingestion interference with sary, “Evidence for opponent-process actions of intravenous brain function prevents attenuation of neophobia in rats,” cocaine,” Pharmacology Biochemistry and Behavior, vol. 64, Behavioural Brain Research, vol. 1, pp. 299–312, 1980. pp. 507–512, 1999. [127] H. Cappell and A. E. LeBlanc, “Gustatory avoidance condi- [143] M. A. Reicher and E. W. Holman, “Location preference and tioning by drugs of abuse,” in Food aversion learning,N. W. flavor aversion reinforced by amphetamine in rats,” Animal Milgram, L. Krames, and T. M. Alloway, Eds., pp. 133–167, Learning & Behavior, vol. 5, pp. 343–346, 1977. Springer, Boston, MA, 1977. [144] H. E. King, A. Wakeford, W. Taylor, B. Wetzell, K. C. Rice, [128] E. Gamzu, “The multifaceted nature of taste aversion induc- and A. L. Riley, “Sex differences in 3,4-methylenedioxypyro- ing agents: is there a single common factor?,” in Learning valerone (MDPV)-induced taste avoidance and place prefer- Mechanisms in Food Selection, L. Barker, M. Best, and M. ences,” Pharmacology Biochemistry and Behavior, vol. 137, Domjan, Eds., pp. 477–510, Baylor University Press, Waco, pp. 16–22, 2015. TX, 1977. [145] K. H. Nelson, H. N. Manke, A. Imanalieva, K. C. Rice, and [129] W. J. McBride, J. M. Murphy, and S. Ikemoto, “Localization A. L. Riley, “Sex differences in α-pyrrolidinopentiophenone of brain reinforcement mechanisms: Intracranial self- (α-PVP)-induced taste avoidance, place preference, hyper- administration and intracranial place-conditioning studies,” thermia and locomotor activity in rats,” Pharmacology Bio- Behavioural Brain Research, vol. 101, pp. 129–152, 1999. chemistry and Behavior, vol. 185, article 172762, 2019. [130] A. L. Riley and L. L. Baril, “Conditioned taste aversions: a bib- [146] K. H. Nelson, H. M. Manke, J. M. Bailey et al., “Ethanol pre- liography,” Animal Learning & Behavior, vol. 4, pp. 1S–13S, exposure differentially impacts the rewarding and aversive effects of α-pyrrolidinopentiophenone (α-PVP): implications [131] S. Klosterhalfen and W. Klosterhalfen, “Conditioned taste for drug use and abuse,” Pharmacology Biochemistry and Behavior, vol. 211, article 173286, 2021. aversion and traditional learning,” Psychological Research, vol. 47, no. 2, pp. 71–94, 1985. [147] C. A. Dannenhoffer and L. P. Spear, “Age differences in con- ditioned place preferences and taste aversions to nicotine,” [132] P. S. Grigson and R. C. Twining, “Cocaine-induced suppres- sion of saccharin intake: a model of drug-induced devalua- Developmental Psychobiology, vol. 58, pp. 660–666, 2016. tion of natural rewards,” Behavioral Neuroscience, vol. 116, [148] J. E. Sherman, T. Roberts, S. E. Roskam, and E. W. Holman, pp. 321–333, 2002. “Temporal properties of the rewarding and aversive effects [133] L. H. Sellings, G. Baharnouri, L. E. McQuade, and P. B. of amphetamine in rats,” Pharmacology Biochemistry and Clarke, “Rewarding and aversive effects of nicotine are segre- Behavior, vol. 13, pp. 597–599, 1980. gated within the nucleus accumbens,” European Journal of [149] Y. C. Wang, A. C. W. Huang, and S. Hsiao, “Paradoxical Neuroscience, vol. 28, pp. 342–352, 2008. simultaneous occurrence of amphetamine-induced condi- [134] R. C. Twining, M. Bolan, and P. S. Grigson, “Yoked delivery tioned taste aversion and conditioned place preference with of cocaine is aversive and protects against the motivation the same single drug injection: a new “pre-and post- for drug in rats,” Behavioral Neuroscience, vol. 123, association” experimental paradigm,” Pharmacology Bio- pp. 913–925, 2009. chemistry and Behavior, vol. 95, pp. 80–87, 2010. [135] A. M. Cason and P. S. Grigson, “Prior access to a sweet is [150] A. Verendeev and A. L. Riley, “Relationship between the more protective against cocaine self-administration in female rewarding and aversive effects of morphine and amphet- rats than in male rats,” Physiology & Behavior, vol. 112-113, amine in individual subjects,” Learning & Behavior, vol. 39, pp. 96–103, 2013. pp. 399–408, 2011. [136] R. M. Carelli and E. A. West, “When a good taste turns bad: [151] J. E. Sherman, C. Pickman, A. Rice, J. C. Liebeskind, and neural mechanisms underlying the emergence of negative E. W. Holman, “Rewarding and aversive effects of morphine: affect and associated natural reward devaluation by cocaine,” temporal and pharmacological properties,” Pharmacology Neuropharmacology, vol. 76, pp. 360–369, 2014. Biochemistry and Behavior, vol. 13, pp. 501–505, 1980. [137] R. Wise, P. Yokel, and H. De Wit, “Both positive reinforce- [152] G. R. Simpson and A. L. Riley, “Morphine preexposure facil- ment and conditioned aversion from amphetamine and from itates morphine place preference and attenuates morphine apomorphine in rats,” Science, vol. 191, pp. 1273-1274, 1976. taste aversion,” Pharmacology Biochemistry and Behavior, vol. 80, pp. 471–479, 2005. [138] A. Ettenberg and T. D. Geist, “Animal model for investigating the anxiogenic effects of self-administered cocaine,” Psycho- [153] H. E. King and A. L. Riley, “A history of morphine-induced pharmacology, vol. 103, pp. 455–461, 1991. taste aversion learning fails to affect morphine-induced place [139] A. Ettenberg and T. D. Geist, “Qualitative and quantitative preference conditioning in rats,” Learning & Behavior, vol. 41, pp. 433–442, 2013. differences in the operant runway behavior of rats working for cocaine and heroin reinforcement,” Pharmacology Bio- [154] G. C. Loney, C. P. King, and P. J. Meyer, “Systemic nicotine chemistry and Behavior, vol. 44, pp. 191–198, 1993. enhances opioid self-administration and modulates the for- [140] N. White, L. Sklar, and Z. Amit, “The reinforcing action of mation of opioid-associated memories partly through actions within the insular cortex,” Scientific Reports, vol. 11, pp. 1–13, morphine and its paradoxical side effect,” Psychopharmacol- ogy, vol. 52, pp. 63–66, 1977. 2021. [141] A. Ettenberg, V. Fomenko, K. Kaganovsky, K. Shelton, and [155] Y. C. Wang, W. C. Chiu, C. N. Cheng, C. Lee, and A. C. W. J. M. Wenzel, “On the positive and negative affective Huang, “Examination of neuroinflammatory cytokine responses to cocaine and their relation to drug self- interleukin-1 beta expression in the medial prefrontal cortex, 22 Behavioural Neurology [170] T. S. Shippenberg, C. H. Heidbreder, and A. Lefevour, “Sensi- amygdala, and hippocampus for the paradoxical effects of reward and aversion induced by morphine,” Neuroscience tization to the conditioned rewarding effects of morphine: Letters, vol. 760, article 136076, 2021. pharmacology and temporal characteristics,” European Jour- nal of Pharmacology, vol. 299, pp. 33–39, 1996. [156] C. W. Wu, C. Y. Ou, Y. H. Yu, Y. C. Yu, B. C. Shyu, and A. C. W. Huang, “Involvement of the Ventral Tegmental Area but [171] H. E. King, B. Wetzell, K. C. Rice, and A. L. Riley, “An assess- Not Periaqueductal Gray Matter in the Paradoxical Reward- ment of MDPV-induced place preference in adult Sprague- ing and Aversive Effects of Morphine,” Behavioral Neurosci- Dawley rats,” Drug and Alcohol Dependence, vol. 146, ence, vol. 135, pp. 762–770, 2021. pp. 116–119, 2015. [157] Y. Yu, A. B. He, M. Liou et al., “The paradoxical effect [172] H. I. Risca, J. D. Zuarth-Gonzalez, and L. E. Baker, “Condi- hypothesis of abused drugs in a rat model of chronic mor- tioned place preference following concurrent treatment with phine administration,” Journal of Clinical Medicine, vol. 10, 3, 4-methylenedioxypyrovalerone (MDPV) and metham- p. 3197, 2021. phetamine in male and female Sprague-Dawley rats,” Phar- macology Biochemistry and Behavior, vol. 198, article [158] L. A. Mayer and L. A. Parker, “Rewarding and aversive prop- 173032, 2020. erties of IP and SC cocaine: assessment by place and taste conditioning,” Psychopharmacology, vol. 112, pp. 189–194, [173] M. B. Gatch, S. B. Dolan, and M. J. Forster, “Comparative 1993. behavioral pharmacology of three pyrrolidine-containing synthetic cathinone derivatives,” Journal of Pharmacology [159] R. L. Pomfrey, T. A. Bostwick, B. B. Wetzell, and A. L. Riley, and Experimental Therapeutics, vol. 354, pp. 103–110, 2015. “Adolescent nicotine exposure fails to impact cocaine reward, aversion and self-administration in adult male rats,” Pharma- [174] J. A. Marusich, T. W. Lefever, B. E. Blough, B. F. Thomas, and cology Biochemistry and Behavior, vol. 137, pp. 30–37, 2015. J. L. Wiley, “Pharmacological effects of methamphetamine and alpha-PVP vapor and injection,” Neurotoxicology, [160] M. M. Clasen, T. V. Sanon, D. N. Kearns, T. L. Davidson, and vol. 55, pp. 83–91, 2016. A. L. Riley, “Ad libitum high fat diet consumption during adolescence and adulthood fails to impact the affective prop- [175] J. B. Bedingfield, D. A. King, and F. A. Holloway, “Cocaine erties of cocaine in male Sprague-Dawley rats,” Experimental and caffeine: conditioned place preference, locomotor activ- and Clinical Psychopharmacology, vol. 28, pp. 438–448, 2020. ity, and additivity,” Pharmacology Biochemistry and Behav- ior, vol. 61, pp. 291–296, 1998. [161] A. B. H. He, Y. C. Chang, A. W. Y. Meng, and A. C. W. Huang, “Re-evaluation of the reward comparison hypothesis [176] A. L. Riley, C. M. Davis, and P. G. Roma, “Strain differences for alcohol abuse,” Behavioural Brain Research, vol. 332, in taste aversion learning: Implications for animal models of pp. 218–222, 2017. drug abuse,” in Conditioned Taste Aversion: Behavioral and Neural Processes, S. Reilly and T. R. Schachtman, Eds., [162] N. T. Brockwell, R. Eikelboom, and R. J. Beninger, “Caffeine- pp. 226–261, Oxford University Press, New York, NY, 2009. induced place and taste conditioning: production of dose- dependent preference and aversion,” Pharmacology Biochem- [177] A. L. Riley, B. J. Hempel, and M. M. Clasen, “Sex as a biolog- istry and Behavior, vol. 38, pp. 513–517, 1991. ical variable: drug use and abuse,” Physiology & Behavior, vol. 187, pp. 79–96, 2018. [163] P. G. Roma, W. W. Flint, J. D. Higley, and A. L. Riley, “Assessment of the aversive and rewarding effects of alcohol [178] I. P. Stolerman and G. D. D'Mello, “Oral self-administration in Fischer and Lewis rats,” Psychopharmacology, vol. 189, and the relevance of conditioned taste aversions,” in pp. 187–199, 2006. Advances in Behavioral Pharmacology, T. Thompson, P. B. Dews, and W. A. McKim, Eds., pp. 169–214, Elsevier, [164] A. G. Wakeford, S. M. Flax, R. L. Pomfrey, and A. L. Riley, Amsterdam, Netherlands, 1981. “Adolescent delta-9-tetrahydrocannabinol (THC) exposure fails to affect THC-induced place and taste conditioning in [179] A. Ettenberg, “The runway model of drug self-administra- adult male rats,” Pharmacology Biochemistry and Behavior, tion,” Pharmacology Biochemistry and Behavior, vol. 91, vol. 140, pp. 75–81, 2016. pp. 271–277, 2009. [165] B. J. Hempel, A. G. Wakeford, M. M. Clasen, M. A. Friar, and [180] S. D. Turenne, C. Miles, L. A. Parker, and S. Siegel, “Individ- A. L. Riley, “Delta-9-tetrahydrocannabinol (THC) history ual differences in reactivity to the rewarding/aversive proper- fails to affect THC's ability to induce place preferences in ties of drugs: assessment by taste and place conditioning,” rats,” Pharmacology Biochemistry and Behavior, vol. 144, Pharmacology Biochemistry and Behavior, vol. 53, pp. 511– pp. 1–6, 2016. 516, 1996. [166] A. L. Riley, “The paradox of drug taking: the role of the aver- [181] J. A. Chester, F. O. Risinger, and C. L. Cunningham, “Ethanol sive effects of drugs,” Physiology & Behavior, vol. 103, pp. 69– reward and aversion in mice bred for sensitivity to ethanol 78, 2011. withdrawal,” Alcoholism: Clinical and Experimental Research, vol. 22, pp. 468–473, 1998. [167] C. M. Davis, “Animal models of drug abuse: place and taste conditioning,” in Animal Models for the Study of Human Dis- [182] D. V. Gauvin, T. J. Baird, and R. J. Briscoe, “Differential ease, M. P. Conn, Ed., pp. 681–707, Academic Press, Cam- development of behavioral tolerance and the subsequent bridge, MA, 2013. hedonic effects of alcohol in AA and ANA rats,” Psychophar- macology, vol. 151, pp. 335–343, 2000. [168] M. J. Shram, D. Funk, Z. Li, and A. D. Lê, “Periadolescent and adult rats respond differently in tests measuring the reward- [183] J. M. Wheeler, C. Reed, S. Burkhart-Kasch et al., “Genetically ing and aversive effects of nicotine,” Psychopharmacology, correlated effects of selective breeding for high and low meth- vol. 186, pp. 201–208, 2006. amphetamine consumption,” Genes, Brain and Behavior, vol. 8, pp. 758–771, 2009. [169] B. T. Lett, “Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and [184] W. S. Hyatt and W. E. Fantegrossi, “Δ9-THC exposure atten- cocaine,” Psychopharmacology, vol. 98, pp. 357–362, 1989. uates aversive effects and reveals appetitive effects of K2/ Behavioural Neurology 23 [199] L. A. Parker, S. A. Rana, and C. L. Limebeer, “Conditioned spice constituent JWH-018 in mice,” Behavioural Pharmacol- ogy, vol. 25, pp. 253–257, 2014. nausea in rats: assessment by conditioned disgust reactions, rather than conditioned taste avoidance,” Canadian Journal [185] K. G. Hill, H. Alva, Y. A. Blednov, and C. L. Cunningham, of Experimental Psychology, vol. 62, pp. 198–209, 2008. “Reduced ethanol-induced conditioned taste aversion and conditioned place preference in GIRK2 null mutant mice,” [200] B. J. Hempel, M. M. Clasen, K. H. Nelson, C. J. Woloshchuk, Psychopharmacology, vol. 169, pp. 108–114, 2003. and A. L. Riley, “An assessment of concurrent cannabidiol and Δ -tetrahydrocannabinol administration in place aver- [186] X. Li, B. J. Hempel, H. J. Yang et al., “Dissecting the role of sion and taste avoidance conditioning,” Experimental and CB1 and CB2 receptors in cannabinoid reward versus aver- Clinical Psychopharmacology, vol. 26, pp. 205–213, 2018. sion using transgenic CB1-and CB2-knockout mice,” Euro- pean Neuropsychopharmacology, vol. 43, pp. 38–51, 2021. [201] L. M. Barker, J. C. Smith, and E. M. Suarez, “Sickness and the backward conditioning of taste aversions,” in Learning Mech- [187] W. L. Isaac, A. J. Nonneman, J. Neisewander, T. Landers, and anisms in Food Selection, L. M. Barker, M. Best, and M. Dom- M. T. Bardo, “Prefrontal cortex lesions differentially disrupt jan, Eds., pp. 533–553, Baylor University Press, Waco, TX, cocaine-reinforced conditioned place preference but not con- ditioned taste aversion,” Behavioral Neuroscience, vol. 103, pp. 345–355, 1989. [202] L. A. Parker, “Conditioned flavor avoidance and conditioned gaping: rat models of conditioned nausea,” European Journal [188] T. M. Mosher, J. G. Smith, and A. J. Greenshaw, “Aversive of Pharmacology, vol. 722, pp. 122–133, 2014. stimulus properties of the 5-HT2C receptor agonist WAY 161503 in rats,” Neuropharmacology, vol. 51, pp. 641–650, [203] H. J. Grill and R. Norgren, “The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically nor- mal rats,” Brain Research, vol. 143, pp. 263–279, 1978. [189] F. O. Risinger, P. A. Freeman, P. Greengard, and A. A. Fien- berg, “Motivational effects of ethanol in DARPP-32 knock- [204] L. A. Schier, K. M. Hyde, and A. C. Spector, “Conditioned out mice,” The Journal of Neuroscience, vol. 21, pp. 340– taste aversion versus avoidance: a re-examination of the sep- 348, 2001. arate processes hypothesis,” Plos One, vol. 14, article e0217458, 2019. [190] Y. A. Blednov, J. M. Benavidez, C. Geil, S. Perra, H. Morikawa, and R. Harris, “Activation of inflammatory sig- [205] L. A. Parker, “Nonconsummatory and consummatory behav- naling by lipopolysaccharide produces a prolonged increase ioral CRs elicited by lithium-and amphetamine-paired fla- of voluntary alcohol intake in mice,” Brain, Behavior, and vors,” Learning and Motivation, vol. 13, pp. 281–303, 1982. Immunity, vol. 25, pp. S92–S105, 2011. [206] L. A. Parker, “Emetic drugs produce conditioned rejection [191] B. M. Rabin, J. A. Joseph, and B. Shukitt-Hale, “Long-term reactions in the taste reactivity test,” Journal of Psychophysiol- changes in amphetamine-induced reinforcement and aver- ogy, vol. 12, pp. 3–13, 1998. sion in rats following exposure to Fe particle,” Advances [207] L. A. Parker, “Taste-reactivity responses elicited by reinforc- in Space Research, vol. 31, pp. 127–133, 2003. ing drugs: a dose-response analysis,” Behavioral Neurosci- [192] A. Bechara, K. A. Zito, and D. Van Der Kooy, “Peripheral ence, vol. 105, pp. 955–964, 1991. receptors mediate the aversive conditioning effects of mor- [208] L. A. Parker, “Rewarding drugs produce taste avoidance, but phine in the rat,” Pharmacology Biochemistry and Behavior, not taste aversion,” Neuroscience & Biobehavioral Reviews, vol. 28, pp. 219–225, 1987. vol. 19, no. 1, pp. 143–151, 1995. [193] A. B. H. He, C. L. Huang, A. Kozłowska et al., “Involvement [209] L. A. Parker, “Taste avoidance and taste aversion: evidence of neural substrates in reward and aversion to methamphet- for two different processes,” Animal Learning & Behavior, amine addiction: testing the reward comparison hypothesis vol. 31, pp. 165–172, 2003. and the paradoxical effect hypothesis of abused drugs,” Neu- [210] C. L. Limebeer and L. A. Parker, “The antiemetic drug ondan- robiology of Learning and Memory, vol. 166, article 107090, setron intereferes with lithium-induced conditioned rejection reactions, but not lithium induced taste avoidance in rats,” [194] S. Ghozland, H. W. Matthes, F. Simonin, D. Filliol, B. L. Kief- Journal of Experimental Psychology: Animal Behavior Pro- fer, and R. Maldonado, “Motivational effects of cannabinoids cesses, vol. 26, pp. 371–384, 2000. are mediated by μ-opioid and κ-opioid receptors,” The Jour- [211] J. Y. Lin, J. Arthurs, L. R. Amodeo, and S. Reilly, “Reduced nal of Neuroscience, vol. 22, pp. 1146–1154, 2002. palatability in drug-induced taste aversion: I. Variations in [195] N. R. Gubner, C. Reed, C. S. McKinnon, and T. J. Phillips, the initial value of the conditioned stimulus,” Behavioral “Unique genetic factors influence sensitivity to the rewarding Neuroscience, vol. 126, pp. 423–432, 2012. and aversive effects of methamphetamine versus cocaine,” [212] J. Y. Lin, J. Arthurs, and S. Reilly, “Reduced palatability in Behavioural Brain Research, vol. 256, pp. 420–427, 2013. pain-induced conditioned taste aversions,” Physiology & [196] J. Garcia and D. J. Kimeldorf, “Temporal relationship within Behavior, vol. 119, pp. 79–85, 2013. the conditioning of a saccharine aversion through radiation [213] J. Y. Lin, J. Arthurs, and S. Reilly, “Conditioned taste aver- exposure,” Journal of Comparative and Physiological Psychol- sion, drugs of abuse and palatability,” Neuroscience & Biobe- ogy, vol. 50, pp. 180–183, 1957. havioral Reviews, vol. 45, pp. 28–45, 2014. [197] J. Garcia and D. J. Kimeldorf, “Some factors which influence [214] J. Y. Lin, J. Arthurs, and S. Reilly, “Conditioned taste aver- radiation-conditioned behavior of rats,” Radiation Research, sions: from poisons to pain to drugs of abuse,” Psychonomic vol. 12, pp. 719–727, 1960. Bulletin & Review, vol. 24, pp. 335–351, 2017. [198] A. J. Goudie, I. P. Stolerman, C. Demellweek, and G. D. [215] J. Y. Lin, J. Arthurs, and S. Reilly, “Anesthesia-inducing drugs D'Mello, “Does conditioned nausea mediate drug-induced also induce conditioned taste aversions,” Physiology & Behav- conditioned taste aversion?,” Psychopharmacology, vol. 78, ior, vol. 177, pp. 247–251, 2017. pp. 277–281, 1982. 24 Behavioural Neurology [230] S. N. Gartner, F. Aidney, A. Klockars et al., “Intragastric pre- [216] D. M. Dwyer, R. A. Boakes, and A. J. Hayward, “Reduced pal- atability in lithium-and activity-based, but not in amphet- loads of L-tryptophan reduce ingestive behavior via oxytoci- amine-based, taste aversion learning,” Behavioral nergic neural mechanisms in male mice,” Appetite, vol. 125, Neuroscience, vol. 122, pp. 1051–1060, 2008. pp. 278–286, 2018. [217] D. M. Dwyer, “Licking and liking: the assessment of hedonic [231] M. P. Gillum, D. Zhang, X. M. Zhang et al., “N-Acylphospha- responses in rodents,” Quarterly Journal of Experimental Psy- tidylethanolamine, a gut-derived circulating factor induced chology, vol. 65, pp. 371–394, 2012. by fat ingestion, inhibits food intake,” Cell, vol. 135, pp. 813–824, 2008. [218] T. Hunt and Z. Amit, “Conditioned taste aversion induced by self-administered drugs: paradox revisited,” Neuroscience & [232] K. Proulx, D. Cota, T. R. Castañeda et al., “Mechanisms of oleoylethanolamide-induced changes in feeding behavior Biobehavioral Reviews, vol. 11, pp. 107–130, 1987. and motor activity,” American Journal of Physiology-Regula- [219] A. L. Riley and G. R. Simpson, “The attenuating effects of tory, Integrative and Comparative Physiology, vol. 289, drug preexposure on taste aversion conditioning: generality, pp. R729–R737, 2005. experimental parameters, underlying mechanisms, and implications for drug use and abuse,” in Handbook of Con- [233] P. S. Grigson, “Conditioned taste aversions and drugs of abuse: a reinterpretation,” Behavioral Neuroscience, vol. 111, temporary Learning Theories, R. R. Mowrer and S. B. Klein, Eds., pp. 505–559, Lawrence Erlbaum Associates Publishers, pp. 129–136, 1997. NJ, 2001. [234] A. C. W. Huang and S. Hsiao, “Re-examination of amphetamine-induced conditioned suppression of tastant [220] C. L. Cunningham, D. M. Hawks, and D. R. Niehus, “Role of intake in rats: the task-dependent drug effects hypothesis,” hypothermia in ethanol-induced conditioned taste aversion,” Behavioral Neuroscience, vol. 122, pp. 1207–1216, 2008. Psychopharmacology, vol. 95, pp. 318–322, 1988. [221] R. A. Wheeler, R. C. Twining, J. L. Jones, J. M. Slater, P. S. [235] A. C. W. Huang, C. C. Wang, and S. Wang, “Examinations of the reward comparison hypothesis: the modulation of gender Grigson, and R. M. Carelli, “Behavioral and electrophysiolog- ical indices of negative affect predict cocaine self-administra- and footshock,” Physiology & Behavior, vol. 151, pp. 129–138, tion,” Neuron, vol. 57, pp. 774–785, 2008. [236] C. L. Cunningham, C. M. Gremel, and P. A. Groblewski, [222] E. M. Colechio, D. N. Alexander, C. G. Imperio, K. Jackson, “Genetic influences on conditioned taste aversion,” in Condi- and P. S. Grigson, “Once is too much: early development of tioned Taste Aversion: Behavioral and Neural Processes,S. the opponent process in taste reactivity behavior is associated Reilly and T. R. Schachtman, Eds., pp. 387–421, Oxford Uni- with later escalation of cocaine self-administration in rats,” versity Press, New York, NY, 2009. Brain Research Bulletin, vol. 138, pp. 88–95, 2018. [237] D. B. Newlin and R. M. Renton, “High risk groups often have [223] K. G. Guenther, C. E. Wideman, E. M. Rock, C. L. Limebeer, higher levels of alcohol response than low risk: the other side and L. A. Parker, “Conditioned aversive responses produced of the coin,” Alcoholism: Clinical and Experimental Research, by delayed, but not immediate, exposure to cocaine and mor- vol. 34, pp. 199–202, 2010. phine in male Sprague-Dawley rats,” Psychopharmacology, vol. 235, pp. 3315–3327, 2018. [238] M. A. Schuckit, “Low level of response to alcohol as a predic- tor of future alcoholism,” American Journal of Psychiatry, [224] L. A. Parker, C. L. Limebeer, and S. A. Rana, “Conditioned vol. 151, pp. 184–189, 1994. disgust, but not conditioned taste avoidance, may reflect con- ditioned nausea in rats,” in Conditioned Taste Aversions: [239] H. J. Edenberg, “The genetics of alcohol metabolism: role of Behavioral and Neural Processes, S. Reilly and T. R. Schacht- alcohol dehydrogenase and aldehyde dehydrogenase vari- man, Eds., pp. 92–113, Oxford University Press, New York, ants,” Alcohol Research & Health, vol. 30, pp. 5–13, 2007. NY, 2009. [240] J. C. Crabbe, “Genetic contributions to addiction,” Annual [225] G. Takács, B. Lukáts, S. Papp, C. Szalay, and Z. Karádi, “Taste Review of Psychology, vol. 53, pp. 435–462, 2002. reactivity alterations after IL-1β microinjection into the ven- [241] R. L. Elkins, “Separation of taste-aversion-prone and taste- tromedial hypothalamic nucleus of the rat,” Neuroscience aversion-resistant rats through selective breeding: implica- Research, vol. 62, pp. 118–122, 2008. tions for individual differences in conditionability and [226] T. M. Barney, A. S. Vore, A. Gano, J. E. Mondello, and aversion-therapy alcoholism treatment,” Behavioral Neuro- T. Deak, “The influence of central interleukin-6 on behavioral science, vol. 100, pp. 121–124, 1986. changes associated with acute alcohol intoxication in adult [242] R. L. Elkins, P. A. Walters, and T. E. Orr, “Continued devel- male rats,” Alcohol, vol. 79, pp. 37–45, 2019. opment and unconditioned stimulus characterization of [227] J. D. Patel and I. S. Ebenezer, “The effect of intraperitoneal selectively bred lines of taste aversion prone and resistant administration of leptin on short-term food intake in rats,” rats,” Alcoholism: Clinical and Experimental Research, European Journal of Pharmacology, vol. 580, pp. 143–152, vol. 16, pp. 928–934, 1992. [243] T. E. Orr, J. L. Whitford-Stoddard, and R. L. Elkins, “Taste- [228] K. Abegg, L. Bernasconi, M. Hutter et al., “Ghrelin receptor aversion-prone (TAP) rats and taste-aversion-resistant inverse agonists as a novel therapeutic approach against (TAR) rats differ in ethanol self-administration, but not in obesity-related metabolic disease,” Diabetes, Obesity and ethanol clearance or general consumption,” Alcohol, vol. 33, Metabolism, vol. 19, pp. 1740–1750, 2017. pp. 1–7, 2004. [229] J. A. Rodriguez, J. A. Fehrentz, J. Martinez, K. B. H. Salah, and [244] R. L. Elkins, T. E. Orr, J. L. Rausch et al., “Cocaine-induced P. J. Wellman, “The GHR-R antagonist JMV 2959 neither expression differences in glutamate receptor subunits and induces malaise nor alters the malaise property of LiCl in transporters in amygdalae of taste aversion-prone and taste the adult male rat,” Physiology & Behavior, vol. 183, pp. 46– aversion-resistant rats,” Annals of the New York Academy of 48, 2018. Sciences, vol. 1003, pp. 381–385, 2003. Behavioural Neurology 25 [260] J. M. Vishwanath, A. G. Desko, and A. L. Riley, “Caffeine- [245] S. H. Hobbs, P. A. Walters, E. F. Shealy, and R. L. Elkins, “Radial-maze learning by lines of taste-aversion-prone and induced taste aversions in Lewis and Fischer rat strains: dif- taste-aversion-resistant rats,” Bulletin of the Psychonomic ferential sensitivity to the aversive effects of drugs,” Pharma- Society, vol. 31, pp. 171–174, 1993. cology Biochemistry and Behavior, vol. 100, pp. 66–72, 2011. [246] T. E. Orr, P. A. Walters, and R. L. Elkins, “Differences in free- [261] P. G. Roma, C. M. Davis, and A. L. Riley, “Effects of cross- choice ethanol acceptance between taste aversion-prone and fostering on cocaine-induced conditioned taste aversions in taste aversion-resistant rats,” Alcoholism: Clinical and Exper- Fischer and Lewis rats,” Developmental Psychobiology, imental Research, vol. 21, pp. 1491–1496, 1997. vol. 49, pp. 172–179, 2007. [247] D. S. Cannon and L. E. Carrell, “Rat strain differences in eth- [262] M. Gomez-Serrano, L. Tonelli, S. Listwak, E. Sternberg, and anol self-administration and taste aversion learning,” Phar- A. L. Riley, “Effects of cross fostering on open-field behavior, macology Biochemistry and Behavior, vol. 28, pp. 57–63, acoustic startle, lipopolysaccharide-induced corticosterone 1987. release, and body weight in Lewis and Fischer rats,” Behavior Genetics, vol. 31, pp. 427–436, 2001. [248] S. Cailhol and P. Mormède, “Conditioned taste aversion and alcohol drinking: strain and gender differences,” Journal of [263] M. A. Gomez-Serrano, E. M. Sternberg, and A. L. Riley, Studies on Alcohol, vol. 63, pp. 91–99, 2002. “Maternal behavior in F344/N and LEW/N rats: effects on carrageenan-induced inflammatory reactivity and body [249] J. Broadbent, K. J. Muccino, and C. L. Cunningham, “Etha- weight,” Physiology & Behavior, vol. 75, pp. 493–505, 2002. nol-induced conditioned taste aversion in 15 inbred mouse strains,” Behavioral Neuroscience, vol. 116, pp. 138–148, [264] M. C. Camp, M. Feyder, J. Ihne et al., “A novel role for PSD- 2002. 95 in mediating ethanol intoxication, drinking and place preference,” Addiction Biology, vol. 16, pp. 428–439, 2011. [250] C. L. Cunningham, “Genetic relationships between ethanol- induced conditioned place aversion and other ethanol pheno- [265] Y. A. Blednov, J. M. Benavidez, M. Black, J. Mayfield, and types in 15 inbred mouse strains,” Brain Sciences, vol. 9, R. A. Harris, “Role of interleukin-1 receptor signaling in the pp. 209–229, 2019. behavioral effects of ethanol and benzodiazepines,” Neuro- pharmacology, vol. 95, pp. 309–320, 2015. [251] C. L. Cunningham, “Genetic relationship between ethanol- induced conditioned place preference and other ethanol phe- [266] R. Legastelois, E. Darcq, S. A. Wegner, P. J. Lombroso, and notypes in 15 inbred mouse strains,” Behavioral Neurosci- D. Ron, “Striatal-enriched protein tyrosine phosphatase con- ence, vol. 128, pp. 430–445, 2014. trols responses to aversive stimuli: implication for ethanol drinking,” Plos One, vol. 10, article e0127408, 2015. [252] S. Shabani, C. S. McKinnon, C. Reed, C. L. Cunningham, and T. J. Phillips, “Sensitivity to rewarding or aversive effects of [267] T. Isse, T. Oyama, K. Kitagawa et al., “Diminished alcohol methamphetamine determines methamphetamine intake,” preference in transgenic mice lacking aldehyde dehydroge- Genes, Brain and Behavior, vol. 10, pp. 625–636, 2011. nase activity,” Pharmacogenetics and Genomics, vol. 12, pp. 621–626, 2002. [253] S. Shabani, C. S. McKinnon, C. L. Cunningham, and T. J. Phillips, “Profound reduction in sensitivity to the aversive [268] T. Isse, K. Matsuno, T. Oyama, K. Kitagawa, and effects of methamphetamine in mice bred for high metham- T. Kawamoto, “Aldehyde dehydrogenase 2 gene targeting phetamine intake,” Neuropharmacology, vol. 62, pp. 1134– mouse lacking enzyme activity shows high acetaldehyde level 1141, 2012. in blood, brain, and liver after ethanol gavages,” Alcoholism: Clinical & Experimental Research, vol. 29, pp. 1959–1964, [254] D. Lancellotti, B. M. Bayer, J. R. Glowa, R. A. Houghtling, and A. L. Riley, “Morphine-induced conditioned taste aversions in the LEW/N and F344/N rat strains,” Pharmacology Bio- [269] N. L. Schramm-Sapyta, Q. D. Walker, J. M. Caster, E. D. chemistry and Behavior, vol. 68, pp. 603–610, 2001. Levin, and C. M. Kuhn, “Are adolescents more vulnerable to drug addiction than adults? Evidence from animal [255] C. M. Davis, K. C. Rice, and A. L. Riley, “Opiate-agonist models,” Psychopharmacology, vol. 206, pp. 1–21, 2009. induced taste aversion learning in the Fischer 344 and Lewis inbred rat strains: evidence for differential mu opioid recep- [270] L. P. Spear, “Adolescents and alcohol: acute sensitivities, tor activation,” Pharmacology Biochemistry and Behavior, enhanced intake, and later consequences,” Neurotoxicology vol. 93, pp. 397–405, 2009. and Teratology, vol. 41, pp. 51–59, 2014. [256] C. M. Davis, J. L. Cobuzzi, and A. L. Riley, “Assessment of the [271] M. M. Clasen, T. V. Sanon, B. J. Hempel et al., “Ad-libitum aversive effects of peripheral mu opioid receptor agonism in high fat diet consumption during adolescence and adulthood Fischer 344 and Lewis rats,” Pharmacology Biochemistry impacts the intravenous self-administration of cocaine in and Behavior, vol. 101, pp. 181–186, 2012. male Sprague-Dawley rats,” Experimental and Clinical Psy- chopharmacology, vol. 28, pp. 32–43, 2020. [257] K. A. Pescatore, J. R. Glowa, and A. L. Riley, “Strain differ- ences in the acquisition of nicotine-induced conditioned taste [272] A. L. Riley, M. M. Clasen, and M. A. Friar, “Conditioned taste aversion,” Pharmacology Biochemistry and Behavior, vol. 82, avoidance drug discrimination procedure: assessments and pp. 751–757, 2005. applications,” Current Topics in Behavioral Neurosciences, vol. 39, pp. 297–317, 2018. [258] M. M. Foynes and A. L. Riley, “Lithium-chloride-induced conditioned taste aversions in the Lewis and Fischer 344 rat [273] M. M. Clasen, A. L. Riley, and T. L. Davidson, “Hippocampal- strains,” Pharmacology Biochemistry and Behavior, vol. 79, dependent inhibitory learning and memory processes in the pp. 303–308, 2004. control of eating and drug taking,” Current Pharmaceutical Design, vol. 26, pp. 2334–3352, 2020. [259] J. R. Glowa, A. E. Shaw, and A. L. Riley, “Cocaine-induced conditioned taste aversions: comparisons between effects in [274] L. D. Hill-Bowen, M. C. Riedel, R. Poudel et al., “The cue- LEW/N and F344/N rat strains,” Psychopharmacology, reactivity paradigm: an ensemble of networks driving atten- vol. 114, pp. 229–232, 1994. tion and cognition when viewing drug and natural reward- 26 Behavioural Neurology [291] S. D. Grabus, S. T. Smurthwaite, and A. L. Riley, “Nalorphine’s related stimuli,” Neuroscience & Biobehavioral Reviews, vol. 130, pp. 201–213, 2021. ability to substitute for morphine in a drug discrimination pro- cedure is a function of training dose,” Pharmacology Biochem- [275] H. Ekhtiari, P. Nasseri, F. Yavari, A. Mokri, and istry and Behavior, vol. 63, pp. 481–488, 1999. J. Monterosso, “Neuroscience of drug craving for addiction medicine: from circuits to therapies,” Progress in Brain [292] Y. Awasaki, H. Nojima, and N. Nishida, “Application of the Research, vol. 223, pp. 115–141, 2016. conditioned taste aversion paradigm to assess discriminative stimulus properties of psychostimulants in rats,” Drug and [276] M. M. Torregrossa and J. R. Taylor, “Neuroscience of learn- Alcohol Dependence, vol. 118, no. 2-3, pp. 288–294, 2011. ing and memory for addiction medicine: from habit forma- tion to memory reconsolidation,” Progress in Brain [293] J. P. Mastropaolo, K. H. Moskowitz, R. J. Dacanay, and A. L. Research, vol. 223, pp. 91–113, 2016. Riley, “Conditioned taste aversions as a behavioral baseline for drug discrimination learning: an assessment with phency- [277] C. J. Perry, I. Zbukvic, J. H. Kim, and A. J. Lawrence, “Role of clidine,” Pharmacology Biochemistry and Behavior, vol. 32, cues and contexts on drug-seeking behaviour,” British Jour- pp. 1–8, 1989. nal of Pharmacology, vol. 171, pp. 4636–4672, 2014. [294] I. Lucki, “Rapid discrimination of the stimulus properties of [278] L. V. Panlilio, E. B. Thorndike, and C. W. Schindler, “A 5-hydroxytryptamine agonists using conditioned taste aver- stimulus-control account of regulated drug intake in rats,” sion,” Journal of Pharmacology and Experimental Therapeu- Psychopharmacology, vol. 196, pp. 441–450, 2008. tics, vol. 247, pp. 1120–1127, 1988. [279] S. Jones, A. Hyde, and T. L. Davidson, “Reframing appetitive [295] T. V. Jaeger and R. F. Mucha, “A taste aversion model of drug reinforcement learning and reward valuation as effects medi- discrimination learning: training drug and condition influ- ated by hippocampal-dependent behavioral inhibition,” ence rate of learning, sensitivity and drug specificity,” Psycho- Nutrition Research, vol. 79, pp. 1–12, 2020. pharmacology, vol. 100, pp. 145–150, 1990. [280] V. L. Tsibulsky and A. B. Norman, “Satiety threshold during [296] D. M. Skinner, G. M. Martin, R. D. Howe, A. Pridgar, and maintained cocaine self-administration in outbred mice,” D. van der Kooy, “Drug discrimination learning using a taste Neuroreport, vol. 12, pp. 325–328, 2001. aversion paradigm: an assessment of the role of safety cues,” [281] S. Trask, E. A. Thrailkill, and M. E. Bouton, “Occasion set- Learning and Motivation, vol. 26, pp. 343–369, 1995. ting, inhibition, and the contextual control of extinction in [297] G. M. Martin, M. Gans, and D. van der Kooy, “Discriminative Pavlovian and instrumental (operant) learning,” Behavioural properties of morphine that modulate associations between Processes, vol. 137, pp. 64–72, 2017. tastes and lithium chloride,” Journal of Experimental Psychol- [282] K. A. Carr, T. O. Daniel, H. Lin, and L. H. Epstein, “Rein- ogy: Animal Behavior Processes, vol. 16, no. 1, pp. 56–68, 1990. forcement pathology and obesity,” Current Drug Abuse [298] S. Maren and W. Holt, “The hippocampus and contextual Reviews, vol. 4, pp. 190–196, 2011. memory retrieval in Pavlovian conditioning,” Behavioural [283] T. L. Davidson, A. L. Tracy, L. A. Schier, and S. E. Swithers, Brain Research, vol. 110, no. 1-2, pp. 97–108, 2000. “A view of obesity as a learning and memory disorder,” Jour- [299] A. P. Maurer and L. Nadel, “The continuity of context: a role nal of Experimental Psychology: Animal Learning and Cogni- tion, vol. 40, pp. 261–279, 2014. for the hippocampus,” Trends in Cognitive Sciences, vol. 25, pp. 187–199, 2021. [284] S. Dohle, K. Diel, and W. Hofmann, “Executive functions and the self-regulation of eating behavior: a review,” Appetite, [300] P. C. Holland and M. E. Bouton, “Hippocampus and context in classical conditioning,” Current Opinion in Neurobiology, vol. 124, pp. 4–9, 2018. vol. 9, pp. 195–202, 1999. [285] R. L. Balster, “Drugs as chemical stimuli,” Transduction [301] N. Hebben, S. Corkin, H. Eichenbaum, and K. Shedlack, Mechanisms of Drug Stimuli, vol. 4, pp. 3–11, 1988. “Diminished ability to interpret and report internal states [286] F. C. Colpaert, “Drug discrimination in neurobiology,” Phar- after bilateral medial temporal resection: case H.M,” Behav- macology Biochemistry and Behavior, vol. 64, no. 2, pp. 337– ioral Neuroscience, vol. 99, pp. 1031–1039, 1985. 345, 1999. [302] P. Rozin, S. Dow, M. Moscovitch, and S. Rajaram, “What [287] J. H. Porter and A. J. Prus, “Discriminative stimulus proper- causes humans to begin and end a meal? A role for memory ties of atypical and typical antipsychotic drugs: a review of for what has been eaten, as evidenced by a study of multiple preclinical studies,” Psychopharmacology, vol. 203, pp. 279– meal eating in amnesic patients,” Psychological Science, 294, 2009. vol. 9, pp. 392–396, 1998. [288] J. R. Troisi and N. L. Michaud, “Can the discriminative stim- [303] S. Higgs, A. C. Williamson, P. Rotshtein, and G. W. Hum- ulus effects of nicotine function concurrently as modulatory phreys, “Sensory-specific satiety is intact in amnesics who opponents in operant and Pavlovian occasion setting para- eat multiple meals: research report,” Psychological Science, digms in rats?,” Behavioural Processes, vol. 158, pp. 144– vol. 19, pp. 623–628, 2008. 150, 2019. [304] T. L. Davidson and L. E. Jarrard, “A role for hippocampus in [289] R. A. Glennon, T. U. Järbe, and J. Frankenheim, Drug Dis- the utilization of hunger signals,” Behavioral and Neural Biol- crimination: Applications to Drug Abuse Research. US ogy, vol. 59, pp. 167–171, 1993. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administra- [305] T. L. Davidson, S. E. Kanoski, K. Chan, D. J. Clegg, S. C. tion, National Institute on Drug Abuse, Rockville, MD, 1991. Benoit, and L. E. Jarrard, “Hippocampal lesions impair reten- tion of discriminative responding based on energy state [290] A. L. Riley, “Use of drug discrimination learning in behav- cues,” Behavioral Neuroscience, vol. 124, pp. 97–105, 2010. ioral toxicology: classification and characterization of toxins,” in Neurotoxicology: Approaches and Methods, L. Chang and [306] Y. O. Henderson, G. P. Smith, and M. B. Parent, “Hippocam- W. Slikker, Eds., pp. 309–321, Academic Press, San Diego, pal neurons inhibit meal onset,” Hippocampus, vol. 23, CA, 1995. pp. 100–107, 2013. Behavioural Neurology 27 [307] R. Hannapel, J. Ramesh, A. Ross, R. T. Lalumiere, A. G. Rose- berry, and M. B. Parent, “Postmeal optogenetic inhibition of dorsal or ventral hippocampal pyramidal neurons increases future intake,” Eneuro, vol. 6, pp. 1–16, 2019. [308] S. B. Briggs, R. Hannapel, J. Ramesh, and M. B. Parent, “Inhi- biting ventral hippocampal NMDA receptors and arc increases energy intake in male rats,” Learning & Memory, vol. 28, pp. 187–194, 2021. [309] T. L. Davidson, K. Chan, L. E. Jarrard, S. E. Kanoski, D. J. Clegg, and S. C. Benoit, “Contributions of the hippocampus and medial prefrontal cortex to energy and body weight reg- ulation,” Hippocampus, vol. 19, pp. 235–252, 2009. [310] C. H. Sample, S. Jones, S. L. Hargrave, L. E. Jarrard, and T. L. Davidson, “Western diet and the weakening of the interocep- tive stimulus control of appetitive behavior,” Behavioural Brain Research, vol. 312, pp. 219–230, 2016. [311] S. D. Glick and R. D. Cox, “Changes in morphine self- administration after tel-diencephalic lesions in rats,” Psycho- pharmacology, vol. 57, pp. 283–288, 1978. [312] R. M. Karlsson, D. M. Kircher, Y. Shaham, and P. O’Donnell, “Exaggerated cue-induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia,” Psychopharmacology, vol. 226, pp. 45–51, 2013. [313] R. A. Chambers and D. W. Self, “Motivational responses to natural and drug rewards in rats with neonatal ventral hippo- campal lesions: an animal model of dual diagnosis schizo- phrenia,” Neuropsychopharmacology, vol. 27, pp. 889–905, [314] S. K. Conroy, Z. Rodd, and R. A. Chambers, “Ethanol sensiti- zation in a neurodevelopmental lesion model of schizophre- nia in rats,” Pharmacology Biochemistry and Behavior, vol. 86, pp. 386–394, 2007. [315] A. M. Brady, R. D. Saul, and M. K. Wiest, “Selective deficits in spatial working memory in the neonatal ventral hippocampal lesion rat model of schizophrenia,” Neuropharmacology, vol. 59, pp. 605–611, 2010. [316] S. A. Berg, A. M. Sentir, B. S. Cooley, E. A. Engleman, and R. A. Chambers, “Nicotine is more addictive, not more cogni- tively therapeutic in a neurodevelopmental model of schizo- phrenia produced by neonatal ventral hippocampal lesions,” Addiction Biology, vol. 19, pp. 1020–1031, 2014. [317] T. L. Davidson, S. L. Hargrave, D. N. Kearns et al., “Cocaine impairs serial-feature negative learning and blood-brain bar- rier integrity,” Pharmacology Biochemistry and Behavior, vol. 170, pp. 56–63, 2018. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioural Neurology Hindawi Publishing Corporation

Impact of the Aversive Effects of Drugs on Their Use and Abuse

Loading next page...
 
/lp/hindawi-publishing-corporation/impact-of-the-aversive-effects-of-drugs-on-their-use-and-abuse-9gfMscLnK0

References (323)

Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2022 Anthony L. Riley et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
0953-4180
eISSN
1875-8584
DOI
10.1155/2022/8634176
Publisher site
See Article on Publisher Site

Abstract

Hindawi Behavioural Neurology Volume 2022, Article ID 8634176, 27 pages https://doi.org/10.1155/2022/8634176 Review Article Anthony L. Riley , Hayley N. Manke , and Shihui Huang Psychopharmacology Laboratory, Department of Neuroscience, Center for Neuroscience and Behavior, American University, 4400 Massachusetts Ave NW, Washington, D.C. 20016, USA Correspondence should be addressed to Anthony L. Riley; alriley@american.edu Received 27 November 2021; Revised 16 January 2022; Accepted 30 March 2022; Published 20 April 2022 Academic Editor: Andrew Huang Copyright © 2022 Anthony L. Riley et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Drug use and abuse are complex issues in that the basis of each may involve different determinants and consequences, and the transition from one to the other may be equally multifaceted. A recent model of the addiction cycle (as proposed by Koob and his colleagues) illustrates how drug-taking patterns transition from impulsive (acute use) to compulsive (chronic use) as a function of various neuroadaptations leading to the downregulation of DA systems, upregulation of stress systems, and the dysregulation of the prefrontal/orbitofrontal cortex. Although the nature of reinforcement in the initiation and mediation of these effects may differ (positive vs. negative), the role of reinforcement in drug intake (acute and chronic) is well characterized. However, drugs of abuse have other stimulus properties that may be important in their use and abuse. One such property is their aversive effects that limit drug intake instead of initiating and maintaining it. Evidence of such effects comes from both clinical and preclinical populations. In support of this position, the present review describes the aversive effects of drugs (assessed primarily in conditioned taste aversion learning), the fact that they occur concurrently with reward as assessed in combined taste aversion/place preference designs, the role of aversive effects in drug-taking (in balance with their rewarding effects), the dissociation of these affective properties in that they can be affected in different ways by the same manipulations, and the impact of various parametric, experiential, and subject factors on the aversive effects of drugs and the consequent impact of these factors on their use and abuse potential. 1. Drug Use and Abuse once in the past two weeks) was at 5%, 10%, and 17% for th th th 8 , 10 , and 12 graders, respectively [1]. Related findings According to recent results from Monitoring the Future have been reported by the NSDUH that found that 40.3 mil- th th (MTF, 2021), a national survey on drug use by 8 , 10 , lion people had a past year substance use disorder [2] as th and 12 graders, 27.3% of students (averaged across grades) defined by the Diagnostic and Statistical Manual of Mental reported use of illicit drugs in the past year [1] (for more Disorders (DSM-5) (see [2] for the basis of the dramatic dif- recent unpublished findings, see https://www.drugabuse ference in the rates of drug abuse when diagnoses are based .gov/drug-topics/trends-statistics/monitoring-future). In a on the DSM-4 vs. the DSM-5). Further, according to the sample of participants aged 12 years and older in 2020, the World Drug Report (2021), the Global Burden of Disease National Survey of Drug Use and Health (NSDUH, 2020) Study (GBD) in 2019 found that substance use disorders found that 13.5% used an illicit drug in the past month [2]. accounted for the largest portion of disability-adjusted life These surveys clearly indicate that a variety of drugs are years (DALYs), a measure of disease burden taken from used, but importantly, they also indicate that a smaller sub- the combination of both the number of years of life lost set of individuals abuse these same drugs. For example, MTF because of premature death and the number of years of life reported patterns and amounts of drug intake generally lived with disability [3]. In fact, drug use disorders associated with abuse. Specifically, daily marijuana preva- accounted for 59% of DALYs with approximately 18.1 mil- lence in 2020 was at 1.1%, 4.4%, and 6.9%, and binge drink- lion years of “healthy” life lost due to disabilities or prema- ing (defined as at least 5 or more drinks in a row at least ture death [3]. Interestingly, among people aged 12 or 2 Behavioural Neurology older, only 1.4% received any treatment for substance use [2]. Abstinence Abstinence Abstinence 2. Allostatic Model of Drug Use and Abuse Relapse Relapse Relapse Given the multiple causes and consequences of drug use and Late dependence- Use Heavy Use Early abuse, understanding this complexity is critical to preven- neuroadapted state dependence tion and treatment strategies [4]. One comprehensive model Impulsive Stage Compulsive Stage of these issues has recently been presented by Koob and his Prolonged Binge colleagues who describe the various stages of drug use and Intoxication Intoxication abuse, the factors important in their display, and the neuro- Reward Pleasurable Relief Relief biological substrates of each (as well as the role of these sub- craving effects craving strates in the transition from use to abuse, drug Protracted maintenance, and relapse; see [4–7]). Specifically, Koob Abstinence abstinence and his colleagues describe a neuroadaptation model of Neutral affect Negative affect addiction that consists of three distinct stages: binge/intoxi- Figure 1: Transition from the impulsive (acute) to the compulsive cation, withdrawal/negative affect, and preoccupation/antic- (abuse) patterns of drug-taking. Adapted from Meyer and Quenzer ipation, which differ significantly between acute and chronic [8] using BioRender.com. drug use (see Figure 1). Acute use represents a pattern of drug intake in the majority of the population using drugs (roughly between anxiety, irritability, and sleep disturbances) when the drug 85 and 90%) that is more impulsive and controlled. Applica- is no longer present. This negative affect drives further drug tion of Koob’s model to individuals in this group reveals a intake by negative reinforcement which is exacerbated by sensitized brain stress systems (primarily in the extended specific characterization of the effects of the drug (binge/ intoxication), the affective state of the individual following amygdala, i.e., central nucleus of the amygdala, the bed the cessation of the drug effect (withdrawal/negative affect), nucleus of the stria terminalis, and a transition zone in the and the subsequent desire for the drug in its absence (preoc- nucleus accumbens) that reflect further compensation to ele- cupation/anticipation). As noted in Figure 1, for acute use vated intake. Finally, these individuals now crave the drug when it is absent as the negative affect grows with time since (the impulsive condition), the drug itself is rewarding, gener- ating an effect preferred by the user (i.e., a rewarding effect). taking the drug. Intake is increased as well by neuroadapta- After the drug’seffects have subsided, there is no change in tions in yet other systems, e.g., orbitofrontal cortex, which the user’saffective state, i.e., the user is relatively neutral in normally mediates salience for traditional reinforcers such the drug’s absence. Finally, there is no true craving for the as food and sex, is now shifted toward the drug, and the sys- tems involved in executive function (prefrontal cortex; plan- drug in this group, but if such anticipation of the drug does occur, it is one of a desire to repeat its rewarding effects. ning, inhibition, memory, and attention) are downregulated. Importantly, the drug does initiate a compensatory response Consequently, these individuals have difficulty targeting rel- (allostasis) that generally is opposite in nature to that of its evant reinforcers and inhibiting further drug intake. The initial effect. If the user takes the drug relatively infrequently, cycle continues and spirals out of control with escalated intake, more frequent use, and high rates of relapse (poten- at low doses, and by routes of administration that have a slow onset and offset, this allostatic state subsides and there tiated by the presence of cues and stress that reactivate the is no appreciable change in the abovementioned characteri- mesolimbic and cortical areas via increased input from the zation. The drug maintains its reinforcing effects with little frontal cortex). change with its absence and no appreciable craving. However, if the pattern of drug use changes, e.g., 3. Role of Reward in Drug Use and Abuse increased frequency of use at higher doses and by routes of administration with more rapid onset (and offset), neuroad- The addiction cycle proposed by Koob and his colleagues [5, aptations occur that drive the transition from use to abuse 7] illustrates how drug-taking patterns transition from (involving roughly 10-15% of individual drug users). These impulsive (acute use) to compulsive (chronic use) as a func- neuroadaptations move impulsive use to compulsive use tion of neuroadaptations leading to the downregulation of where an individual loses control over abstaining from the dopamine pathways and processes, upregulation of stress drug, escalates drug intake, and relapses [5]. For this group systems, and the dysregulation of the prefrontal cortex (see of individuals, the drug may still have positively reinforcing above). Important to this analysis is that although the nature effects, although they are likely to be diminished as a result of reinforcement initiating and mediating these effects dif- of the drug-induced downregulation of mesolimbic and fers (positive vs. negative), the general role of reinforcement mesocortical pathways [7] that mediate these effects. This in drug intake (both acute and chronic) is well characterized tolerance induces escalation of drug intake. Further, because [9–12]. However, drugs have other stimulus properties that these systems are involved in regulating natural reward, their may be important as well in drug use and abuse. One such diminished state (a compensatory reaction to elevated drug property is a drug’s aversive effect that limits drug-taking intake) results in a negative affect (anhedonia-dysphoria, instead of initiating and maintaining it. The evidence for Behavioural Neurology 3 intake among those with the gene for this enzyme (see such effects comes from both clinical and preclinical research (for an excellent review of how initial responses to [22]; for evidence of acetaldehyde’s rewarding and motivat- a drug impact subsequent use in both clinical and preclinical ing effects, see [23]. The use of the drug disulfiram, a drug that blocks the metabolism of acetaldehyde, in the treatment populations, see [13]). of alcoholism is based on this same principle. In an assessment of patterns of alcohol intake in 4. Clinical Evidence of the Aversive Effects of humans, Baker and Cannon [24] noted that approximately Drugs of Abuse 45% of individuals hospitalized for the treatment of alcohol- ism reported aversions to the flavor of specific Clinical anecdotal reports note that drugs have both reward- alcohol prep- ing and aversive effects (with their use a function of the bal- arations most of which were acquired as a function of ance of these two properties; see [14] for a discussion; for overconsumption during early adolescence. That is, becom- factors impacting drug intake, see [9, 13, 15]). For example, ing sick with their initial alcohol experience limited subse- smokers often report the first exposure to nicotine as aver- quent consumption of those specific beverages. Similarly, sive (heart palpitations, feeling faint, dizziness, throat irrita- based on a survey of taste aversions in humans, Logue tion, coughing, and nausea) and adjust their intake to reduce et al. [25] reported upwards of 25% of 517 individuals who these effects or as tolerance develops allowing them to con- answered the survey indicated aversions to alcohol that were tinue to smoke. Interestingly, DiFranza and colleagues [16] associated with earlier patterns of alcohol consumption. It is noted that among first-time users (primarily young adoles- interesting in this context that one chemical treatment of cents), throat irritation with the first puff is a predictor of alcoholism utilizes aversion therapy in which alcohol con- reduced cigarette use whereas relaxation, dizziness, and nau- sumption is associated with an injection of a nauseant drug sea predict subsequent cigarette use disorder (see also [17, that induced aversions to the taste of alcohol ([26–28]; for 18]). In a self-report of the effects of mescaline, the user reviews, [29, 30]). Further (and along the lines noted above described vivid hallucinations but noted aversive side effects with genetic mutations), individuals appear to be differen- such as nausea and dizziness that led to speculation that the tially sensitive to these aversive effects of alcohol evidencing drug would not likely become popular given that such side another genetic vulnerability, in this case toward greater effects would spoil the generally positive effects of the drug consumption in those individuals less affected by alcohol’s [14]. One also sees these aversive effects with injected heroin aversive effects. Importantly, these vulnerabilities appear to as the drug has been reported to induce an orgasmic rush interact with experience as well given that individuals who that is often accompanied by nausea, retching, and vomiting. do not initially experience aversive effects seem to be pro- These aversive side effects diminish with repeated dosing tected from subsequent aversive reactions (either through [19]. Effects of caffeine have also been reported to reflect tolerance to alcohol or the added rewarding effects of alcohol the interaction of its rewarding and aversive effects, and this in ameliorating withdrawal symptoms; see [24]). interaction appears to be dose-dependent. For example, in These data from clinical populations illustrate that drugs an assessment of intake and reactions to varying doses of of abuse are complex pharmacological agents that possess caffeine, low doses (e.g., 100 mg) were found to be positively multiple stimulus effects, with the rewarding effects increas- rewarding to all subjects (with none reporting any negative ing vulnerability to initial use and subsequent abuse and the effects). With increases in dose, a general preference for aversive effects limiting intake. Such effects can occur at the the drug decreased as specific aversive or unwanted effects same dose; some are dose-dependent. Some effects appear to such as jitteriness and nervousness appeared [14]. Similar be impacted by genetic vulnerabilities; some are affected by dose-related effects have been reported with phencyclidine experience. Independent of the drug and the factors that (PCP). For example, at low doses, PCP produces a rewarding modulate its effects, what is clear is that individuals weigh effect that is often accompanied by a range of aversive the balance of these effects and intake is either adjusted or effects, e.g., thought disturbances, as well as violent behavior. continued with the anticipation that the aversive effects will With even greater doses, the aversive and unpleasant side be lessened with use (tolerance) or will become less salient as effects such as panic, fear paranoia, incoherent speech, and the rewarding effects increase (sensitization). bizarre behaviors become more intense that may dimmish the likelihood of further intake (see also [15, 20]). 5. Preclinical Evidence of the Aversive Effects of Work with alcohol further demonstrates the aversive Drugs of Abuse: Taste Aversions effects of drugs and how these effects modulate or impact drug intake. For example, the mutation in the gene coding Work with preclinical populations also reports evidence of for the enzyme aldehyde dehydrogenase (from the typical aversive effects of drugs of abuse. While there is considerable isozyme ACDH2 to the less efficient isozyme ACDH2*2; support for such effects in preclinical literature, the roots of found predominately in East Asian populations) results in this evidence are in toxicology [31]. In fact, work demon- the reduced ability to metabolize acetaldehyde, a metabolite strating such effects came from investigations related to mil- of alcohol [21]. Acetaldehyde has been reported to produce a itary applications during World War II, i.e., the effects of variety of adverse reactions, e.g., flushing of the face, head- toxins on rodent infestations (see [32]) and the effects of aches, and heart palpitations (with the severity of these reac- radiation exposure on biological systems (see [33]; for a tions greater in individuals homozygous for the ACDH2*2 review, see [34]). Initial field trials on rodent management gene), and appears to be protective against further alcohol with baits (i.e., a poison mixed with food base) presented a 4 Behavioural Neurology extended to the selective nature of CTA learning that pre- major difficulty, as rats exhibit a neophobic response toward novel foods and rarely sample enough of the bait to ingest a vents irrelevant stimuli (e.g., external cues) from interfering lethal amount of the poison. In early studies of this phenom- with the learning of a taste-illness association [38–40]. enon (bait-shyness), Rzóska [32] fed rats a food base laced with poison and noted that rats that had initially accepted 6. Taste Aversions as an Index of Toxicity the poisoned bait avoided the same bait in successive trials, but when a new base laced with the same poison was offered, Although the initial investigations into CTAs primarily they readily consumed the new bait. In speculating on these focused on their empirical assessments and theoretical empirical findings, i.e., refusal of identical poisoned bait and implications, subsequent research in this area shifted to acceptance of experienced poison in the new base, Rzóska explore the conditions under which CTA learning can be concluded that the rats associated the food base, rather than acquired, effects of various manipulations on its expression, the poison itself, with the illness experienced following and issues of mechanisms and applications. An important ingestion of the bait so they avoided the same food on sub- extension involved the use of CTA preparation as a tool to sequent trials. detect and characterize the behavioral and physiological In the early 1950s, this phenomenon of associative learn- effects of a toxin [31]. Empirically, the application of CTA ing between a novel taste and illness was further demon- as an index of toxicity is supported by the evidence that a strated with the effects of radiation by Garcia and his wide range of classical toxins that were characterized by colleagues who observed that rats given water in plastic bot- other behavioral and pharmacological tests could also condi- tles during radiation exposure subsequently avoided drink- tion taste aversions under various experimental conditions ing water from those plastic bottles. Importantly, the same (for a review, see [31]). For example, Nachman and Hartley rats would drink the water provided in glass bottles, suggest- [41] demonstrated that various rodenticides highly toxic to ing that the plastic bottle gave the water a unique taste that rats (i.e., copper sulfate, red squill, and sodium fluoroace- was associated with the effects of radiation (for a history of tate) produced strong taste aversions often with only a single Garcia’s early work with radiation, see [34]). In subsequent pairing of a novel taste with the compound. In addition to studies, Garcia and colleagues [33] tested the basis of these being rapidly learned, CTAs appeared relatively sensitive to aversions by giving rats a novel saccharin solution to drink detecting the aversive effects of drugs relative to other indi- during radiation exposure and reported that those rats ces of toxicity. For example, trimethyltin, a known neurotox- strongly suppressed consumption of the saccharin solution icant that causes specific damage to the hippocampus, after a single pairing of saccharin with radiation compared induces taste aversions [42, 43]. In more traditional behav- to the control group that was not exposed to radiation fol- ioral assays, a single administration of trimethyltin disrupts lowing intake of the saccharin. Garcia et al. concluded that hippocampus-dependent performance as measured in a the aversive effects of radiation conditioned an aversion to number of tasks, e.g., Hebb-Williams maze, radial-arm the radiation-paired flavor (see Figure 2). This initial report maze, and differential reinforcement of low rates of respond- demonstrated the fast and robust nature of conditioned taste ing (DRL). Interestingly, the dose of trimethyltin needed to aversions (CTAs) as a form of classical conditioning, condition a taste aversion is 500% less than that required wherein learning occurred with a single pairing; the aversion to produce effects in other behavioral indices of toxicity was dose-dependent (30 vs. 57 roentgen (r)) and evident for [42, 43]. These dose-response comparisons substantiate the over 30 days post conditioning despite the fact that animals taste aversion design as a sensitive index in detecting toxic- were given continuous access to the initially preferred sac- ity, as compounds that support taste aversions generally do charin solution and water during this period. Such aversions so at lower doses than are necessary to produce effects in have been reported to be maintained with a year (53 weeks) more traditional assessments of toxicity. From a theoretical intervening between its acquisition and eventual test [35]. perspective, the sensitivity of the taste aversion design Subsequently, Garcia et al. [36] demonstrated that an appears to be a natural extension of the concept of adaptive aversion to saccharin was acquired with an interstimulus specialization in normal consummatory behavior. An organ- interval as long as 75 min (i.e., when the delay between con- ism that can learn the toxic potential of its food source is sumption and radiation was 75 min). In a separate study likely to quickly avoid subsequent toxicosis and reduce the published the same year, taste aversion learning appeared possibility of ingesting the fatal dose of the toxin (see above). selective to gustatory stimuli, wherein rats selectively associ- Research investigating other compounds with toxic and ated saccharin with radiation but audiovisual cues with foot adverse effects within the CTA preparation steadily shock [37]. These unique conditions under which CTA was increased throughout the 1970s with several well-known acquired, that is, learning with one trial, over long delays and toxins such as barium sulfate, cyanide, red squill, strychnine relatively selective to tastes, led to the reconceptualization of sulfate, and sodium fluoride reportedly producing CTAs (for the role of evolution in shaping behavior and learning. It a more comprehensive list of compounds with toxic and seems plausible that natural selection favored organisms able adverse effects that induce CTAs, see Table 1). Although to quickly learn the taste-illness association. Given that aver- most classical toxins (and neurotoxins) reliably condition sive outcomes are likely to occur after some delay as the nat- taste aversion, several compounds with known toxicity have ural function of digestion, the ability to learn a taste-illness been reported to be ineffective. While such caveats clearly association over long delays prevents repeated consumption suggest a limitation of the CTA preparation as an index of of toxic foods. Such adaptive specialization for survival also toxicity, alternative interpretations have been raised in Behavioural Neurology 5 90 Preirradiation preference score 3 7 11 19 35 51 59 63 15 23 27 31 39 43 47 55 Days postirradiation Figure 2: Median saccharin preference scores for animals previously given saccharin access during radiation exposure. Redrawn from Garcia et al. [33]. relation to specific procedures in assaying taste aversions 7. Conditioned Taste Aversions Induced by that might account for these failures (see [31] for a discus- Drugs of Abuse sion of the basis for the failure of known toxins to condition taste aversions and procedural variations of the CTA prepa- Although the initial work on the conditions supporting taste ration that could increase the efficacy of those compounds to aversion learning assessed compounds with adverse or toxic induce CTA). effects as potential aversive stimuli, by the early 1970s, a host There are certainly other behavioral assays for the aver- of other compounds were being investigated, some of which sive effects of drugs than taste aversion learning, e.g., sup- included drugs of abuse. For example, Lester et al. [100] pression of normal regulatory behavior (food and water assessed taste aversion learning with ethanol in which male intake) and disruptions of scheduled-controlled responding, Wistar rats were given 10 min access to a saccharin solution activity, learning and memory, and hedonic shifts (see Riley that was then followed by administration of ethanol (at var- and Tuck, 1985 [31]). One assay very related procedurally to ious concentrations and doses and by different routes of conditioned taste aversions is the conditioned place aversion administration). Under these parametric conditions and (CPA) preparation in which specific environments (or con- with only a single conditioning trial, ethanol induced signif- textual cues) are associated with drug injection. In this prep- icant suppression of saccharin consumption, and as reported aration, animals avoid or spend less time in the drug-paired with work with known toxins [34], the degree of the aver- environment than in one that is paired with the drug vehicle. sions induced was dose-, concentration-, and route- Although this procedure is often used to assess the aversive dependent. Importantly, control subjects receiving the same effects of a drug, it should be noted that when direct compar- saccharin solution paired with injections of the ethanol vehi- isons have been made between the taste and place aversion cle readily consumed it, indicating that the suppression evi- designs, aversions are generally more rapidly acquired and dent in the ethanol-treated animals was a function of the more strongly evident in taste (than place) conditioning association of saccharin with ethanol. (for a direct comparison between LiCl-induced taste and The following year, Cappell and LeBlanc [101] assessed place aversions and a review of other drug comparisons in the aversive effects of several other drugs of abuse, specifi- these two designs, see [99]). These differences between the cally mescaline and d-amphetamine. In the assessment with taste and place conditioning procedures in such assessments mescaline, male Wistar rats were given access to a novel sac- are likely a function of the relatively greater associability of charin solution and injected intraperitoneally with 0 (vehi- taste (over place) in the conditioning of aversive effects cle), 20, 36, or 62.4 mg/kg mescaline hydrochloride, and (see [38–40]). It is important to note that the majority of after, only a single pairing saccharin consumption was sig- drugs of abuse that reliably induce taste aversions fail to nificantly suppressed in all groups injected with mescaline induce a place aversion (in fact, generally inducing a place (maximum suppression at 36 mg/kg). In other groups of preference; see below) or produce a CPA under specific rats, amphetamine (administered intraperitoneally at 0, 2, parametric conditions (high doses, without a drug history, 4, and 8 mg/kg) was given following saccharin consumption, and time of injection relative to placement in chamber) or and significant aversions were again evident at all doses with specific sex, age group, or species (for a discussion, (maximum suppression at 2 mg/kg). Control subjects con- see [99]). Given that taste aversion conditioning has been sumed at high levels following the saccharin-saline pairing. more extensively examined as a behavioral assay of the aver- Subsequent work by Cappell and his colleagues [102] repli- sive effects of drugs and does so with greater sensitivity and cated Lester et al. [100] by reporting dose-dependent generality, the present review focuses primarily on condi- ethanol-induced CTAs in male Wistar rats and extended tioned taste aversion learning in our analysis. the classes of drugs that were effective in inducing aversions 30r 57r Saccharin preference score 6 Behavioural Neurology Table 1: Compounds with adverse or toxic effects effective in producing CTAs. Compound Reference α-Naphthylthiourea (rodenticide) Rzóska, 1954a [32] 1,1,2-Trichloroethane (carcinogen) Kallman et al., 1983 [44] 1,2-Dicholoethane (probable carcinogen) Kallman et al., 1983 [44] 1,2-Dichloroethylene (health hazard) Kallman et al., 1983 [44] 2,3,5-Trimethylphenyl methyl carbamate (neurotoxin) Nicolaus, 1987 [45] 2,4,5-Trichlorophenoxyacetic acid (herbicide) Sjödén and Archer, 1977 [46] 6-Formylindolo (3,2-b) carbazole (FICZ) (carcinogen) Mahiout and Pohjanvirta, 2016 [47] Acetaldehyde (primary metabolite of ethanol) Brown et al., 1978 [48] Acetoxycycloheximide (protein synthesis inhibitor) Ungerer et al., 1975 [49] Acrylamide (neurotoxin) Anderson et al., 1982 [50] Adriamycin (gastrointestinal tract toxin) Bernstein et al., 1980 [51] Aflatoxin B1 (toxic to liver and kidney) Rappold et al., 1984 [52] Alloxan monohydrate (diabetogenic agent) Brookshire et al., 1972 [53] Arsenic (rodenticide) Rzóska, 1954a [32] Atrazine (chlorotriazine herbicide) Hotchkiss et al., 2012 [54] barium carbonate (rodenticide) Rzóska, 1954a [32] Baygon (insecticide) Ebeling, 1969 [55] Benzo[α]pyrene (BaP) (dioxins) Mahiout and Pohjanvirta, 2016 [47] Boric acid (pesticide) Ebeling, 1969 [55] Bufotoxin (neurotoxin) Ward-Fear et al., 2016 [56] Cadmium (toxic metal) Wellman et al., 1984 [57] Carbaryl (insecticide) MacPhail and Leander, 1980 [58] Chloral hydrate (potent sedative) Kallman et al., 1983 [44] Chlordimeform (insecticide) Landauer et al., 1984 [59] Cisplatin (cytotoxin) Revusky and Reilly, 1989 [60] Clorgyline (neurotoxin) Buresová and Bures, 1987 [61] Cobalt chloride (toxic to organs) Wellman et al., 1984 [57] Cobra venom (neurotoxin) Islam, 1980 [62] Copper sulfate (pesticide) Nachman and Hartley, 1975 [41] Cyanide (cytotoxin) O’Connor and Matthews, 1995 [63] Cycloheximide (protein synthesis inhibitor) Booth and Simson, 1973 [64] Cyclophosphamide (gastrointestinal tract toxin) Dragoin et al., 1971 [65] Cytoxan (cytotoxin) Bernstein et al., 1980 [51] Dactinomycin (cytotoxin) Revusky and Martin, 1988 [66] Denatonium benzoate (rodenticide) El Hani et al., 1998 [67] Doxorubicin (cytotoxin) Revusky and Martin, 1988 [66] Emetine hydrochloride (emetic) Cannon and Baker, 1981 [68] Ferric nitrilotriacetate (Fe-NTA) (renal carcinogen) Irie et al., 2000 [69] Formalin (systemic poison) Stricker and Wilson,1970 [70] Ipecacuanha (emetic) Rudd et al., 1998 [71] Krait venom (neurotoxin) Islam, 1980 [62] Lead (toxic metal) Leander and Gau, 1980 [72] Lipopolysaccharide (endotoxin) Exton et al., 1995 [73] Mechlorethamine (vesicant) Revusky and Martin, 1988 [66] Mercuric chloride (cumulative poison) Klein et al., 1974 [74] Methyl bromide vapor (cumulative poison) Miyagawa, 1982 [75] Methylmercury (neurotoxin) Levine, 1978 [76] Methiocarb (pesticide) Mason and Reidinger, 1982 [77] Behavioural Neurology 7 Table 1: Continued. Compound Reference Metrazol (convulsant) Millner and Palfai, 1975 [78] Mesurol (pesticide) Gustavson et al., 1982 [79] Sodium fluoroacetate (rodenticide) Nachman and Hartley, 1975 [41] n-Butyraldoxime (aldehyde dehydrogenase inhibitor) Nachman et al., 1970 [80] N-N-Ethyl-2-bromobenzylamine (neurotoxin) Archer et al., 1983 [81] Ochratoxin (mycotoxin) Clark and Wellman, 1989 [82] Ozone (toxic to lung) MacPhail and Peele, 1992 [83] Paraquat (herbicide) Dey et al., 1987 [84] p-Chlorophenylalanine (neurotoxin) Nachman et al., 1970 [80] Phenylthiocarbamide (neurotoxin) St. John et al., 2005 [85] Picrotoxin (GABA receptor inhibitor) Chester and Cunningham, 1999 [86] Red squill (rodenticide) Rzóska, 1954a [32] Sarin (neurotoxin) Landauer and Romano, 1984 [87] Scorpion venom (neurotoxin) Islam, 1980 [62] Sodium cyanide (rodenticide) Nachman and Hartley, 1975 [41] Soman (neurotoxin) Romano et al., 1985 [88] Staphylococcal enterotoxin B (exotoxin) Kusnecov et al., 1999 [89] Strychnine sulfate (rodenticide) Howard et al., 1968 [90] T-2 toxin (mycotoxin) Wellman et al., 1989 [91] Thallium sulfate (rodenticide) Nachman and Hartley, 1975 [41] Thiabendazole (pesticide) Gustavson et al., 1983 [92] Thiram (fungicide) Tobajas et al., 2019 [93] Tumour necrosis factor α (cytokines) Goehler et al., 1995 [94] Trichloroethylene (carcinogen) Kallman et al., 1983 [44] Trichloromethane (neurotoxin) Balster and Borsellca, 1982 [95] Triethyltin (neurotoxin) MacPhail, 1982 [42] Trimethyltin (neurotoxin) MacPhail, 1982 [42] Triphenyltin (fungicide) MacPhail and Peele, 1992 [83] Toluene (systemic toxin) Miyagawa et al., 1984 [96] Viper venom (hemotoxic) Islam et al., 1982 [62] Vomitoxin (mycotoxin) Clark et al., 1987 [97] Xylene (systemic toxin) MacPhail and Peele, 1992 [83] Ziram (fungicide) Baker et al., 2005 [98] to morphine and chlordiazepoxide (3, 6, and 9 mg/kg; intra- ulus effects seemed paradoxical. At the outset, it was recog- peritoneal). Importantly, this work revealed that while aver- nized that these two effects, i.e., rewarding and aversive, sions were dose-dependent, the strength of the aversions and were generally assessed via different procedures (and gener- the doses at which significant aversions were evident varied ally in different laboratories). As such, demonstrations of these multiple stimulus effects may be a function of the spe- across drugs, suggesting drug-specific aversive effects. Con- current with (and subsequent to) these initial investigations, cific procedure under which they were assessed and not nec- a wide range of drugs of abuse known for their ability to sup- essarily paradoxical. As examples of these differences, port self-administration [103] induced taste aversions as well Cappell and his colleagues [127] noted that with work asses- (see Table 2 for a comprehensive list of various drugs of sing the self-administration of drugs, the drug is generally administered intravenously and under the control of the abuse effective in inducing conditioned taste aversions), sug- gesting that such drugs produce a number of stimulus effects subject (for a discussion of alternatives, see [10, 129]), (both rewarding and aversive). whereas in typical taste aversion studies, subjects are given Almost immediately upon these various demonstrations, the drug intraperitoneally, subcutaneously, or orally ([34, a question was raised as to how drugs that were readily self- 130, 131]; though see [132–136] for evidence of taste aver- sions induced by intravenously delivered drug) and at the administered could also be aversive (as indexed by taste aversion learning; see [127, 128], i.e., the two opposing stim- control of the experimenter and not the subject (though 8 Behavioural Neurology Table 2: Drugs of abuse that are effective in producing a CTA. Each drug has the reference for one of the initial studies examining that specific drug. Compound Reference α-Pyrrolidinopentiophenone (α-PVP) (synthetic cathinone; CNS stimulant) Nelson et al., 2017 [104] 9 9 Δ -Tetrahydrocannabinol (Δ -THC) (cannabinoid) Elsmore and Fletcher, 1972 [105] 3,4-Methylenedioxymethamphetamine (MDMA) (hallucinogen) Lin et al., 1993 [106] 3,4-Methylenedioxypyrovalerone (MDPV) (synthetic cathinone; CNS stimulant) King et al., 2014 [107] Amobarbital (CNS depressant) Vogel and Nathan, 1975 [108] Amphetamine (CNS stimulant) Berger, 1972 [109] Barbital (CNS depressant) Jolicoeur et al., 1977 [110] Caffeine (CNS stimulant) Dickens and Trethowan, 1971 [111] Cathinone (CNS stimulant) Goudie and Newton, 1985 [112] Cannabidiol (CBD) (cannabinoid) Corcoran et al., 1974 [113] Cannabigerol (CBG) (cannabinoid) Corcoran et al., 1974 [113] Cocaine (CNS stimulant) Goudie et al., 1978 [114] CP 55,940 (synthetic cannabinoid) McGregor et al., 1996 [115] d-Amphetamine (CNS stimulant) Cappell and LeBlanc, 1971 [101] Diazepam (CNS depressant) Jolicoeur et al., 1977 [110] Ethanol (CNS depressant) Lester et al., 1970 [100] Ethanol (CNS depressant)+cocaine (CNS stimulant) Busse et al., 2005 [116] Flurazepam (CNS depressant) Vogel and Nathan, 1975 [108] Heroin (analgesic) Grigson et al., 2000 [117] Heroin (analgesic)+cocaine (CNS stimulant) Riley et al., 2019 [118] Hexobarbital (CNS depressant) Vogel and Nathan, 1975 [108] Ketamine (hallucinogen) Etscorn and Parson, 1979 [119] l-Amphetamine (CNS stimulant) Carey and Goodall, 1974 [120] Lysergic acid diethylamide (LSD) (hallucinogen) Parker, 1996 [121] Methamphetamine (CNS stimulant) Martin and Ellinwood, 1973 [122] Mescaline (hallucinogen) Cappell and LeBlanc, 1971 [101] Methaqualone (sedative hypnotic) Vogel and Nathan, 1975 [108] Methyprylon (sedative hypnotic) Jolicoeur et al., 1977 [110] Methylone (synthetic cathinone; CNS stimulant) Manke et al., 2021 [123] Methylphenidate (CNS stimulant) Riley and Zellner, 1978 [124] Morphine (analgesic) Cappell et al., 1973 [102] Nicotine (CNS stimulant) Etscorn, 1980 [125] Pentobarbital (CNS depressant) Buresova and Bures, 1980 [126] Phencyclidine (PCP) (hallucinogen) Etscorn and Parson, 1979 [119] Phenobarbital (CNS depressant) Vogel and Nathan, 1975 [108] see [117, 137–139] for demonstrations of aversions induced effects of many drugs of abuse could be seen in a design that when the drug was self-administered and/or under the con- concurrently assessed these effects which assured that the trol of the subject). parametric conditions under which any effects were tested In addition to these basic procedural differences in drug were identical. For example, Wise et al. [137] gave rats access self-administration vs. taste aversion learning, such demon- to saccharin and then immediately allowed them to self- strations of the rewarding and aversive effects were often administer apomorphine (0.5 mg/kg per infusion; all sub- assessed under different parametric conditions, e.g., with dif- jects had previous experience with the intravenous self- ferent sexes, at different ages, in different strains, at different administration of amphetamine). On the subsequent expo- doses, and under different deprivation schedules, following sure to saccharin, 10 of the 11 subjects trained and tested acute and chronic exposure. The possibility that demonstra- displayed aversions to the apomorphine-associated saccha- tions of reward and aversion were a function of simple para- rin solution with the degree of the aversion directly related metric differences between such demonstrations was soon to the amount of apomorphine self-administered during dismissed with reports that the aversive and rewarding the initial training session. Thus, both the rewarding (self- Behavioural Neurology 9 administration) and aversive (CTA) effects of apomorphine aversions were reported with the combined design (for were evident under the same parametric conditions (and at reviews, see [166, 167]). comparable doses), suggesting multiple (and opposing) The advantage of using a combined procedure to exam- stimulus effects of the drug. In a related study, White et al. ine a drug’s aversive and rewarding effects in the same ani- [140] reported that rats injected with morphine after run- mal is that it addresses the concern that the two effects are ning down a straight alley to obtain food ran faster to obtain simply a function of different experimental conditions under the food (reward) but failed to consume it (aversion), again which they are tested (see above). While this is true, the revealing dual (and concurrent) effects of a drug, in this case combined procedure as generally used does train the animal morphine. Interestingly, animals given the emetic LiCl in a serial manner, i.e., the animal is given access to some under the same conditions displayed reduced running speed novel solution, e.g., saccharin, injected with the drug and to obtain the food and failed to eat the food, as well. In then put on one side of the place preference apparatus. related work, Ettenberg and Geist [138, 139] have reported Under such conditions, one could argue that acquisition of both positive and negative effects of cocaine in a runway the CTA itself or the conditions under which the CTA is model. In this design, animals are allowed to run down a generally trained and tested, i.e., water deprivation, could straight alley for an intravenous injection of cocaine. After impact the acquisition (or display) of the place preference. several such trials, the latency to leave the start box As such, the measure of reward in terms of place preference decreased (indicative of cocaine’s rewarding effects) and conditioning within the combined design might differ from the running time to enter the goal box increased as animals what one would see if place preferences were assessed began to retreat from the goal box with further training separately. (indicative of cocaine’s aversive effects). Ettenberg et al. sug- Although there are many studies using the combined gested that the immediate actions of cocaine were rewarding design (see above), there are only a few that have addressed (decreasing response latencies) that were quickly followed by this potential confound. For example, in one such study, ani- an opponent process crash that resulted in an approach/ mals were given morphine-induced taste aversion training, avoidance reaction and increased running time as animals and once aversions were established, the same animals were retreated from (avoided) the goal box that was associated assessed for place preference conditioning with morphine. with cocaine (see also [141]; for evidence of this time- Place preferences were then compared between groups that dependent opponent process of reward/aversions, see [142]). had the aversion history vs. those that had been given con- trol injections during the taste aversion training, i.e., control subjects with no pairings of the taste with morphine. Under 8. Combined Taste Aversion/Place these conditions, there were no differences between animals with or without the taste aversion history, as morphine- Preference Procedure induced place preferences were similar for both groups Shortly after the demonstrations by Wise et al. [137] and [153]. These results suggest that having a history in which White et al. [140], Reicher and Holman [143] used a differ- a specific drug induced an aversion had no effect on its abil- ent procedure to assess the aversive and rewarding effects of ity to induce a place preference for that same drug. While this addresses the effects of an aversion history on place pref- amphetamine. Specifically, this group used a combined con- ditioned taste aversion and conditioned place preference erence conditioning, it does not address the possibility that (CTA/CPP) design in which they gave female Sprague- the procedures used in the combined design to induce an Dawley rats an intraperitoneal injection of amphetamine aversion might impact the acquisition of the place prefer- (1.43 mg/kg) and placed them on one side of a two- ence. One factor that might impact such learning would be compartment shuttle box during which they had access to water deprivation (or its associated stress). In the combined a novel-flavored solution (banana or almond). On the next design, animals are generally water deprived to encourage day, the animals were injected with the amphetamine vehicle consumption, but it is present as well during the place pref- erence assessment, a condition not typically used in inde- and placed on the opposite side of the shuttle box with access to the other novel solution (almond or banana). Six pendent assessments of place preference conditioning. In a such alternating trials were given followed by tests for side recent study, Dannenhoffer and Spear [147] examined the and flavor preferences. Under these conditions, amphet- combined CTA/CPP procedure with nicotine in nonde- amine induced significant taste aversions and place prefer- prived adolescent and adult rats. To induce drinking in these nondeprived animals, a highly palatable sucrose/saccharin ences, again demonstrating both aversive and rewarding effects of the same drug and under identical parametric solution was given after which the animals were injected conditions. Subsequent to the initial work by Reicher and with nicotine and placed on one side of a place preference Holman, a variety of drugs have now been shown to sup- chamber. As expected, nicotine induced significant taste port both effects in the combined CTA/CPP procedure aversions and place preferences, and importantly, place pref- erences (and taste aversions) were similar to those reported including 3,4-methylenedioxypyrovalerone (MDPV) [144], α-pyrrolidinopentiophenone (α-PVP) [104, 145, 146], nic- in independent assessments of each. Further, adolescents otine [147], amphetamine [148–150], morphine were more sensitive to the rewarding effects of nicotine [150–157], cocaine [158–160], alcohol [161], and caffeine (and less sensitive to its aversive effects) relative to adults [162]; for several drugs, e.g., ethanol [163] and Δ -tetrahy- (for comparison, see [168] who reported these same relative sensitivities of CPP and CTA when separately assessed). drocannabinol (THC) ([164, 165], both taste and place Affective Value 10 Behavioural Neurology Rewarding Other comparisons across studies have shown that place preference conditioning is comparable when assessed in a combined CTA/CPP design or as an independent CPP and that manipulations in either design impact place preference conditioning similarly (see [152, 157] for assessments of the combined CTA/CPP assay with morphine compared to [169, 170] for assessments of morphine using only CPP; for a similar comparison with MDPV, see [171] compared to [172]; for α-PVP, see [104] compared to [173, 174]; and for caffeine, see [162] compared to [175]). 9. Implications of the Aversive and Rewarding Effects of Drugs Aversive The fact that drugs have both rewarding and aversive effects Drug Dose raises an interesting issue regarding their possible role in drug intake. Specifically, the balance of these two effects Figure 3: A hypothetical model of the aversive and rewarding may be important in the likelihood of a drug’s initial use effects of a drug and their potential interaction to impact its self- administration (which is a function of the overall affective and its continued (regulated) intake (see Figure 3). Further, response to the drug). The drug produces both aversive and we are suggesting that it is this very balance that predicts rewarding effects in a dose-dependent manner. As illustrated in the abuse vulnerability of a specific drug [20, 137, 141, 166, this specific example, the drug’s rewarding effects are produced at 176–179]. If the rewarding effects of the drug (at any given lower doses that increase the drug’s overall affective property that, dose) are greater than its aversive effects at that same dose, in turn, drives the drug’s intake. With increases in the dose, the the abuse vulnerability of this drug might be predicted to drug’s rewarding effects asymptote while the drug’s aversive be high as intake may increase with its overall greater affec- effects increase, reducing the overall affective value of the drug tive value. If at the outset the drug’s aversive effects (at any and decreasing the drug’s self-administration. In this model, the given dose) exceed its rewarding effects at that same dose, drug’s rewarding effects are assumed to initiate and maintain it might be expected that drug intake would not continue drug intake (at least under acute conditions) while its aversive and the drug would have limited abuse potential. It is impor- effects limit it. The nature of such an interaction is not static and tant to note that this balance is not fixed for any specific depends upon a host of factors (see Sections 11 and 12). Further, drug as a wide range of factors have been reported to affect the relative contributions of the aversive effects in limiting intake change as drug intake go from regulated to dysregulated given the both its rewarding and aversive effects (see below) which, change in the reward valence from positive to negative. Created in turn, can shift the affective balance. It is also important with BioRender.com. to note that the nature of the drug’s rewarding effects changes with more frequent and chronic use (from positive associated with acute and regulated intake to negative asso- Interestingly, animals that acquired strong morphine- ciated with dysregulated intake and the onset of dependence, induced taste aversions were just as likely to display weak anhedonia, and withdrawal (see [4–7]). Although under or strong morphine-induced place preferences. Similarly, these latter conditions, drug intake may still be a function animals that acquired weak morphine-induced taste aver- of the balance of reward and aversion; the very nature of sions were just as likely to display weak or strong place pref- anhedonia may weaken the relative contribution of the erences (for related findings with serial conditioning of drug’s aversive effects as individuals use the drug for relief CTAs and CPPs, see [180]). That is, there was no relation from withdrawal despite their aversive effects which would between the two measures. The same pattern emerged with normally limit intake. amphetamine. King et al. [171] have also reported similar independence with the synthetic cathinone, MDPV. In this report, males and females both acquired dose-dependent 10. Dissociation between the Aversive and taste aversions with males displaying greater aversions than Rewarding Effects of Drugs females. On the other hand, while both sexes acquired The fact that these two stimulus effects are evident in the MDPV-induced place preferences, these were independent same animals and often under similar parametric conditions of sex and correlational analysis between the degree of taste aversions and place preferences did not reveal a consistent supports the position that a drug has multiple affective prop- erties. Interestingly, it appears that these two effects can be relationship between the two measures (see [145] for related dissociated. For example, Verendeev and Riley [150] (see findings with the synthetic cathinone a-PVP in which both also [180]) have reported that animals trained in a combined males and females displayed significant and dose- CTA/CPP procedure with morphine (5 or 10 mg/kg, intra- dependent CTAs (M> F), but only males displayed signifi- cant place preferences). peritoneal) or amphetamine (3 or 5 mg/kg, intraperitoneal) acquired taste aversions as well as place preferences; how- The apparent dissociation of taste aversions and place ever, there was no relationship between the strength of taste preferences as measured in the combined CTA/CPP design aversion and place preference conditioning for either drug. argues that these two effects occur concurrently but are not (- ) Affective Properties (+) Behavioural Neurology 11 aversions based on studies for which the doses supporting related. The fact that the aversive effects of the drug are asso- ciated with taste (CTA) while the rewarding effects are asso- the two effects differ (see [161, 162, 164, 165, 195]), it is ciated with a specific place (CPP) is likely a function of the important to note that under most of the assessments cited relative selectivity of taste and environment conditioning above reporting the dissociation of CTAs and CPPs, compa- with these specificaffective properties (see [33, 38, 40]; for rable doses were administered, yet the two indices of the a review, see [34]). Although apparently dissociable, any drug’saffective properties were still differentially affected attempt to relate these behaviors in a correlational analysis by various manipulations [116, 145–147, 152, 159, 168, should be made cautiously, given that CTA and CPP proce- 181, 182, 188, 191], i.e., the different effects reported for dures may differ in their relative sensitivity as measures of CTA and CPP were not simply due to animals being tested the aversive and rewarding effects of drugs, respectively. under different doses in the two designs. For example, CTA may be less sensitive as a measure of the aversive effects of a drug than CPP is as a measure of 11. Nature of the Aversive Effects of Drugs its rewarding effects, and the drug’s aversive effects may not be accurately reflected in the expression of taste aver- The present review has discussed conditioned taste aversions sions. Conversely, CPP may be less sensitive as a measure in the context of their origins and extensions. As such, it has of the rewarding effects of a drug than CTA is as a measure used the animal’s suppression of consumption of a specific of its aversive effects. That is, the drug’s rewarding effects taste following its pairing with either a toxin or drug of abuse may not be accurately reflected in the expression of place to be a function of the compound’s aversive effects that preferences. As such, any attempt to relate these behaviors become conditioned to the taste itself. Noting that drugs of in a correlational analysis should be made cautiously. Inter- abuse have aversive effects that may limit (or modify) their estingly, under conditions where taste aversions and place intake suggests that these effects may be important in regu- preferences have been analyzed in individual subjects most lated drug intake; however, such a position does not indicate sensitive to either aversive (high CTA) or rewarding (high their nature which has been somewhat elusive over the his- CPP) effects of drugs, there still is no consistent relationship tory of the phenomenon of taste aversion learning [34]. between the ability of either drug to produce these effects The present review is somewhat neutral on this issue, but (see [144, 150]), supporting the ability of the aversive and suffice it to say, the literature has had much to discuss rewarding effects to cooccur and at the same time being dis- (and debate) regarding the basis of taste aversion condition- sociable—a position consistent with the drugs having cooc- ing. At the outset of work on this phenomenon [33, 196], the curring, but unrelated, effects. avoidance was thought to be a function of conditioning of Such a position is supported by other assessments of the radiation-induced gastrointestinal effects, e.g., sickness. drug-induced taste aversions and place preferences that have The resulting avoidance was a reflection of conditioned sick- found similar dissociations between the two effects in a ness/malaise itself, i.e., a conditioned aversion to that taste number of studies evaluating the impact of a variety of [38]. As reported by Garcia and Kimeldorf [197], radiation manipulations on their acquisition and display, e.g., age localized to the abdomen induced significant taste aversions [147, 168, 181], sex [145], strain [181–183], drug history at doses that had no effect when targeted to other areas [146, 152, 182, 184], drug interactions [116], genetic knock- (including the head; higher doses localized to the head, pel- outs/knockins [185, 186], lesions [133, 187], state depen- vis, or thorax did produce aversions, but even here, they did dency [188], role of DARRP-32 [189], effects of LPS [190], not approximate those targeting the abdomen). Garcia and effects of Fe particles [191], neuroanatomical and neuro- Kimeldorf noted that abdomen radiation induced aversions chemical mediation [157, 192, 193], and receptor subtype at the same dose that decreased gastric distension and tran- [186, 194]. For these assessments, CTA and CPP were differ- sit, leading them to conclude that gastric disruption is the entially affected, suggesting that the two were unrelated, i.e., stimulus likely necessary to condition aversions. As other if related one would expect that the two effects would be agents (mostly toxins) were reported to induce aversions, it similarly impacted. In the above evaluations, CPP could be was assumed that these compounds also produced sickness seen with no evidence of a CTA (and vice versa) or CPP or malaise, but these conclusions were generally made in the absence of direct corroborative evidence of such effects could be increased and CTA decreased (or vice versa) by chemical and neuroanatomical challenges. Although these (and often in the context of contrary evidence, e.g., the gen- demonstrations were generally made with separate analyses eral inability of antiemetic drugs to affect CTAs [198, 199], of reward and aversion, i.e., using the CTA (or conditioned the ability of antiemetics to induce CTAs themselves [109, place aversion) design to assess the drug’s aversive effect 200], and the absence of a relationship between the degree and the CPP design to assess reward, some were made with of sickness and CTAs [201]. the combined design demonstrating again that the dissocia- A similar explanation was used by many to account for tions were not a simple function of parametric conditions. the avoidance of taste paired with drugs of abuse which, in One specific manipulation that deserves special attention part, created the initial paradox of how drugs of abuse could is that of dose. As noted in the clinical literature (see above), be both aversive (via sickness) and rewarding at the same the rewarding and aversive effects of some drugs were time. While conditioned aversions (sickness) were often reported to be dose-dependent, specifically rewarding at applied to the suppression of consumption of tastes paired low doses and aversive at higher ones. While there is evi- with drugs of abuse, others challenged this position. For dence of dissociations between place preferences and taste example, in an elegant series of studies, Parker assessed taste 12 Behavioural Neurology from use to abuse, see [5]); any disruption in this state is per- reactivity as an index of the sickness-inducing effects of drugs and found that although most drugs of abuse resulted ceived as dangerous and defended. In one of the first reports in the suppression of consumption of solutions paired with on this possibility, Gamzu [128] discussed drug novelty itself as being the necessary condition for disruptions of homeo- the drug (see [202]; see also above; Table 2), these same drugs did not produce signs of sickness in the taste reactivity stasis and in conditioning taste aversions (see [218] for a assessments ([203]; for recent work with LiCl vs. lactose, see related position that argued that the actual rewarding effects [204]). In assessments of taste reactivity, a taste previously of drugs were the novel stimulus that induced taste aver- associated with some drug, e.g., LiCl, amphetamine, and sions). Although drug novelty is important in the condition- ing of taste aversions (as exposure to the drug prior to cocaine, is infused into the animal’s mouth via an indwelling cannula and both aversive and positive taste reactions to the conditioning weakens the acquisition of taste aversions), infused solution are recorded. If the taste has been paired several arguments challenged this specific account. For with LiCl (and other emetics), a host of aversive taste reac- example, as noted above, a number of classic toxins such tions are increased, e.g., gaping, chin wipes, and paw tread- as strychnine and cyanide as well as convulsants fail to induce CTAs (see [41]). It is difficult to explain how drugs ing, which are used as an index of sickness/malaise induced by the conditioned taste (via its pairing with a drug with clear toxicity fail to induce a novel state. More impor- that induced such effects unconditionally; see [205, 206]). As tantly, although drug history weakens taste aversion acquisi- noted, tastes paired with drugs of abuse generally do not tion, with repeated conditioning trials (where the taste and induce aversive taste reactivity (for reviews, see [207–209]). familiar drug are repeatedly paired), aversions do develop despite the fact that the drug is no longer novel (for a review, Parker and her colleagues concluded from these analyses that drugs of abuse do not induce sickness (as indexed by see [219]). the taste reactivity test), and thus, the suppression of con- Disruptions in homeostasis can be produced by toxins, sumption of the taste associated with such drugs is not a chemicals with adverse effects, and drugs of abuse, and function of a conditioned aversion to the taste itself. Impor- according to the evolutionary importance of recognizing such disruptions as potentially dangerous, all such com- tantly, Parker has shown that even drugs such as LiCl which do induce aversive taste reactivity (reflective of conditioned pounds should be effective in inducing taste aversions (and sickness) do not suppress the intake of LiCl-associated solu- for the most part they are). However, stating that such dis- ruptions are important in inducing aversions does not sug- tions through this mechanism in that antiemetics can atten- uate aversive taste reactivity while leaving LiCl-taste gest that there is a common mechanism mediating all of these compounds. For example, even though drugs of abuse aversions intact [210] (for a review, see [199]). From her analysis of the basis of the suppressed consumption of solu- are rewarding as assessed in standard operant and Pavlovian tions induced by drugs of abuse, Parker suggests that sick- designs that index these effects, collateral effects such as sick- ness (morphine), hyperthermia (synthetic cathinones [145]), ness plays no role and even questions the role of sickness in suppression induced by emetics such as LiCl (for evidence anxiety (cocaine and amphetamine [138, 139]), sedation (barbiturates), hypothermia (alcohol [220]), and opponent critical of Parker’s position of the importance of sickness in taste aversion learning using measures other than taste reac- process-related withdrawal (cocaine and morphine [136, tivity, i.e., lick pattern and rate, to assess sickness and palat- 183, 221–223]), may be the stimuli important in inducing aversions by virtue of their ability to disrupt homeostasis. ability shifts, see [211–215]; see also [216, 217]). Given the diminishing role of sickness as the common What is critical about this explanation of homeostasis is that the aversive effects of drugs that condition aversions are mediator of the effects induced by various agents to induce taste aversions, others turned to different mediators of such drug (and parameter)-specific (and not due to a general effects. In this context, it was generally stated that issue of malaise or stress; for a discussion of a potential com- mon mediator, i.e., fear, see [224]). It is important to note aversion-inducing agents had toxic (adverse) effects (but not necessarily sickness or malaise) that were responsible here that few of the proposed mediating stimulus effects for taste aversion conditioning [31]. As such, interpretations have been directly tested and the failure of specific toxins became couched not in sickness but in rather general terms to induce aversions still needs to be explained (see [31] for of toxicity. Such a general term conveyed no clear mecha- an explanation of failure of several rodenticides and toxins). Further, over the past 20 years, a wide range of neuroactive nisms of the toxicity, and, further, drugs with reported tox- icity in other behavioral toxicological screens did not compounds as well as neurochemicals involved in the mod- always induce aversions [41] (for a discussion, see [31]). ulation of normal neuronal function (and behaviorally Also, when drugs of abuse were reported to induce taste active) are not effective in inducing CTAs, failures that chal- aversions (see above), the explanations were even more dif- lenge a simple homeostatic disruption as mediating aversion learning, e.g., interleukin-1B [225], interleukin-6 [226], lep- ficult in the context of general toxicity as such drugs in addi- tion to being rewarding in other preparations produced no tin [227], GHR-R antagonist JMV 2959 [228, 229], L- obvious toxic effects at the doses tested [128] (see [20]). To tryptophan [230], N-acylphosphatidylethanolamine [231], address this issue, a number of individuals noted that such and oleoylethanolamide [232]. drugs of abuse were aversive by disrupting normal homeo- Although each of these mechanistic accounts has been offered stasis [31, 127, 128, 207, 214]. That is, given that general as a basis for taste aversion learning and most papers homeostasis is a well-defended state (see [128]; for related refer to one of these interpretations in their analysis of discussion on drugs of abuse in terms of their transition CTAs, no individual perspective is generally accepted. Behavioural Neurology 13 and marijuana) whether the initial response to these com- Independent of which interpretation eventually garners con- sensus, all argue that the drug (whether a toxin, exogenous pounds is associated with subsequent use and/or abuse. As chemical agent, peptide, neurochemical, or drug of abuse) they describe, individuals differ significantly in their initial response to these drugs (as a function of environmental has some adverse effect that induces aversions (for an alter- native interpretation that argues that the avoidance of drug- and genetic influences) and that for several drugs the initial paired tastes is a function of a reward comparison in which responses (either positive or negative) are correlated with the taste is devalued relative to the injected drug, i.e., antic- subsequent use (and in some instances substance use disor- ipatory contrast, see [155–157, 233–235]; see [20] for a der). For example, with alcohol, individuals who initially dis- play greater stimulant-like effects as breath alcohol review of the reward comparison hypothesis). concentrations are rising (see [237]) and feel fewer depres- sant effects as these levels decrease [238] are more likely to 12. Implications for the Aversive and use and abuse alcohol. Conversely, those individuals that experience unpleasant effects are less likely to subsequently Rewarding Effects of Drugs to Use consume alcohol, effects and outcomes similar to what was and Abuse previously described for individuals with metabolic differ- ences in the ability to metabolize the alcohol metabolite acet- The fact that drugs of abuse have both aversive and reward- ing effects is now well characterized by a wide range of such aldehyde (see above; see also [22, 239]). compounds. The fact that the two effects are also dissociable For other drugs (e.g., nicotine), the initial positive response was a better predictor of use and abuse (although is important given that they can be differentially impacted by a host of parametric, experiential, and subject factors (see negative responses limited intake under some conditions). For others (e.g., marijuana), only initial positive responses above). That is, the balance between these two affective properties can be differentially impacted by these factors were associated with later use that, in turn, had little associ- and, in turn, can change abuse vulnerability. In this context, ation with initial negative reactivity. For caffeine, unpleasant effects or negative subjective responses predicted lower con- the hypothetical interaction of aversion and reward as illus- trated in Figure 3 is not static but is one that will differ sumption. Finally, for heroin, individuals having greater depending upon the drug examined (including its dose, positive experience were more associated with later abuse route of administration, and frequency of use) and the myr- (although no data have been reported on the relative associ- iad of subject (sex, age, and genetics) and experiential (drug ation with any negative effects, e.g., nausea). In a summary of their work, De Wit and Phillips [13] cautioned that an interactions, drug history, drug expectancy, and condition- ing history) factors that can modulate each affective understanding of the contribution of the initial affective response (for a discussion, see [166, 176, 236]). Knowing response to a drug to its later use and/or abuse must be the impact of these factors on drug aversion and reward assessed in the context of many other factors such as expec- and their balance should provide insight into the drug’s tancies, cognitive control, drug history, learning, and physi- use and its abuse vulnerability. cal dependence, all of which clearly impact the likelihood of The questions then become how this impact occurs and continued drug use and its escalation (e.g., the fact that indi- under what conditions. The complexity of these questions viduals adjust doses of heroin or become tolerant to its aver- becomes clear when one examines facets of drug-taking sive effects may limit generalization about the relative role of (see [4]) that range from controlled to dysregulated use initial positive and negative effects to its continued use). (abuse). In this context, aversion and reward (and their bal- Interestingly, De Wit and Phillips [13] also assessed ance) could impact the likelihood of initial drug intake and related work on positive and negative drug effects in animal its maintenance as well as the dysregulation of drug intake models and noted the relative paucity of data assessing affec- that may escalate to abuse. Although each of these is impor- tive valence in nonhuman subjects and its relationship to tant in assessing how drug use and abuse may be impacted drug intake in animals. The one area for which considerable by the affective properties of drugs, relatively little has data have been reported has used selectively bred animals addressed these specific issues. This review will highlight (lines selectively bred for specific phenotypes) and inbred some of the work in these areas and what could be done. animal strains (derived from full-sibling mating that maxi- These issues have recently been addressed by De Wit and mize genetic homogeneity) as their focus (for reviews, see Phillips [13] in their review “Do initial responses to drugs [176, 236, 240]). The creation of selectively bred lines that predict future drug use?.” In this review, they raise the point are differentially sensitive to the aversive effects of drugs that drugs can vary on a number of characteristics, including has been reported for many years (see [241, 242]). Such ani- the magnitude, quality, and duration of their effects, all of mals (taste aversion prone and taste aversion resistant, TAP which may impact subsequent use. One characteristic which and TAR, respectively) display significant differences in their is highlighted in their review is the affective valence of a ability to acquire aversions induced by a variety of drugs, drug’seffects, i.e., the positive and negative effects that may e.g., cyclophosphamide, LiCl, and emetine hydrochloride facilitate and discourage use, respectively (similar to the [241, 242], and importantly by drugs of abuse, e.g., alcohol affective properties noted in the present review). Using both ([243]; see also [244]), with the TAP animals displaying retrospective and prospective assessments (along with aversions at lower doses and acquiring aversions at a faster human laboratory studies), they then assess for a variety of rate than the TAR animals. These differences in aversion drugs (alcohol, nicotine, caffeine, psychostimulants, heroin, learning do not reflect differential abilities to learn in general 14 Behavioural Neurology methamphetamine displayed no differential aversive (as as TAP and TAR rats are similar in other learning prepara- tions that do not utilize aversion conditioning (see [245, measured by CTA) or rewarding (as measured by CPP) 246]). effects of cocaine, showing that the genetic sensitivity to the aversive and rewarding effects of methamphetamine Although Elkins and his group did not assess the poten- tial contribution of these differential sensitivities of the aver- does not impact cocaine susceptibility [195]. Such findings sive effects of alcohol (and cocaine) to drug intake in these of the inverse relationship between the aversive effects of a same animals, others have done related work and have drug and its tendency to be self-administered in selectively shown in both inbred strains and other selected lines that bred strains are not limited to methamphetamine and the low and high drinking mice. For example, our laboratory animals that show greater drug-induced taste aversions induced by specific compounds such as alcohol, metham- has also focused on this issue in selectively bred rat strains, phetamine, and heroin are less likely to self-administer those specifically the Lewis (LEW) and Fischer (F344) strains that same compounds (orally or intravenously) (see [166, 176, are well characterized for their differences in intravenous 236]). For example, the Wistar Kyoto (WKY) rat strain that self-administration of a variety of drugs. These two strains were originally selectively bred for cancer susceptibility and generally displays low consumption of alcohol in free-choice assessments displays strong taste aversions to novel solu- tissue inflammation (for discussion of the origins of these tions paired with exogenously administered ethanol (and lines, see [176]) but subsequently were shown to differ for differ significantly in both measures relative to the Marshal a myriad of other behaviors, including stress reactivity and strain (M520) that generally consumes high levels of alcohol drug intake, although the two strains were not selectively bre and only weak aversions to ethanol-paired solutions). In d for differences in these latter two effects. In relation to other words, there is an inverse relationship between alcohol drug intake, the LEW and F344 rat strains are well charac- consumption and its aversive effects (see [247, 248] for sim- terized for their differences in the self-administration of a ilar comparisons between the high alcohol-consuming Wis- variety of drugs of abuse, including alcohol (oral), morphine, tar Kyoto hyperactive rat (WKHA) and the WKY and etonitazene, methamphetamine, cocaine, and nicotine, and spontaneously hypertensive rat strains). under most comparisons, LEW rats self-administer greater The vast majority of work assessing the relationship amounts of drugs than does the F344 strain (for a review, between the aversive effects of drugs and drug intake has see [176]). The general conclusion regarding these genetic been with inbred strains of mice, specifically the C57BL/6J differences in drug intake is that the two strains differ signif- and DBA/2J strains. These two strains have been examined icantly in their sensitivity to the drugs’ rewarding effects, a for alcohol preference and ethanol-induced taste aversions conclusion supported by the fact that for a variety of drugs in a number of contexts and have consistently been shown the LEW strain displays conditioned place preferences at to display an inverse relationship between alcohol intake lower doses than the F344 strain (see [176]). Interestingly, and ethanol-induced taste aversions. Specifically, DBA mice however, these strains also differ significantly in the aversive (alcohol avoiding) acquire ethanol-induced taste aversions at effects of the same drugs. For example, we have demon- a lower dose/concentration and at a faster rate relative to strated for morphine [254–256], alcohol [163], and nicotine alcohol-preferring C57 mice. In a comprehensive analysis [257] that the F344 strain acquires morphine-, alcohol-, and of 15 inbred mouse strains, Broadbent et al. [249] reported nicotine-induced taste aversions at lower doses than the a significant inverse relationship between alcohol consump- LEW strain. Such differences in sensitivity to the aversive tion and ethanol-induced taste aversions, suggesting that the effects of these drugs are not a general function of learning sensitivity to the aversive effects of alcohol may serve as a as these strains differ in the opposite direction for the drugs’ protection against elevated alcohol intake (see [250] for a rewarding effects as indexed by place preference condition- similar inverse relationship between oral alcohol intake ing (L>F). Further, the two strains do not differ in aversions and ethanol-induced place aversion conditioning, another induced by compounds with no abuse potential, e.g., the index of the aversive effects of drugs; see [251] for related emetic LiCl [258], the kappa opiate receptor agonist work showing that ethanol-induced place preference condi- U50,488H [255], the delta opiate receptor agonist SNC80 tioning was not significantly correlated with alcohol con- [255], and the peripherally acting mu opiate receptor agonist sumption, suggesting a greater role for the aversive effects loperamide [256]. of alcohol in strain differences in alcohol acceptability). Thus, similar to work with inbred strains, we see an Other work has focused on selective breeding to assess inverse relationship between drug intake and the relative the relationships between the aversive effects of drugs and sensitivity to taste aversion conditioning, i.e., animals readily their self-administration. For example, Phillips and her col- self-administering the drug display weaker taste aversions leagues have reported similar findings with methamphet- (and vice versa), again substantiating a genetic component amine. Specifically, rats that are selectively bred for high mediating the basis for drug use. In that context, there are oral self-administration of methamphetamine were less several important caveats. First, when cocaine is used as likely to display methamphetamine-taste aversion (an index the aversion-inducing agent, the LEW strain displays greater of its aversive effects) and more likely to display aversions, i.e., the LEW strain self-administers cocaine at methamphetamine-place preferences (an index of its higher rates than the F344 strain and displays greater rewarding effects) than rats selectively bred for low metham- cocaine-induced taste aversions [259] (see [260] for related phetamine intake (see [183]; see also [252, 253]). Interest- findings with caffeine). While this challenges the inverse ingly, rats selectively bred for low and high drinking of relationship reported with alcohol, morphine, and nicotine, Behavioural Neurology 15 overconsumption followed by a reduced ability to control it should be noted that such a finding is not necessarily inconsistent with the position that drug intake is a balance the desire to obtain drugs regardless of the risks involved, of reward and aversion. In the case of cocaine, the LEW ultimately resulting in compulsive drug seeking [7]. The pos- strain is more sensitive to both affective properties, but the sibility that environmental stimuli associated with the post- balance may nonetheless be shifted toward reward, support- ingestive rewarding effects of drugs strongly motivate ing greater self-administration (see above discussion on the consumption has guided much of the research exploring balance of reward and aversion). A second caveat concerns the role of neuroadaptations in the mesolimbic and meso- the implications of the findings in general for a genetic cortical dopamine systems as well as in the prefrontal and mediation of the aversive and rewarding effects of drugs orbitofrontal cortices mediating responses to drug rewards based on the selective breeding model. While the difference [5, 274]. There is little doubt that the memory of highly between the LEW and F344 rat strains clearly represents rewarding postingestive drug effects can strongly influence effects that have genetic influence, it does not mean that expectations about the outcomes a particular drug will pro- these differences cannot be impacted by environmental fac- duce. The strength to which drug-related contexts (e.g., time tors. Support for this position comes from work on cross- and space) can excite retrieval of those memories is a key fostering in the strains. For example, we have reported that determinant of current and future consummatory behavior while LEW and F344 stains differ in their sensitivity to the [275, 276]. aversive effects of morphine (F>L; see [254]), these differ- However, the response to drug-related cues involves ential sensitivities are partially reversed with cross- more than excitatory associations that predict rewarding fostering. That is, F344 animals that normally display robust postingestive outcomes that, in turn, generate drug-taking. morphine-induced aversions resemble pups for the LEW As demonstrated by the majority of individuals consuming strain that are relatively insensitive to morphine if they are drugs, the patterns of drug intake are generally well regu- reared by a LEW dam; conversely, LEW animals that gener- lated, indicating that the capacity for drug-related cues to ally show weak morphine-induced aversions acquire strong evoke intake is not without limits [277, 278]. That is, bouts aversions (similar to the F344 strain) if reared by a F344 of drug intake stop even when environmental cues (and dam [261]. Partial reversals were also seen when cocaine the drug itself) that have gained the power to initiate intake was used as the aversion-inducing drug, i.e., the F344 strain are still present. Such regulatory control involves higher- that normally displays weak cocaine-induced taste aversion level learning and memory processes that counter the power display strong aversion characteristics of the LEW strain if of palatable drugs (and drug-related stimuli) to inhibit fur- reared by a LEW dam (see [176]; for reports of reversals of ther intake [271, 279–281]. The same environmental stimuli other behavioral effects by cross-fostering, see [262, 263]). associated with the rewarding consequences on some occa- The major work showing how the aversive (and reward- sions, e.g., at the outset of consumption, can also predict ing) effects of drugs may impact drug intake has primarily nonrewarding or even aversive consequences on other occa- been within various genetic models (see above; for related sions, e.g., toward the end of a bout of drug use. Thus, both work with KO mice, see also [186, 189, 264–266]; see also excitatory and inhibitory associations are formed between [267, 268] for effects of aldehyde dehydrogenase type 2 KO drug cues and positive and negative postingestive outcomes, and alcohol consumption and acetaldehyde brain, blood, respectively, depending on the context. The ambiguous and liver levels). It is important to note here that the aversive nature of the associations between drug-related cues and effects of drugs are impacted by a variety of other factors these consequences suggests that additional signals must be used to predict when taking the drug will produce rewarding such as sex [177], drug history [219], and age [269, 270], and the impact of these factors on drug use and abuse has outcomes and when the drug will produce nonrewarding or only recently been explored in this context. It will be critical even aversive effects, leading to an end in the bout of drug in such analyses that the impact of their effects be explored intake. We are suggesting that regulatory control of drug not only on the initial use of various drugs of abuse (i.e., intake is dependent in part on the ability of contextual drug reflecting the drug’s initial acceptability) but also on how states to disambiguate conflicting associations between drug these factors impact the likelihood of drug escalation and cues and postingestion outcomes. In this framework, choice as well as relapse of extinguished drug response (rein- although the initiation of drug-taking depends on the activa- statement) (for an example of such assessments on the com- tion of excitatory associations that predict rewarding effects, plexity of drug-taking, see [271]). contextual stimuli suppress intake by activating the inhibi- tory associations between the same drug cues associated with nonrewarding or aversive postingestive outcomes. Dysregu- 13. Drug Regulation lated intake, in turn, may be a function of poor control by Although the aversive effects of a drug on its subsequent these drug state cues that would produce an imbalance that intake have primarily been discussed as a limiting or protect- favors the excitatory associations, leading to overconsump- tion (see evidence by [282–284] for the role of similar pro- ing factor (see [20, 141, 236]), these effects may also be important to the regulation of normal intake or dysregula- cesses involved in the regulation/dysregulation of food intake). tion of intake that transitions drug use to drug abuse. This possibility has recently been suggested by our laboratory in Although the processes of cognitive inhibition described discussions on the role of drug states in regulated drug above have primarily been implicated in the regulation of food intake, the imbalance between inhibitory and excitatory intake [272, 273]. A principal feature of drug addiction is 16 Behavioural Neurology suppress the retrieval of memories of rewarding outcomes control mechanisms may also explain why some people progress from regulated to dysregulated drug use. Given free [298–300]. Hippocampal damage has been shown to impair drug access, animals learn to regulate drug intake to achieve the ability of humans [301–303] and rats [304, 305] to dis- criminate interoceptive satiety cues from hunger and to sup- a particular level of intoxication by titrating drug levels within the brain and bloodstream [15]. Characteristics of press food-reinforced conditioned response maintained drug self-administration indicate that drug or overconsumption. Rats with impaired hippocampal- drug-associated stimuli encountered by an animal in a dependent inhibitory control showed greater intake and drug-free state will initiate drug intake, but when the drug meal frequency within a shorter interval [306–308] and greater weight gain within weeks [309] or months [310]. level reaches above a satiety threshold, i.e., the minimal drug level at which self-administration is maintained, animals Specific to the issue of drug intake, we suggest that neu- temporarily suspend drug seeking [15, 280]. Consistent with roadaptations resulting from chronic drug use disrupt the this position, the presence or absence of a drug in the biolog- ability of the hippocampus to mediate inhibitory control ical system has been demonstrated to serve discriminative over responses to drug-related cues. In this context, hippo- campal impairments have been implicated to modulate the functions that signal the availability of certain reinforcers, e.g., food and water [285–288]. Not only can drugs serve as transition from regulated to dysregulated drug intake. In discriminative stimuli in general but also the discriminative chronic drug users, various drugs of abuse have been control of the training drug can also be generalized to drugs reported to impair the functional integrity of the hippocam- with comparable mechanisms of action [289–292]. pus and interfere with learning and memory [311, 312]. Hip- pocampal lesions have also been demonstrated to increase We [293] and others [294–297] have extended the anal- ysis on drug discrimination learning to show that interocep- the oral consumption of alcohol and the intravenous self- tive drug cues can also signal the presence and absence of an administration of cocaine, methamphetamine, morphine, aversive outcome using a modified conditioned taste aver- and nicotine in rodents [313–316]. Furthermore, we have sion design (for a review of the conditioned taste aversion recently reported that chronic administration of cocaine interfered with the ability of rats to solve a hippocampal- baseline of drug discrimination learning, see [272]). In one demonstration, rats received PCP followed by a pairing of dependent discriminative task known as the serial feature saccharin with the emetic LiCl on the conditioning day, negative (sFN) discrimination that requires the animals to use contextual signals to disambiguate postingestive out- and on the subsequent 3 days, the same animals received the PCP vehicle followed by paring of saccharin with the comes [317]. Interestingly, chronic administration of cocaine in the same animals had no effect on simple discrim- LiCl vehicle. Over multiple trials, animals avoided consum- ing saccharin when it was preceded by PCP and consumed ination problem that does not require a functional hippo- saccharin when it was preceded by the PCP vehicle. The campus, indicating that the type of learning and memory processes required to resolve approach-avoidance conflict control group that received the same PCP/vehicle injections prior to saccharin, but never the postsaccharin injection of in the sFN discrimination task does not rely on nonspecific factors (e.g., motivation and attention) but a higher-level LiCl, consumed high levels of saccharin throughout the study, indicating that the suppressed saccharin consumption regulatory mechanism dependent on the hippocampus to in the LiCl-treated group was a function of PCP signalling disambiguate conflicting associations. Taken together, these data highlight the fact that the hip- the saccharin-LiCl contingency rather than an uncondi- tioned suppression on saccharin consumption [293] (for pocampus is critically involved in regulating consummatory behaviors and that chronic drug use uniquely targets related work with morphine, see [295, 297]). To date, accumulating evidence that a wide range of hippocampal-dependent forms of learning and memories. drugs can serve such a discriminative function provides clear If chronic drug use disrupts the hippocampal function to modulate the ability of interoceptive cues of drug satiety to support for the ability of drug stimuli to modulate consum- matory behavior by signalling postingestive outcomes. Simi- engage inhibitory associations, then chronic drug exposure lar to the function of satiety cues in food intake regulation, might reduce the power of drug satiety cues to inhibit intake. discriminative learning may be important in regulating drug In support of this idea, future studies in drug addiction intake. Humans and other animals might use interoceptive should not be limited to reward- and motivation-based models; rather, future research should also explore a model drug signals to determine when a sufficient drug level has been achieved and whether to continue or refrain from con- predicated upon hippocampal functioning underlying regu- tinued or elevated consumption (see [13] for a discussion of lated drug use that could potentially contribute to prevent- the possible role of the inability to detect such stimulus ing the transition to dysregulated drug use and effects in alcoholics). Such an evaluation of drugs and conse- pathological state of drug abuse. quences of intake is governed by prior learning of various consequences of drug use. Further, memory processes repre- 14. Conclusions sent associations between drug-taking contexts, drug cues, and the consequences of drug-taking acquired over a In this review, we have discussed drug use and abuse in the repeated experience that strongly influence the cognitive context of a reward model and have qualified this analysis by inhibition of drug intake. A rich literature has demonstrated arguing that drugs of abuse have multiple stimulus proper- that the hippocampus modulates the capacity of any contex- ties (both rewarding and aversive) that need to be considered tual or discrete cues to activate inhibitory associations to in any account of drug-taking behavior. We provided Behavioural Neurology 17 [6] G. F. Koob, “The dark side of emotion: the addiction perspec- evidence that drugs have aversive effects (from both clinical tive,” European Journal of Pharmacology, vol. 753, pp. 73–87, and preclinical populations) and have introduced and dis- cussed these effects in their historical context (generated by [7] G. F. Koob and N. D. Volkow, “Neurobiology of addiction: a work on conditioned taste aversions). We indicate that the neurocircuitry analysis,” The Lancet Psychiatry, vol. 3, aversive effects can occur concurrent with rewarding ones pp. 760–773, 2016. in the same subject trained and tested under identical condi- [8] J. S. Meyer and L. F. Quenzer, Psychopharmacology: Drugs, tions and that their relative balance is important to the use the Brain, and Behavior, Sinauer Associates, Inc, Sunderland, and/or abuse of the drug. While both rewarding and aversive MA, 2nd edition, 2018. effects occur, we describe reports indicating that these effects [9] E. C. O’Connor, K. Chapman, P. Butler, and A. N. Mead, appear dissociable, suggesting that manipulations can “The predictive validity of the rat self-administration model impact them differently. We further suggest that an aware- for abuse liability,” Neuroscience & Biobehavioral Reviews, ness of each affective property and the multiple parametric, vol. 35, pp. 912–938, 2011. experiential, and subject factors that impact them and their [10] B. Kuhn, P. Kalivas, and A. C. Bobadilla, “Understanding relative balance will give insight into use and abuse vulnera- addiction using animal models,” Frontiers in Behavioral Neu- bility (for example, see [177]). Data supporting such a posi- roscience, vol. 13, pp. 1–24, 2019. tion were provided by an overview of the relationship [11] M. A. Smith, “Nonhuman animal models of substance use between initial and subsequent drug use (in humans) and a disorders: translational value and utility to basic science,” more detailed analysis of the inverse relationship between Drug and Alcohol Dependence, vol. 206, article 107733, 2020. perceived aversive effects of drugs and their intake. We close [12] Y. Swain, J. C. Gewirtz, and A. C. Harris, “Behavioral predic- our review by noting that the interaction of reward and aver- tors of individual differences in opioid addiction vulnerability sion may also be involved within bouts of drug intake as the as measures using i.v. self-administration in rats,” Drug and ability to use the drug state itself to set the occasion for aver- Alcohol Dependence, vol. 221, article 108561, 2021. sive effects that may accompany elevated use. We conclude [13] H. De Wit and T. J. Phillips, “Do initial responses to drugs from these issues that examining a drug’s aversive effects predict future use or abuse?,” Neuroscience & Biobehavioral (in addition to the myriad of other stimulus effects pro- Reviews, vol. 36, pp. 1565–1576, 2012. duced) is critical to understanding drug intake and develop- [14] A. Goldstein, Addiction: From Biology to Drug Policy, Oxford ing prevention and treatment strategies associated with the University Press, Inc, New York, NY, 2nd edition, 2001. transition from use to abuse. [15] W. J. Lynch and M. E. Carroll, “Regulation of drug intake,” Experimental and Clinical Psychopharmacology, vol. 9, pp. 131–143, 2001. Conflicts of Interest [16] J. R. DiFranza, J. A. Savageau, K. Fletcher et al., “Susceptibility to nicotine dependence: the development and assessment of The authors declare that they have no conflicts of interest. nicotine dependence in youth 2 study,” Pediatrics, vol. 120, pp. e974–e983, 2007. Acknowledgments [17] J. R. DiFranza, J. A. Savageau, K. Fletcher, J. K. Ockene, and N. A. Rigott, “Recollections and repercussions of the first The present work described was funded by grants from the inhaled cigarette,” Addictive Behaviors, vol. 29, no. 2, Mellon Foundation (ALR). pp. 261–272, 2004. [18] J. R. DiFranza, J. A. Savageau, N. A. Rigotti et al., “Trait anx- iety and nicotine dependence in adolescents: a report from References the DANDY study,” Addictive Behaviors, vol. 29, pp. 911– 919, 2004. [1] L. D. Johnston, R. A. Miech, P. M. O’Malley, J. G. Bachman, [19] L. Lasagna, J. M. von Felsinger, and H. K. Beecher, “Drug- J. E. Schulenberg, and M. E. Patrick, Monitoring the Future induced mood changes in man. I. Observations on healthy National Survey Results on Drug Use, 1975-2020, Institute subjects, chronically ill patients, and postaddicts,” Journal of for Social Research, The University of Michigan, Michigan, the American Medical Association, vol. 157, pp. 1006–1020, USA, 2021. [2] Substance Abuse and Mental Health Services Administration [20] A. Verendeev and A. L. Riley, “Conditioned taste aversion [SAMHSA], Key substance use and mental health indicators and drugs of abuse: history and interpretation,” Neuroscience in the United States: results from the 2020 National Survey & Biobehavioral Reviews, vol. 36, pp. 2193–2205, 2012. on Drug Use and Health, Center for Behavioral Health Statis- tics and Quality, Substance Abuse and Mental Health Ser- [21] S. J. Kohut and A. L. Riley, “Conditioned taste aversions and the vices Administration, Rockville, MD, 2021. assessment of the aversive effects of drugs: implications for drug [3] United Nations Office on Drugs and Crime (UNODC), use and abuse,” in Encyclopedia of Psychopharmacology,I. P. Stolerman, Ed., Springer Verlag, Berlin, Germany, 2010. World Drug Report 2021, United Nations Publication, 2021, Sales No. E.21.XI.8. [22] R. F. Suddendorf, “Research on alcohol metabolism among [4] N. D. Volkow, G. F. Koob, and A. T. McLellan, “Neurobiolo- Asians and its implications for understanding causes of alco- holism,” Public Health Reports, vol. 104, pp. 615–620, 1989. gic advances from the brain disease model of addiction,” New England Journal of Medicine, vol. 374, pp. 363–371, 2016. [23] C. Cannizzaro, F. Plescia, and S. Cacace, “Role of acetalde- [5] G. F. Koob, M. A. Arends, and M. Le Moal, Drugs, Addiction hyde in alcohol addiction: current evidence and future per- and the Brain, Academic Press, Waltham, MA, 2014. spectives,” Malta Medical Journal, vol. 23, pp. 27–31, 2011. 18 Behavioural Neurology [42] R. C. MacPhail, “Studies on the flavor aversions induced by [24] T. B. Baker and D. S. Cannon, “Alcohol and taste-mediated learning,” Addictive Behaviors, vol. 7, pp. 211–230, 1982. trialkyltin compounds,” Neurobehavioral Toxicology & Tera- tology, vol. 4, pp. 225–230, 1982. [25] A. W. Logue, K. R. Logue, and K. E. Strauss, “The acquisition of taste aversions in humans with eating and drinking disor- [43] A. L. Riley, R. J. Dacanay, and J. P. Mastropaolo, “The effects ders,” Behaviour Research and Therapy, vol. 21, pp. 275–289, of trimethyltin chloride on the acquisition of long delay con- 1983. ditioned taste aversion learning in the rats,” Neurotoxicology, vol. 5, pp. 291–295, 1984. [26] F. Lemere and W. L. Voegtlin, “Conditioned reflex therapy of alcoholic addiction: specificity of conditioning against [44] M. J. Kallman, M. R. Lynch, and M. R. Landauer, “Taste aver- chronic alcoholism,” California and Western Medicine, sions to several halogenated hydrocarbons,” Neurobehavioral vol. 53, pp. 268-269, 1940. Toxicology and Teratology, vol. 5, pp. 23–27, 1983. [27] W. L. Voegtlin, “The treatment of alcoholism by establishing [45] L. K. Nicolaus, “Conditioned aversions in a guild of egg preda- a conditioned reflex,” American Journal of the Medical Sci- tors: implications for aposematism and prey defense mimicry,” ences, vol. 199, pp. 802–809, 1940. American Midland Naturalist, vol. 117, pp. 405–419, 1987. [28] W. L. Voegtlin, F. Lemere, W. R. Broz, and P. O’Hollaren, [46] P. O. Sjödén and T. Archer, “Conditioned taste aversion to “Conditioned reflex therapy of chronic alcoholism; IV. A pre- saccharin induced by 2,4,5-trichlorophenoxyacetic acid in liminary report on the value of reinforcement,” Quarterly albino rats,” Physiology & Behavior, vol. 19, no. 1, pp. 159– Journal of Studies on Alcohol, vol. 2, pp. 505–511, 1941. 161, 1977. [29] R. L. Elkins, “An appraisal of chemical aversion (emetic ther- [47] S. Mahiout and R. Pohjanvirta, “Aryl hydrocarbon receptor apy) approaches to alcoholism treatment,” Behaviour agonists trigger avoidance of novel food in rats,” Physiology Research and Therapy, vol. 29, pp. 387–413, 1991. & Behavior, vol. 167, pp. 49–59, 2016. [30] S. H. Revusky, “Chemical aversion treatment of alcoholism,” [48] Z. W. Brown, Z. Amit, B. Smith, and G. E. Rockman, “Differ- in Conditioned Taste Aversion: Behavioral and Neural Pro- ential effects on conditioned taste aversion learning with cesses, S. Reilly and T. R. Schactman, Eds., pp. 445–472, peripherally and centrally administered acetaldehyde,” Neu- Oxford University Press, New York, NY, 2009. ropharmacology, vol. 17, pp. 931–935, 1978. [31] A. L. Riley and D. L. Tuck, “Conditioned taste aversions: a [49] A. Ungerer, D. Marchi, P. Ropartz, and J.-H. Weil, “Aversive behavioral index of toxicity,” Annals of the New York Acad- effects and retention impairment induced by acetoxycyclo- emy of Sciences, vol. 5, pp. 272–292, 1985. heximide in an instrumental task,” Physiology & Behavior, vol. 15, pp. 55–62, 1975. [32] J. Rzóska, “Bait shyness, a study in rat behavior,” The British Journal of Animal Behaviour, vol. 1, pp. 128–135, 1954. [50] C. E. Anderson, H. A. Tilson, and C. L. Mitchell, “Condi- [33] J. Garcia, D. J. Kimeldorf, and R. A. Koelling, “Conditioned tioned taste aversion following acutely administered acrylam- ide,” Neurobehavioral Toxicology & Teratology, vol. 4, aversion to saccharin resulting from exposure to gamma radi- pp. 497–499, 1982. ation,” Science, vol. 122, pp. 157-158, 1955. [51] I. L. Bernstein, M. V. Vitiello, and R. A. Sigmundi, “Effects of [34] K. B. Freeman and A. Riley, “The origins of conditioned taste tumor growth on taste-aversion learning produced by antitu- aversion learning: a historical analysis,” in Conditioned Taste mor drugs in the rat,” Physiological Psychology, vol. 8, pp. 51– Aversion: Behavioral and Neural Processes, S. Reilly and T. R. Schactman, Eds., pp. 9–33, Oxford University Press, New 55, 1980. York, NY, 2009. [52] V. A. Rappold, J. H. Porter, and G. C. Llewellyn, “Evaluation [35] J. Rzóska, “Stomach analysis of brown rats poisoned in the of the toxic effects of aflatoxin B with a taste aversion para- digm in rats,” Neurobehavioral Toxicology and Teratology, field,” in Control of Rats and Mice, D. Chitty, Ed., pp. 395– 413, Clarendon Press, Oxford, England, 1954. vol. 6, pp. 51–58, 1984. [53] K. H. Brookshire, C. N. Stewart, and H. N. Bhagavan, “Sac- [36] J. Garcia, F. R. Ervin, and R. A. Koelling, “Learning with pro- charin aversion in alloxan-diabetic rats,” Journal of Compar- longed delay of reinforcement,” Psychonomic Science, vol. 5, ative and Physiological Psychology, vol. 79, pp. 385–393, 1972. pp. 121-122, 1966. [54] M. G. Hotchkiss, D. S. Best, R. L. Cooper, and S. C. Laws, [37] J. Garcia and R. A. Koelling, “Relation of cue to consequence in avoidance learning,” Psychonomic Science, vol. 4, pp. 123- “Atrazine does not induce pica behavior at doses that increase hypothalamic–pituitary–adrenal axis activation and cause 124, 1966. conditioned taste avoidance,” Neurotoxicology and Teratol- [38] J. Garcia and F. R. Ervin, “Gustatory-visceral and ogy, vol. 34, pp. 295–302, 2012. telereceptor-cutaneous conditioning—adaptation in internal and external milieus,” Communications in Behavioral Biol- [55] W. Ebeling, “The cockroach learns to avoid insecticides,” Cal- ifornia Agriculture, vol. 23, pp. 12–15, 1969. ogy, vol. 1, pp. 389–415, 1968. [39] S. Revusky and J. Garcia, “Learned associations over long [56] G. Ward-Fear, D. J. Pearson, G. P. Brown, B. Rangers, and delays,” in Psychology of Learning and Motivation: Advances R. Shine, “Ecological immunization: in situ training of free- in Research and Theory, G. H. Bower and J. T. Spence, Eds., ranging predatory lizards reduces their vulnerability to inva- sive toxic prey,” Biology Letters, vol. 12, 2017. pp. 1–84, Academic Press, Cambridge, MA, 1970. [40] P. Rozin and J. W. Kalat, “Specific hungers and poison avoid- [57] P. J. Wellman, P. A. Watkins, J. R. Nation, and D. E. Clark, ance as adaptive specializations of learning,” Psychological “Conditioned taste aversion in the adult rat induced by die- Review, vol. 78, pp. 459–486, 1971. tary ingestion of cadmium or cobalt,” Neurotoxicology, vol. 5, pp. 81–90, 1984. [41] M. Nachman and P. L. Hartley, “Role of illness in producing learned taste aversions in rats: a comparison of several roden- [58] R. C. MacPhail and D. J. Leander, “Flavor aversion induced ticides,” Journal of Comparative and Physiological Psychology, by chlordimeform,” Neurobehavioral Toxicology, vol. 2, vol. 89, pp. 1010–1018, 1975. pp. 363–365, 1980. Behavioural Neurology 19 [76] T. E. Levine, “Conditioned aversion following ingestion of [59] M. R. Landauer, T. W. Tomlinson, R. L. Balster, and R. C. MacPhail, “Some effects of the formamidine pesticide chlor- methylmercury in rats and mice,” Behavioral Biology, dimeform on the behavior of mice,” Neurotoxicology, vol. 5, vol. 22, pp. 489–496, 1978. pp. 91–100, 1984. [77] R. J. Mason and R. F. Reidinger, “Observational learning of food aversions in red-winged blackbirds (Agelaius phoeni- [60] S. Revusky and S. Reilly, “Attenuation of conditioned taste ceus),” The Auk, vol. 99, pp. 548–554, 1982. aversions by external stressors,” Pharmacology Biochemistry and Behavior, vol. 33, pp. 219–226, 1989. [78] J. R. Millner and T. Palfai, “Metrazol impairs conditioned aversion produced by LiCl: a time dependent effect,” Phar- [61] O. Buresová and J. Bures, “Conditioned taste aversion macology Biochemistry and Behavior, vol. 3, pp. 201–204, induced in rats by intracerebral or systemic administration of monoamine oxidase inhibitors,” Psychopharmacology, vol. 91, pp. 209–212, 1987. [79] C. R. Gustavson, G. A. Holzer, J. C. Gustavson, and D. L. Vakoch, “An evaluation of phenol methylcarbamates as taste [62] S. Islam, “Snake neurotoxins and conditioned taste aversion aversion producing agents in caged blackbirds,” Applied Ani- in mice,” International Journal of Neuroscience, vol. 11, mal Ethology, vol. 8, pp. 551–559, 1982. pp. 41–43, 1980. [80] M. Nachman, D. Lester, and J. L. Magnen, “Alcohol aversion [63] C. E. O’Connor and L. R. Matthews, “Cyanide induced aver- in the rat: behavioral assessment of noxious drug effects,” Sci- sions in the possum (Trichosurus vulpecula): effect of route of ence, vol. 168, pp. 1244–1246, 1970. administration, dose, and formulation,” Physiology & Behav- ior, vol. 58, pp. 265–271, 1995. [81] T. Archer, A. K. Mohammed, and T. U. C. Jarbe, “Latent inhi- bition following systemic DSP4: effects due to presence and [64] D. A. Booth and P. C. Simson, “Aversion to a cue acquired by absence of contextual cues in taste-aversion learning,” Behav- its association with effects of an antibiotic in the rat,” Journal ioral and Neural Biology, vol. 38, pp. 287–306, 1983. of Comparative and Physiological Psychology, vol. 2, pp. 319– 323, 1973. [82] D. E. Clark and P. J. Wellman, “Conditioned saccharin taste aversion induced by mycotoxins in rats: lack of effect of och- [65] W. Dragoin, G. E. McCleary, and P. McCleary, “A compari- ratoxin A,” Pharmacology Biochemistry and Behavior, vol. 32, son of two methods of measuring conditioned taste aver- pp. 819–821, 1989. sions,” Behavior Research Methods & Instrumentation, [83] R. C. MacPhail and D. B. Peele, “Animal models for assessing vol. 3, pp. 309-310, 1971. the neurobehavioral impact of airborne pollutants,” Annals of [66] S. Revusky and G. M. Martin, “Glucocorticoids attenuate the New York Academy of Sciences, vol. 30, pp. 294–303, 1992. taste aversions produced by toxins in rats,” Psychopharmacol- [84] M. S. Dey, R. I. Krieger, and R. C. Ritter, “Paraquat-induced, ogy, vol. 96, pp. 400–407, 1988. dose-dependent conditioned taste aversions and weight loss [67] A. El Hani, R. J. Mason, D. L. Nolte, and R. H. Schmidt, “Fla- mediated by the area postrema,” Toxicology and Applied vor avoidance learning and its implications in reducing Pharmacology, vol. 87, pp. 212–221, 1987. strychnine baiting hazards to nontarget animals,” Physiology [85] S. J. St. John, L. Pour, and J. D. Boughter, “Phenylthiocarba- & Behavior, vol. 64, pp. 585–589, 1998. mide produces conditioned taste aversions in mice,” Chemi- [68] D. S. Cannon and T. B. Baker, “Emetic and electric shock cal Senses, vol. 30, pp. 377–382, 2005. alcohol aversion therapy: assessment of conditioning,” Jour- [86] J. A. Chester and C. L. Cunningham, “Baclofen alters ethanol- nal of Consulting and Clinical Psychology, vol. 49, pp. 20– stimulated activity but not conditioned place preference or 33, 1981. taste aversion in mice,” Pharmacology Biochemistry and [69] M. Irie, S. Asami, S. Nagata, M. Miyata, and H. Kasai, “Clas- Behavior, vol. 63, pp. 325–331, 1999. sical conditioning of oxidative DNA damage in rats,” Neuro- [87] M. R. Landauer and J. A. Romano, “Acute behavioral toxicity science Letters, vol. 288, pp. 13–16, 2000. of the organophosphate sarin in rats,” Neurobehavioral Tox- [70] E. M. Stricker and N. E. Wilson, “Salt-seeking behavior in rats icology & Teratology, vol. 6, pp. 239–243, 1984. following acute sodium deficiency,” Journal of Comparative [88] J. A. Romano, J. M. King, and D. M. Penetar, “A comparison and Physiological Psychology, vol. 72, pp. 416–420, 1970. of physostigmine and soman using taste aversion and noci- [71] J. A. Rudd, M. P. Ngan, and M. K. Wai, “5-HT receptors are ception,” Neurobehavioral Toxicology & Teratology, vol. 7, not involved in conditioned taste aversions induced by 5- pp. 243–249, 1985. hydroxytryptamine, ipecacuanha or cisplatin,” European [89] A. W. Kusnecov, R. Liang, and G. Shurin, “T-lymphocyte Journal of Pharmacology, vol. 352, pp. 143–149, 1998. activation increases hypothalamic and amygdaloid expres- [72] J. D. Leander and B. A. Gau, “Flavor aversions rapidly pro- sion of CRH mRNA and emotional reactivity to novelty,” duced by inorganic lead and triethyltin,” Neurotoxicology, Journal of Neuroscience, vol. 11, pp. 4533–4543, 1999. vol. 1, pp. 635–642, 1980. [90] W. E. Howard, S. D. Palmateer, and M. Nachman, “Aversion [73] M. S. Exton, D. F. Bull, M. G. King, and A. J. Husband, “Par- to strychnine sulfate by Norway rats, roof rats, and pocket adoxical conditioning of the plasma copper and corticoste- gophers,” Toxicology and Applied Pharmacology, vol. 12, rone responses to bacterial endotoxin,” Pharmacology pp. 229–241, 1968. Biochemistry and Behavior, vol. 52, pp. 347–354, 1995. [91] P. J. Wellman, L. D. Rowe, D. E. Clark, and R. D. Cockroft, [74] S. B. Klein, M. J. Barter, A. L. Murphy, and J. H. Richardson, “Effects of T-2 toxin on saccharin aversion and food con- “Aversion to low doses of mercuric chloride in rats,” Physio- sumption in adult rats,” Physiology & Behavior, vol. 45, logical Psychology, vol. 2, pp. 397–400, 1974. pp. 501–506, 1989. [75] M. Miyagawa, “Conditioned taste aversion induced by inha- [92] C. R. Gustavson, J. C. Gustavson, and G. A. Holzer, “Thiaben- lation exposure to methyl bromide in rats,” Toxicology Let- dazole-based taste aversions in dingoes (Canis familiaris ters, vol. 10, no. 4, pp. 411–416, 1982. dingo) and new guinea wild dogs (Canis familiaris 20 Behavioural Neurology [108] J. R. Vogel and B. A. Nathan, “Learned taste aversions hallstromi),” Applied Animal Ethology, vol. 10, pp. 385–388, 1983. induced by hypnotic drugs,” Pharmacology Biochemistry and Behavior, vol. 3, pp. 189–194, 1975. [93] J. Tobajas, P. Gómez-Ramírez, P. María-Mojica et al., “Selec- tion of new chemicals to be used in conditioned aversion for [109] B. D. Berger, “Conditioning of food aversions by injections of non-lethal predation control,” Behavioural Processes, psychoactive drugs,” Journal of Comparative and Physiologi- vol. 166, article 103905, 2019. cal Psychology, vol. 81, pp. 21–26, 1972. [94] L. E. Goehler, C. R. Busch, N. Tartaglia et al., “Blockade of [110] F. B. Jolicoeur, D. B. Rondeau, M. J. Wayner, R. B. Mintz, and cytokine induced conditioned taste aversion by subdiaphrag- A. D. Merkel, “Barbiturates and alcohol consumption,” Bio- matic vagotomy: further evidence for vagal mediation of behavioral Reviews, vol. 1, pp. 177–196, 1977. immune-brain communication,” Neuroscience Letters, [111] G. Dickens and W. H. Trethowan, “Cravings and aversions vol. 185, no. 163, p. 166, 1995. during pregnancy,” Journal of Psychosomatic Research, [95] R. L. Balster and J. F. Borzelleca, “Behavioral toxicity of tri- vol. 15, pp. 259–268, 1971. halomethane contaminants of drinking water in mice,” Envi- [112] A. J. Goudie and T. Newton, “The puzzle of drug-induced ronmental Health Perspectives, vol. 46, pp. 127–136, 1982. conditioned taste aversion: comparative studies with cathi- [96] M. Miyagawa, T. Honma, M. Sato, and H. Hasegawa, “Condi- none and amphetamine,” Psychopharmacology, vol. 87, tioned taste aversion induced by toluene administration in pp. 328–333, 1985. rats,” Neurobehavioral Toxicology and Teratology, vol. 6, [113] M. E. Corcoran, I. Bolotow, Z. Amit, and J. A. McCaughran pp. 33–37, 1984. Jr., “Conditioned taste aversions produced by active and inac- [97] D. E. Clark, P. J. Wellman, R. B. Harvey, and M. S. Lerma, tive cannabinoids,” Pharmacology Biochemistry and Behav- “Effects of vomitoxin (deoxynivalenol) on conditioned saccha- ior, vol. 2, pp. 725–728, 1974. rin aversion and food consumption in adult rats,” Pharmacol- [114] A. J. Goudie, D. W. Dickins, and E. W. Thornton, “Cocaine- ogy Biochemistry and Behavior,vol. 27,pp.247–252, 1987. induced conditioned taste aversions in rats,” Pharmacology [98] S. E. Baker, S. A. Ellwood, R. W. Watkins, and D. W. Mac- Biochemistry and Behavior, vol. 8, pp. 757–761, 1978. donald, “A dose-response trial with ziram-treated maize [115] I. S. McGregor, C. N. Issakidis, and G. Prior, “Aversive effects and free-ranging European badgers Meles meles,” Applied of the synthetic cannabinoid CP 55,940 in rats,” Pharmacol- Animal Behaviour Science, vol. 93, pp. 309–321, 2005. ogy Biochemistry and Behavior, vol. 53, pp. 657–664, 1996. [99] J. K. Gore-Langton, S. M. Flax, R. L. Pomfrey, B. B. Wetzell, [116] G. D. Busse, A. Verendeev, J. Jones, and A. L. Riley, “The and A. L. Riley, “Measures of the aversive effects of drugs: a effects of cocaine, alcohol and cocaine/alcohol combinations comparison of conditioned taste and place aversions,” Phar- in conditioned taste aversion learning,” Pharmacology Bio- macology Biochemistry and Behavior, vol. 134, pp. 99–105, chemistry and Behavior, vol. 82, pp. 207–214, 2005. [117] P. S. Grigson, R. C. Twining, and R. M. Carelli, “Heroin- [100] D. Lester, M. Nachman, and J. Le Magnen, “Aversive condi- induced suppression of saccharin intake in water-deprived tioning by ethanol in the rat,” Quarterly Journal of Studies and water-replete rats,” Pharmacology Biochemistry and on Alcohol, vol. 31, pp. 578–586, 1970. Behavior, vol. 66, pp. 603–608, 2000. [101] H. Cappell and A. E. LeBlanc, “Conditioned aversion to sac- [118] A. L. Riley, K. H. Nelson, M. E. Crissman, and K. A. Pesca- charin by single administrations of mescaline and d-amphet- tore, “Conditioned taste avoidance induced by the combina- amine,” Psychopharmacologia, vol. 22, pp. 352–356, 1971. tion of heroin and cocaine: implications for the use of [102] H. Cappell, A. E. LeBlanc, and L. Endrenyi, “Aversive condi- speedball,” Pharmacology Biochemistry and Behavior, tioning by psychoactive drugs: effects of morphine, alcohol vol. 187, article 172801, 2019. and chlordiazepoxide,” Psychopharmacologia, vol. 29, [119] F. Etscorn and P. Parson, “Taste aversion in mice using phen- pp. 239–246, 1973. cyclidine and ketamine as the aversive agents,” Bulletin of the [103] M. A. Bozarth, Methods of Assessing the Reinforcing Proper- Psychonomic Society, vol. 14, pp. 19–21, 1979. ties of Abused Drugs, Springer-Verlag, New York, NY, 1987. [120] R. J. Carey and E. B. Goodall, “Amphetamine-induced taste [104] K. H. Nelson, B. J. Hempel, M. M. Clasen, K. C. Rice, and aversion: a comparison of d-versus l-amphetamine,” Phar- A. L. Riley, “Conditioned taste avoidance, conditioned place macology Biochemistry and Behavior, vol. 2, pp. 325–330, preference and hyperthermia induced by the second genera- tion ‘bath salt’ α-pyrrolidinopentiophenone (α-PVP),” Phar- [121] L. A. Parker, “LSD produces place preference and flavor macology Biochemistry and Behavior, vol. 156, pp. 48–55, avoidance but does not produce flavor aversion in rats,” Behavioral Neuroscience, vol. 110, pp. 503–508, 1996. [105] T. F. Elsmore and G. V. Fletcher, “Δ -Tetrahydrocannabinol: [122] J. C. Martin and E. H. Ellinwood, “Conditioned aversion to a aversive effects in rat at high doses,” Science, vol. 175, pp. 911- preferred solution following methamphetamine injections,” 912, 1972. Psychopharmacologia, vol. 29, pp. 253–261, 1973. [106] H. Q. Lin, D. M. Atrens, M. J. Christie, D. M. Jackson, and [123] H. N. Manke, K. H. Nelson, A. Vlachos et al., “Assessment of I. S. McGregor, “Comparison of conditioned taste aversions aversive effects of methylone in male and female Sprague- produced by MDMA and d-amphetamine,” Pharmacology Dawley rats: conditioned taste avoidance, body temperature Biochemistry and Behavior, vol. 46, pp. 153–156, 1993. and activity/stereotypies,” Neurotoxicology and Teratology, [107] H. E. King, B. Wetzell, K. C. Rice, and A. L. Riley, “3, 4- vol. 86, article 106977, 2021. Methylenedioxypyrovalerone (MDPV)-induced conditioned [124] A. L. Riley and D. A. Zellner, “Methylphenidate-induced con- taste avoidance in the F344/N and LEW rat strains,” Pharma- ditioned taste aversions: an index of toxicity,” Physiological cology Biochemistry and Behavior, vol. 126, pp. 163–169, Psychology, vol. 6, pp. 354–358, 1978. 2014. Behavioural Neurology 21 administration in rats,” Psychopharmacology, vol. 232, [125] F. Etscorn, “Sucrose aversions in mice as a result of injected nicotine or passive tobacco smoke inhalation,” Bulletin of pp. 2363–2375, 2015. the Psychonomic Society, vol. 15, pp. 54–56, 1980. [142] A. Ettenberg, M. A. Raven, D. A. Danluck, and B. D. Neces- [126] O. Burešová and J. Bureš, “Post-ingestion interference with sary, “Evidence for opponent-process actions of intravenous brain function prevents attenuation of neophobia in rats,” cocaine,” Pharmacology Biochemistry and Behavior, vol. 64, Behavioural Brain Research, vol. 1, pp. 299–312, 1980. pp. 507–512, 1999. [127] H. Cappell and A. E. LeBlanc, “Gustatory avoidance condi- [143] M. A. Reicher and E. W. Holman, “Location preference and tioning by drugs of abuse,” in Food aversion learning,N. W. flavor aversion reinforced by amphetamine in rats,” Animal Milgram, L. Krames, and T. M. Alloway, Eds., pp. 133–167, Learning & Behavior, vol. 5, pp. 343–346, 1977. Springer, Boston, MA, 1977. [144] H. E. King, A. Wakeford, W. Taylor, B. Wetzell, K. C. Rice, [128] E. Gamzu, “The multifaceted nature of taste aversion induc- and A. L. Riley, “Sex differences in 3,4-methylenedioxypyro- ing agents: is there a single common factor?,” in Learning valerone (MDPV)-induced taste avoidance and place prefer- Mechanisms in Food Selection, L. Barker, M. Best, and M. ences,” Pharmacology Biochemistry and Behavior, vol. 137, Domjan, Eds., pp. 477–510, Baylor University Press, Waco, pp. 16–22, 2015. TX, 1977. [145] K. H. Nelson, H. N. Manke, A. Imanalieva, K. C. Rice, and [129] W. J. McBride, J. M. Murphy, and S. Ikemoto, “Localization A. L. Riley, “Sex differences in α-pyrrolidinopentiophenone of brain reinforcement mechanisms: Intracranial self- (α-PVP)-induced taste avoidance, place preference, hyper- administration and intracranial place-conditioning studies,” thermia and locomotor activity in rats,” Pharmacology Bio- Behavioural Brain Research, vol. 101, pp. 129–152, 1999. chemistry and Behavior, vol. 185, article 172762, 2019. [130] A. L. Riley and L. L. Baril, “Conditioned taste aversions: a bib- [146] K. H. Nelson, H. M. Manke, J. M. Bailey et al., “Ethanol pre- liography,” Animal Learning & Behavior, vol. 4, pp. 1S–13S, exposure differentially impacts the rewarding and aversive effects of α-pyrrolidinopentiophenone (α-PVP): implications [131] S. Klosterhalfen and W. Klosterhalfen, “Conditioned taste for drug use and abuse,” Pharmacology Biochemistry and Behavior, vol. 211, article 173286, 2021. aversion and traditional learning,” Psychological Research, vol. 47, no. 2, pp. 71–94, 1985. [147] C. A. Dannenhoffer and L. P. Spear, “Age differences in con- ditioned place preferences and taste aversions to nicotine,” [132] P. S. Grigson and R. C. Twining, “Cocaine-induced suppres- sion of saccharin intake: a model of drug-induced devalua- Developmental Psychobiology, vol. 58, pp. 660–666, 2016. tion of natural rewards,” Behavioral Neuroscience, vol. 116, [148] J. E. Sherman, T. Roberts, S. E. Roskam, and E. W. Holman, pp. 321–333, 2002. “Temporal properties of the rewarding and aversive effects [133] L. H. Sellings, G. Baharnouri, L. E. McQuade, and P. B. of amphetamine in rats,” Pharmacology Biochemistry and Clarke, “Rewarding and aversive effects of nicotine are segre- Behavior, vol. 13, pp. 597–599, 1980. gated within the nucleus accumbens,” European Journal of [149] Y. C. Wang, A. C. W. Huang, and S. Hsiao, “Paradoxical Neuroscience, vol. 28, pp. 342–352, 2008. simultaneous occurrence of amphetamine-induced condi- [134] R. C. Twining, M. Bolan, and P. S. Grigson, “Yoked delivery tioned taste aversion and conditioned place preference with of cocaine is aversive and protects against the motivation the same single drug injection: a new “pre-and post- for drug in rats,” Behavioral Neuroscience, vol. 123, association” experimental paradigm,” Pharmacology Bio- pp. 913–925, 2009. chemistry and Behavior, vol. 95, pp. 80–87, 2010. [135] A. M. Cason and P. S. Grigson, “Prior access to a sweet is [150] A. Verendeev and A. L. Riley, “Relationship between the more protective against cocaine self-administration in female rewarding and aversive effects of morphine and amphet- rats than in male rats,” Physiology & Behavior, vol. 112-113, amine in individual subjects,” Learning & Behavior, vol. 39, pp. 96–103, 2013. pp. 399–408, 2011. [136] R. M. Carelli and E. A. West, “When a good taste turns bad: [151] J. E. Sherman, C. Pickman, A. Rice, J. C. Liebeskind, and neural mechanisms underlying the emergence of negative E. W. Holman, “Rewarding and aversive effects of morphine: affect and associated natural reward devaluation by cocaine,” temporal and pharmacological properties,” Pharmacology Neuropharmacology, vol. 76, pp. 360–369, 2014. Biochemistry and Behavior, vol. 13, pp. 501–505, 1980. [137] R. Wise, P. Yokel, and H. De Wit, “Both positive reinforce- [152] G. R. Simpson and A. L. Riley, “Morphine preexposure facil- ment and conditioned aversion from amphetamine and from itates morphine place preference and attenuates morphine apomorphine in rats,” Science, vol. 191, pp. 1273-1274, 1976. taste aversion,” Pharmacology Biochemistry and Behavior, vol. 80, pp. 471–479, 2005. [138] A. Ettenberg and T. D. Geist, “Animal model for investigating the anxiogenic effects of self-administered cocaine,” Psycho- [153] H. E. King and A. L. Riley, “A history of morphine-induced pharmacology, vol. 103, pp. 455–461, 1991. taste aversion learning fails to affect morphine-induced place [139] A. Ettenberg and T. D. Geist, “Qualitative and quantitative preference conditioning in rats,” Learning & Behavior, vol. 41, pp. 433–442, 2013. differences in the operant runway behavior of rats working for cocaine and heroin reinforcement,” Pharmacology Bio- [154] G. C. Loney, C. P. King, and P. J. Meyer, “Systemic nicotine chemistry and Behavior, vol. 44, pp. 191–198, 1993. enhances opioid self-administration and modulates the for- [140] N. White, L. Sklar, and Z. Amit, “The reinforcing action of mation of opioid-associated memories partly through actions within the insular cortex,” Scientific Reports, vol. 11, pp. 1–13, morphine and its paradoxical side effect,” Psychopharmacol- ogy, vol. 52, pp. 63–66, 1977. 2021. [141] A. Ettenberg, V. Fomenko, K. Kaganovsky, K. Shelton, and [155] Y. C. Wang, W. C. Chiu, C. N. Cheng, C. Lee, and A. C. W. J. M. Wenzel, “On the positive and negative affective Huang, “Examination of neuroinflammatory cytokine responses to cocaine and their relation to drug self- interleukin-1 beta expression in the medial prefrontal cortex, 22 Behavioural Neurology [170] T. S. Shippenberg, C. H. Heidbreder, and A. Lefevour, “Sensi- amygdala, and hippocampus for the paradoxical effects of reward and aversion induced by morphine,” Neuroscience tization to the conditioned rewarding effects of morphine: Letters, vol. 760, article 136076, 2021. pharmacology and temporal characteristics,” European Jour- nal of Pharmacology, vol. 299, pp. 33–39, 1996. [156] C. W. Wu, C. Y. Ou, Y. H. Yu, Y. C. Yu, B. C. Shyu, and A. C. W. Huang, “Involvement of the Ventral Tegmental Area but [171] H. E. King, B. Wetzell, K. C. Rice, and A. L. Riley, “An assess- Not Periaqueductal Gray Matter in the Paradoxical Reward- ment of MDPV-induced place preference in adult Sprague- ing and Aversive Effects of Morphine,” Behavioral Neurosci- Dawley rats,” Drug and Alcohol Dependence, vol. 146, ence, vol. 135, pp. 762–770, 2021. pp. 116–119, 2015. [157] Y. Yu, A. B. He, M. Liou et al., “The paradoxical effect [172] H. I. Risca, J. D. Zuarth-Gonzalez, and L. E. Baker, “Condi- hypothesis of abused drugs in a rat model of chronic mor- tioned place preference following concurrent treatment with phine administration,” Journal of Clinical Medicine, vol. 10, 3, 4-methylenedioxypyrovalerone (MDPV) and metham- p. 3197, 2021. phetamine in male and female Sprague-Dawley rats,” Phar- macology Biochemistry and Behavior, vol. 198, article [158] L. A. Mayer and L. A. Parker, “Rewarding and aversive prop- 173032, 2020. erties of IP and SC cocaine: assessment by place and taste conditioning,” Psychopharmacology, vol. 112, pp. 189–194, [173] M. B. Gatch, S. B. Dolan, and M. J. Forster, “Comparative 1993. behavioral pharmacology of three pyrrolidine-containing synthetic cathinone derivatives,” Journal of Pharmacology [159] R. L. Pomfrey, T. A. Bostwick, B. B. Wetzell, and A. L. Riley, and Experimental Therapeutics, vol. 354, pp. 103–110, 2015. “Adolescent nicotine exposure fails to impact cocaine reward, aversion and self-administration in adult male rats,” Pharma- [174] J. A. Marusich, T. W. Lefever, B. E. Blough, B. F. Thomas, and cology Biochemistry and Behavior, vol. 137, pp. 30–37, 2015. J. L. Wiley, “Pharmacological effects of methamphetamine and alpha-PVP vapor and injection,” Neurotoxicology, [160] M. M. Clasen, T. V. Sanon, D. N. Kearns, T. L. Davidson, and vol. 55, pp. 83–91, 2016. A. L. Riley, “Ad libitum high fat diet consumption during adolescence and adulthood fails to impact the affective prop- [175] J. B. Bedingfield, D. A. King, and F. A. Holloway, “Cocaine erties of cocaine in male Sprague-Dawley rats,” Experimental and caffeine: conditioned place preference, locomotor activ- and Clinical Psychopharmacology, vol. 28, pp. 438–448, 2020. ity, and additivity,” Pharmacology Biochemistry and Behav- ior, vol. 61, pp. 291–296, 1998. [161] A. B. H. He, Y. C. Chang, A. W. Y. Meng, and A. C. W. Huang, “Re-evaluation of the reward comparison hypothesis [176] A. L. Riley, C. M. Davis, and P. G. Roma, “Strain differences for alcohol abuse,” Behavioural Brain Research, vol. 332, in taste aversion learning: Implications for animal models of pp. 218–222, 2017. drug abuse,” in Conditioned Taste Aversion: Behavioral and Neural Processes, S. Reilly and T. R. Schachtman, Eds., [162] N. T. Brockwell, R. Eikelboom, and R. J. Beninger, “Caffeine- pp. 226–261, Oxford University Press, New York, NY, 2009. induced place and taste conditioning: production of dose- dependent preference and aversion,” Pharmacology Biochem- [177] A. L. Riley, B. J. Hempel, and M. M. Clasen, “Sex as a biolog- istry and Behavior, vol. 38, pp. 513–517, 1991. ical variable: drug use and abuse,” Physiology & Behavior, vol. 187, pp. 79–96, 2018. [163] P. G. Roma, W. W. Flint, J. D. Higley, and A. L. Riley, “Assessment of the aversive and rewarding effects of alcohol [178] I. P. Stolerman and G. D. D'Mello, “Oral self-administration in Fischer and Lewis rats,” Psychopharmacology, vol. 189, and the relevance of conditioned taste aversions,” in pp. 187–199, 2006. Advances in Behavioral Pharmacology, T. Thompson, P. B. Dews, and W. A. McKim, Eds., pp. 169–214, Elsevier, [164] A. G. Wakeford, S. M. Flax, R. L. Pomfrey, and A. L. Riley, Amsterdam, Netherlands, 1981. “Adolescent delta-9-tetrahydrocannabinol (THC) exposure fails to affect THC-induced place and taste conditioning in [179] A. Ettenberg, “The runway model of drug self-administra- adult male rats,” Pharmacology Biochemistry and Behavior, tion,” Pharmacology Biochemistry and Behavior, vol. 91, vol. 140, pp. 75–81, 2016. pp. 271–277, 2009. [165] B. J. Hempel, A. G. Wakeford, M. M. Clasen, M. A. Friar, and [180] S. D. Turenne, C. Miles, L. A. Parker, and S. Siegel, “Individ- A. L. Riley, “Delta-9-tetrahydrocannabinol (THC) history ual differences in reactivity to the rewarding/aversive proper- fails to affect THC's ability to induce place preferences in ties of drugs: assessment by taste and place conditioning,” rats,” Pharmacology Biochemistry and Behavior, vol. 144, Pharmacology Biochemistry and Behavior, vol. 53, pp. 511– pp. 1–6, 2016. 516, 1996. [166] A. L. Riley, “The paradox of drug taking: the role of the aver- [181] J. A. Chester, F. O. Risinger, and C. L. Cunningham, “Ethanol sive effects of drugs,” Physiology & Behavior, vol. 103, pp. 69– reward and aversion in mice bred for sensitivity to ethanol 78, 2011. withdrawal,” Alcoholism: Clinical and Experimental Research, vol. 22, pp. 468–473, 1998. [167] C. M. Davis, “Animal models of drug abuse: place and taste conditioning,” in Animal Models for the Study of Human Dis- [182] D. V. Gauvin, T. J. Baird, and R. J. Briscoe, “Differential ease, M. P. Conn, Ed., pp. 681–707, Academic Press, Cam- development of behavioral tolerance and the subsequent bridge, MA, 2013. hedonic effects of alcohol in AA and ANA rats,” Psychophar- macology, vol. 151, pp. 335–343, 2000. [168] M. J. Shram, D. Funk, Z. Li, and A. D. Lê, “Periadolescent and adult rats respond differently in tests measuring the reward- [183] J. M. Wheeler, C. Reed, S. Burkhart-Kasch et al., “Genetically ing and aversive effects of nicotine,” Psychopharmacology, correlated effects of selective breeding for high and low meth- vol. 186, pp. 201–208, 2006. amphetamine consumption,” Genes, Brain and Behavior, vol. 8, pp. 758–771, 2009. [169] B. T. Lett, “Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and [184] W. S. Hyatt and W. E. Fantegrossi, “Δ9-THC exposure atten- cocaine,” Psychopharmacology, vol. 98, pp. 357–362, 1989. uates aversive effects and reveals appetitive effects of K2/ Behavioural Neurology 23 [199] L. A. Parker, S. A. Rana, and C. L. Limebeer, “Conditioned spice constituent JWH-018 in mice,” Behavioural Pharmacol- ogy, vol. 25, pp. 253–257, 2014. nausea in rats: assessment by conditioned disgust reactions, rather than conditioned taste avoidance,” Canadian Journal [185] K. G. Hill, H. Alva, Y. A. Blednov, and C. L. Cunningham, of Experimental Psychology, vol. 62, pp. 198–209, 2008. “Reduced ethanol-induced conditioned taste aversion and conditioned place preference in GIRK2 null mutant mice,” [200] B. J. Hempel, M. M. Clasen, K. H. Nelson, C. J. Woloshchuk, Psychopharmacology, vol. 169, pp. 108–114, 2003. and A. L. Riley, “An assessment of concurrent cannabidiol and Δ -tetrahydrocannabinol administration in place aver- [186] X. Li, B. J. Hempel, H. J. Yang et al., “Dissecting the role of sion and taste avoidance conditioning,” Experimental and CB1 and CB2 receptors in cannabinoid reward versus aver- Clinical Psychopharmacology, vol. 26, pp. 205–213, 2018. sion using transgenic CB1-and CB2-knockout mice,” Euro- pean Neuropsychopharmacology, vol. 43, pp. 38–51, 2021. [201] L. M. Barker, J. C. Smith, and E. M. Suarez, “Sickness and the backward conditioning of taste aversions,” in Learning Mech- [187] W. L. Isaac, A. J. Nonneman, J. Neisewander, T. Landers, and anisms in Food Selection, L. M. Barker, M. Best, and M. Dom- M. T. Bardo, “Prefrontal cortex lesions differentially disrupt jan, Eds., pp. 533–553, Baylor University Press, Waco, TX, cocaine-reinforced conditioned place preference but not con- ditioned taste aversion,” Behavioral Neuroscience, vol. 103, pp. 345–355, 1989. [202] L. A. Parker, “Conditioned flavor avoidance and conditioned gaping: rat models of conditioned nausea,” European Journal [188] T. M. Mosher, J. G. Smith, and A. J. Greenshaw, “Aversive of Pharmacology, vol. 722, pp. 122–133, 2014. stimulus properties of the 5-HT2C receptor agonist WAY 161503 in rats,” Neuropharmacology, vol. 51, pp. 641–650, [203] H. J. Grill and R. Norgren, “The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically nor- mal rats,” Brain Research, vol. 143, pp. 263–279, 1978. [189] F. O. Risinger, P. A. Freeman, P. Greengard, and A. A. Fien- berg, “Motivational effects of ethanol in DARPP-32 knock- [204] L. A. Schier, K. M. Hyde, and A. C. Spector, “Conditioned out mice,” The Journal of Neuroscience, vol. 21, pp. 340– taste aversion versus avoidance: a re-examination of the sep- 348, 2001. arate processes hypothesis,” Plos One, vol. 14, article e0217458, 2019. [190] Y. A. Blednov, J. M. Benavidez, C. Geil, S. Perra, H. Morikawa, and R. Harris, “Activation of inflammatory sig- [205] L. A. Parker, “Nonconsummatory and consummatory behav- naling by lipopolysaccharide produces a prolonged increase ioral CRs elicited by lithium-and amphetamine-paired fla- of voluntary alcohol intake in mice,” Brain, Behavior, and vors,” Learning and Motivation, vol. 13, pp. 281–303, 1982. Immunity, vol. 25, pp. S92–S105, 2011. [206] L. A. Parker, “Emetic drugs produce conditioned rejection [191] B. M. Rabin, J. A. Joseph, and B. Shukitt-Hale, “Long-term reactions in the taste reactivity test,” Journal of Psychophysiol- changes in amphetamine-induced reinforcement and aver- ogy, vol. 12, pp. 3–13, 1998. sion in rats following exposure to Fe particle,” Advances [207] L. A. Parker, “Taste-reactivity responses elicited by reinforc- in Space Research, vol. 31, pp. 127–133, 2003. ing drugs: a dose-response analysis,” Behavioral Neurosci- [192] A. Bechara, K. A. Zito, and D. Van Der Kooy, “Peripheral ence, vol. 105, pp. 955–964, 1991. receptors mediate the aversive conditioning effects of mor- [208] L. A. Parker, “Rewarding drugs produce taste avoidance, but phine in the rat,” Pharmacology Biochemistry and Behavior, not taste aversion,” Neuroscience & Biobehavioral Reviews, vol. 28, pp. 219–225, 1987. vol. 19, no. 1, pp. 143–151, 1995. [193] A. B. H. He, C. L. Huang, A. Kozłowska et al., “Involvement [209] L. A. Parker, “Taste avoidance and taste aversion: evidence of neural substrates in reward and aversion to methamphet- for two different processes,” Animal Learning & Behavior, amine addiction: testing the reward comparison hypothesis vol. 31, pp. 165–172, 2003. and the paradoxical effect hypothesis of abused drugs,” Neu- [210] C. L. Limebeer and L. A. Parker, “The antiemetic drug ondan- robiology of Learning and Memory, vol. 166, article 107090, setron intereferes with lithium-induced conditioned rejection reactions, but not lithium induced taste avoidance in rats,” [194] S. Ghozland, H. W. Matthes, F. Simonin, D. Filliol, B. L. Kief- Journal of Experimental Psychology: Animal Behavior Pro- fer, and R. Maldonado, “Motivational effects of cannabinoids cesses, vol. 26, pp. 371–384, 2000. are mediated by μ-opioid and κ-opioid receptors,” The Jour- [211] J. Y. Lin, J. Arthurs, L. R. Amodeo, and S. Reilly, “Reduced nal of Neuroscience, vol. 22, pp. 1146–1154, 2002. palatability in drug-induced taste aversion: I. Variations in [195] N. R. Gubner, C. Reed, C. S. McKinnon, and T. J. Phillips, the initial value of the conditioned stimulus,” Behavioral “Unique genetic factors influence sensitivity to the rewarding Neuroscience, vol. 126, pp. 423–432, 2012. and aversive effects of methamphetamine versus cocaine,” [212] J. Y. Lin, J. Arthurs, and S. Reilly, “Reduced palatability in Behavioural Brain Research, vol. 256, pp. 420–427, 2013. pain-induced conditioned taste aversions,” Physiology & [196] J. Garcia and D. J. Kimeldorf, “Temporal relationship within Behavior, vol. 119, pp. 79–85, 2013. the conditioning of a saccharine aversion through radiation [213] J. Y. Lin, J. Arthurs, and S. Reilly, “Conditioned taste aver- exposure,” Journal of Comparative and Physiological Psychol- sion, drugs of abuse and palatability,” Neuroscience & Biobe- ogy, vol. 50, pp. 180–183, 1957. havioral Reviews, vol. 45, pp. 28–45, 2014. [197] J. Garcia and D. J. Kimeldorf, “Some factors which influence [214] J. Y. Lin, J. Arthurs, and S. Reilly, “Conditioned taste aver- radiation-conditioned behavior of rats,” Radiation Research, sions: from poisons to pain to drugs of abuse,” Psychonomic vol. 12, pp. 719–727, 1960. Bulletin & Review, vol. 24, pp. 335–351, 2017. [198] A. J. Goudie, I. P. Stolerman, C. Demellweek, and G. D. [215] J. Y. Lin, J. Arthurs, and S. Reilly, “Anesthesia-inducing drugs D'Mello, “Does conditioned nausea mediate drug-induced also induce conditioned taste aversions,” Physiology & Behav- conditioned taste aversion?,” Psychopharmacology, vol. 78, ior, vol. 177, pp. 247–251, 2017. pp. 277–281, 1982. 24 Behavioural Neurology [230] S. N. Gartner, F. Aidney, A. Klockars et al., “Intragastric pre- [216] D. M. Dwyer, R. A. Boakes, and A. J. Hayward, “Reduced pal- atability in lithium-and activity-based, but not in amphet- loads of L-tryptophan reduce ingestive behavior via oxytoci- amine-based, taste aversion learning,” Behavioral nergic neural mechanisms in male mice,” Appetite, vol. 125, Neuroscience, vol. 122, pp. 1051–1060, 2008. pp. 278–286, 2018. [217] D. M. Dwyer, “Licking and liking: the assessment of hedonic [231] M. P. Gillum, D. Zhang, X. M. Zhang et al., “N-Acylphospha- responses in rodents,” Quarterly Journal of Experimental Psy- tidylethanolamine, a gut-derived circulating factor induced chology, vol. 65, pp. 371–394, 2012. by fat ingestion, inhibits food intake,” Cell, vol. 135, pp. 813–824, 2008. [218] T. Hunt and Z. Amit, “Conditioned taste aversion induced by self-administered drugs: paradox revisited,” Neuroscience & [232] K. Proulx, D. Cota, T. R. Castañeda et al., “Mechanisms of oleoylethanolamide-induced changes in feeding behavior Biobehavioral Reviews, vol. 11, pp. 107–130, 1987. and motor activity,” American Journal of Physiology-Regula- [219] A. L. Riley and G. R. Simpson, “The attenuating effects of tory, Integrative and Comparative Physiology, vol. 289, drug preexposure on taste aversion conditioning: generality, pp. R729–R737, 2005. experimental parameters, underlying mechanisms, and implications for drug use and abuse,” in Handbook of Con- [233] P. S. Grigson, “Conditioned taste aversions and drugs of abuse: a reinterpretation,” Behavioral Neuroscience, vol. 111, temporary Learning Theories, R. R. Mowrer and S. B. Klein, Eds., pp. 505–559, Lawrence Erlbaum Associates Publishers, pp. 129–136, 1997. NJ, 2001. [234] A. C. W. Huang and S. Hsiao, “Re-examination of amphetamine-induced conditioned suppression of tastant [220] C. L. Cunningham, D. M. Hawks, and D. R. Niehus, “Role of intake in rats: the task-dependent drug effects hypothesis,” hypothermia in ethanol-induced conditioned taste aversion,” Behavioral Neuroscience, vol. 122, pp. 1207–1216, 2008. Psychopharmacology, vol. 95, pp. 318–322, 1988. [221] R. A. Wheeler, R. C. Twining, J. L. Jones, J. M. Slater, P. S. [235] A. C. W. Huang, C. C. Wang, and S. Wang, “Examinations of the reward comparison hypothesis: the modulation of gender Grigson, and R. M. Carelli, “Behavioral and electrophysiolog- ical indices of negative affect predict cocaine self-administra- and footshock,” Physiology & Behavior, vol. 151, pp. 129–138, tion,” Neuron, vol. 57, pp. 774–785, 2008. [236] C. L. Cunningham, C. M. Gremel, and P. A. Groblewski, [222] E. M. Colechio, D. N. Alexander, C. G. Imperio, K. Jackson, “Genetic influences on conditioned taste aversion,” in Condi- and P. S. Grigson, “Once is too much: early development of tioned Taste Aversion: Behavioral and Neural Processes,S. the opponent process in taste reactivity behavior is associated Reilly and T. R. Schachtman, Eds., pp. 387–421, Oxford Uni- with later escalation of cocaine self-administration in rats,” versity Press, New York, NY, 2009. Brain Research Bulletin, vol. 138, pp. 88–95, 2018. [237] D. B. Newlin and R. M. Renton, “High risk groups often have [223] K. G. Guenther, C. E. Wideman, E. M. Rock, C. L. Limebeer, higher levels of alcohol response than low risk: the other side and L. A. Parker, “Conditioned aversive responses produced of the coin,” Alcoholism: Clinical and Experimental Research, by delayed, but not immediate, exposure to cocaine and mor- vol. 34, pp. 199–202, 2010. phine in male Sprague-Dawley rats,” Psychopharmacology, vol. 235, pp. 3315–3327, 2018. [238] M. A. Schuckit, “Low level of response to alcohol as a predic- tor of future alcoholism,” American Journal of Psychiatry, [224] L. A. Parker, C. L. Limebeer, and S. A. Rana, “Conditioned vol. 151, pp. 184–189, 1994. disgust, but not conditioned taste avoidance, may reflect con- ditioned nausea in rats,” in Conditioned Taste Aversions: [239] H. J. Edenberg, “The genetics of alcohol metabolism: role of Behavioral and Neural Processes, S. Reilly and T. R. Schacht- alcohol dehydrogenase and aldehyde dehydrogenase vari- man, Eds., pp. 92–113, Oxford University Press, New York, ants,” Alcohol Research & Health, vol. 30, pp. 5–13, 2007. NY, 2009. [240] J. C. Crabbe, “Genetic contributions to addiction,” Annual [225] G. Takács, B. Lukáts, S. Papp, C. Szalay, and Z. Karádi, “Taste Review of Psychology, vol. 53, pp. 435–462, 2002. reactivity alterations after IL-1β microinjection into the ven- [241] R. L. Elkins, “Separation of taste-aversion-prone and taste- tromedial hypothalamic nucleus of the rat,” Neuroscience aversion-resistant rats through selective breeding: implica- Research, vol. 62, pp. 118–122, 2008. tions for individual differences in conditionability and [226] T. M. Barney, A. S. Vore, A. Gano, J. E. Mondello, and aversion-therapy alcoholism treatment,” Behavioral Neuro- T. Deak, “The influence of central interleukin-6 on behavioral science, vol. 100, pp. 121–124, 1986. changes associated with acute alcohol intoxication in adult [242] R. L. Elkins, P. A. Walters, and T. E. Orr, “Continued devel- male rats,” Alcohol, vol. 79, pp. 37–45, 2019. opment and unconditioned stimulus characterization of [227] J. D. Patel and I. S. Ebenezer, “The effect of intraperitoneal selectively bred lines of taste aversion prone and resistant administration of leptin on short-term food intake in rats,” rats,” Alcoholism: Clinical and Experimental Research, European Journal of Pharmacology, vol. 580, pp. 143–152, vol. 16, pp. 928–934, 1992. [243] T. E. Orr, J. L. Whitford-Stoddard, and R. L. Elkins, “Taste- [228] K. Abegg, L. Bernasconi, M. Hutter et al., “Ghrelin receptor aversion-prone (TAP) rats and taste-aversion-resistant inverse agonists as a novel therapeutic approach against (TAR) rats differ in ethanol self-administration, but not in obesity-related metabolic disease,” Diabetes, Obesity and ethanol clearance or general consumption,” Alcohol, vol. 33, Metabolism, vol. 19, pp. 1740–1750, 2017. pp. 1–7, 2004. [229] J. A. Rodriguez, J. A. Fehrentz, J. Martinez, K. B. H. Salah, and [244] R. L. Elkins, T. E. Orr, J. L. Rausch et al., “Cocaine-induced P. J. Wellman, “The GHR-R antagonist JMV 2959 neither expression differences in glutamate receptor subunits and induces malaise nor alters the malaise property of LiCl in transporters in amygdalae of taste aversion-prone and taste the adult male rat,” Physiology & Behavior, vol. 183, pp. 46– aversion-resistant rats,” Annals of the New York Academy of 48, 2018. Sciences, vol. 1003, pp. 381–385, 2003. Behavioural Neurology 25 [260] J. M. Vishwanath, A. G. Desko, and A. L. Riley, “Caffeine- [245] S. H. Hobbs, P. A. Walters, E. F. Shealy, and R. L. Elkins, “Radial-maze learning by lines of taste-aversion-prone and induced taste aversions in Lewis and Fischer rat strains: dif- taste-aversion-resistant rats,” Bulletin of the Psychonomic ferential sensitivity to the aversive effects of drugs,” Pharma- Society, vol. 31, pp. 171–174, 1993. cology Biochemistry and Behavior, vol. 100, pp. 66–72, 2011. [246] T. E. Orr, P. A. Walters, and R. L. Elkins, “Differences in free- [261] P. G. Roma, C. M. Davis, and A. L. Riley, “Effects of cross- choice ethanol acceptance between taste aversion-prone and fostering on cocaine-induced conditioned taste aversions in taste aversion-resistant rats,” Alcoholism: Clinical and Exper- Fischer and Lewis rats,” Developmental Psychobiology, imental Research, vol. 21, pp. 1491–1496, 1997. vol. 49, pp. 172–179, 2007. [247] D. S. Cannon and L. E. Carrell, “Rat strain differences in eth- [262] M. Gomez-Serrano, L. Tonelli, S. Listwak, E. Sternberg, and anol self-administration and taste aversion learning,” Phar- A. L. Riley, “Effects of cross fostering on open-field behavior, macology Biochemistry and Behavior, vol. 28, pp. 57–63, acoustic startle, lipopolysaccharide-induced corticosterone 1987. release, and body weight in Lewis and Fischer rats,” Behavior Genetics, vol. 31, pp. 427–436, 2001. [248] S. Cailhol and P. Mormède, “Conditioned taste aversion and alcohol drinking: strain and gender differences,” Journal of [263] M. A. Gomez-Serrano, E. M. Sternberg, and A. L. Riley, Studies on Alcohol, vol. 63, pp. 91–99, 2002. “Maternal behavior in F344/N and LEW/N rats: effects on carrageenan-induced inflammatory reactivity and body [249] J. Broadbent, K. J. Muccino, and C. L. Cunningham, “Etha- weight,” Physiology & Behavior, vol. 75, pp. 493–505, 2002. nol-induced conditioned taste aversion in 15 inbred mouse strains,” Behavioral Neuroscience, vol. 116, pp. 138–148, [264] M. C. Camp, M. Feyder, J. Ihne et al., “A novel role for PSD- 2002. 95 in mediating ethanol intoxication, drinking and place preference,” Addiction Biology, vol. 16, pp. 428–439, 2011. [250] C. L. Cunningham, “Genetic relationships between ethanol- induced conditioned place aversion and other ethanol pheno- [265] Y. A. Blednov, J. M. Benavidez, M. Black, J. Mayfield, and types in 15 inbred mouse strains,” Brain Sciences, vol. 9, R. A. Harris, “Role of interleukin-1 receptor signaling in the pp. 209–229, 2019. behavioral effects of ethanol and benzodiazepines,” Neuro- pharmacology, vol. 95, pp. 309–320, 2015. [251] C. L. Cunningham, “Genetic relationship between ethanol- induced conditioned place preference and other ethanol phe- [266] R. Legastelois, E. Darcq, S. A. Wegner, P. J. Lombroso, and notypes in 15 inbred mouse strains,” Behavioral Neurosci- D. Ron, “Striatal-enriched protein tyrosine phosphatase con- ence, vol. 128, pp. 430–445, 2014. trols responses to aversive stimuli: implication for ethanol drinking,” Plos One, vol. 10, article e0127408, 2015. [252] S. Shabani, C. S. McKinnon, C. Reed, C. L. Cunningham, and T. J. Phillips, “Sensitivity to rewarding or aversive effects of [267] T. Isse, T. Oyama, K. Kitagawa et al., “Diminished alcohol methamphetamine determines methamphetamine intake,” preference in transgenic mice lacking aldehyde dehydroge- Genes, Brain and Behavior, vol. 10, pp. 625–636, 2011. nase activity,” Pharmacogenetics and Genomics, vol. 12, pp. 621–626, 2002. [253] S. Shabani, C. S. McKinnon, C. L. Cunningham, and T. J. Phillips, “Profound reduction in sensitivity to the aversive [268] T. Isse, K. Matsuno, T. Oyama, K. Kitagawa, and effects of methamphetamine in mice bred for high metham- T. Kawamoto, “Aldehyde dehydrogenase 2 gene targeting phetamine intake,” Neuropharmacology, vol. 62, pp. 1134– mouse lacking enzyme activity shows high acetaldehyde level 1141, 2012. in blood, brain, and liver after ethanol gavages,” Alcoholism: Clinical & Experimental Research, vol. 29, pp. 1959–1964, [254] D. Lancellotti, B. M. Bayer, J. R. Glowa, R. A. Houghtling, and A. L. Riley, “Morphine-induced conditioned taste aversions in the LEW/N and F344/N rat strains,” Pharmacology Bio- [269] N. L. Schramm-Sapyta, Q. D. Walker, J. M. Caster, E. D. chemistry and Behavior, vol. 68, pp. 603–610, 2001. Levin, and C. M. Kuhn, “Are adolescents more vulnerable to drug addiction than adults? Evidence from animal [255] C. M. Davis, K. C. Rice, and A. L. Riley, “Opiate-agonist models,” Psychopharmacology, vol. 206, pp. 1–21, 2009. induced taste aversion learning in the Fischer 344 and Lewis inbred rat strains: evidence for differential mu opioid recep- [270] L. P. Spear, “Adolescents and alcohol: acute sensitivities, tor activation,” Pharmacology Biochemistry and Behavior, enhanced intake, and later consequences,” Neurotoxicology vol. 93, pp. 397–405, 2009. and Teratology, vol. 41, pp. 51–59, 2014. [256] C. M. Davis, J. L. Cobuzzi, and A. L. Riley, “Assessment of the [271] M. M. Clasen, T. V. Sanon, B. J. Hempel et al., “Ad-libitum aversive effects of peripheral mu opioid receptor agonism in high fat diet consumption during adolescence and adulthood Fischer 344 and Lewis rats,” Pharmacology Biochemistry impacts the intravenous self-administration of cocaine in and Behavior, vol. 101, pp. 181–186, 2012. male Sprague-Dawley rats,” Experimental and Clinical Psy- chopharmacology, vol. 28, pp. 32–43, 2020. [257] K. A. Pescatore, J. R. Glowa, and A. L. Riley, “Strain differ- ences in the acquisition of nicotine-induced conditioned taste [272] A. L. Riley, M. M. Clasen, and M. A. Friar, “Conditioned taste aversion,” Pharmacology Biochemistry and Behavior, vol. 82, avoidance drug discrimination procedure: assessments and pp. 751–757, 2005. applications,” Current Topics in Behavioral Neurosciences, vol. 39, pp. 297–317, 2018. [258] M. M. Foynes and A. L. Riley, “Lithium-chloride-induced conditioned taste aversions in the Lewis and Fischer 344 rat [273] M. M. Clasen, A. L. Riley, and T. L. Davidson, “Hippocampal- strains,” Pharmacology Biochemistry and Behavior, vol. 79, dependent inhibitory learning and memory processes in the pp. 303–308, 2004. control of eating and drug taking,” Current Pharmaceutical Design, vol. 26, pp. 2334–3352, 2020. [259] J. R. Glowa, A. E. Shaw, and A. L. Riley, “Cocaine-induced conditioned taste aversions: comparisons between effects in [274] L. D. Hill-Bowen, M. C. Riedel, R. Poudel et al., “The cue- LEW/N and F344/N rat strains,” Psychopharmacology, reactivity paradigm: an ensemble of networks driving atten- vol. 114, pp. 229–232, 1994. tion and cognition when viewing drug and natural reward- 26 Behavioural Neurology [291] S. D. Grabus, S. T. Smurthwaite, and A. L. Riley, “Nalorphine’s related stimuli,” Neuroscience & Biobehavioral Reviews, vol. 130, pp. 201–213, 2021. ability to substitute for morphine in a drug discrimination pro- cedure is a function of training dose,” Pharmacology Biochem- [275] H. Ekhtiari, P. Nasseri, F. Yavari, A. Mokri, and istry and Behavior, vol. 63, pp. 481–488, 1999. J. Monterosso, “Neuroscience of drug craving for addiction medicine: from circuits to therapies,” Progress in Brain [292] Y. Awasaki, H. Nojima, and N. Nishida, “Application of the Research, vol. 223, pp. 115–141, 2016. conditioned taste aversion paradigm to assess discriminative stimulus properties of psychostimulants in rats,” Drug and [276] M. M. Torregrossa and J. R. Taylor, “Neuroscience of learn- Alcohol Dependence, vol. 118, no. 2-3, pp. 288–294, 2011. ing and memory for addiction medicine: from habit forma- tion to memory reconsolidation,” Progress in Brain [293] J. P. Mastropaolo, K. H. Moskowitz, R. J. Dacanay, and A. L. Research, vol. 223, pp. 91–113, 2016. Riley, “Conditioned taste aversions as a behavioral baseline for drug discrimination learning: an assessment with phency- [277] C. J. Perry, I. Zbukvic, J. H. Kim, and A. J. Lawrence, “Role of clidine,” Pharmacology Biochemistry and Behavior, vol. 32, cues and contexts on drug-seeking behaviour,” British Jour- pp. 1–8, 1989. nal of Pharmacology, vol. 171, pp. 4636–4672, 2014. [294] I. Lucki, “Rapid discrimination of the stimulus properties of [278] L. V. Panlilio, E. B. Thorndike, and C. W. Schindler, “A 5-hydroxytryptamine agonists using conditioned taste aver- stimulus-control account of regulated drug intake in rats,” sion,” Journal of Pharmacology and Experimental Therapeu- Psychopharmacology, vol. 196, pp. 441–450, 2008. tics, vol. 247, pp. 1120–1127, 1988. [279] S. Jones, A. Hyde, and T. L. Davidson, “Reframing appetitive [295] T. V. Jaeger and R. F. Mucha, “A taste aversion model of drug reinforcement learning and reward valuation as effects medi- discrimination learning: training drug and condition influ- ated by hippocampal-dependent behavioral inhibition,” ence rate of learning, sensitivity and drug specificity,” Psycho- Nutrition Research, vol. 79, pp. 1–12, 2020. pharmacology, vol. 100, pp. 145–150, 1990. [280] V. L. Tsibulsky and A. B. Norman, “Satiety threshold during [296] D. M. Skinner, G. M. Martin, R. D. Howe, A. Pridgar, and maintained cocaine self-administration in outbred mice,” D. van der Kooy, “Drug discrimination learning using a taste Neuroreport, vol. 12, pp. 325–328, 2001. aversion paradigm: an assessment of the role of safety cues,” [281] S. Trask, E. A. Thrailkill, and M. E. Bouton, “Occasion set- Learning and Motivation, vol. 26, pp. 343–369, 1995. ting, inhibition, and the contextual control of extinction in [297] G. M. Martin, M. Gans, and D. van der Kooy, “Discriminative Pavlovian and instrumental (operant) learning,” Behavioural properties of morphine that modulate associations between Processes, vol. 137, pp. 64–72, 2017. tastes and lithium chloride,” Journal of Experimental Psychol- [282] K. A. Carr, T. O. Daniel, H. Lin, and L. H. Epstein, “Rein- ogy: Animal Behavior Processes, vol. 16, no. 1, pp. 56–68, 1990. forcement pathology and obesity,” Current Drug Abuse [298] S. Maren and W. Holt, “The hippocampus and contextual Reviews, vol. 4, pp. 190–196, 2011. memory retrieval in Pavlovian conditioning,” Behavioural [283] T. L. Davidson, A. L. Tracy, L. A. Schier, and S. E. Swithers, Brain Research, vol. 110, no. 1-2, pp. 97–108, 2000. “A view of obesity as a learning and memory disorder,” Jour- [299] A. P. Maurer and L. Nadel, “The continuity of context: a role nal of Experimental Psychology: Animal Learning and Cogni- tion, vol. 40, pp. 261–279, 2014. for the hippocampus,” Trends in Cognitive Sciences, vol. 25, pp. 187–199, 2021. [284] S. Dohle, K. Diel, and W. Hofmann, “Executive functions and the self-regulation of eating behavior: a review,” Appetite, [300] P. C. Holland and M. E. Bouton, “Hippocampus and context in classical conditioning,” Current Opinion in Neurobiology, vol. 124, pp. 4–9, 2018. vol. 9, pp. 195–202, 1999. [285] R. L. Balster, “Drugs as chemical stimuli,” Transduction [301] N. Hebben, S. Corkin, H. Eichenbaum, and K. Shedlack, Mechanisms of Drug Stimuli, vol. 4, pp. 3–11, 1988. “Diminished ability to interpret and report internal states [286] F. C. Colpaert, “Drug discrimination in neurobiology,” Phar- after bilateral medial temporal resection: case H.M,” Behav- macology Biochemistry and Behavior, vol. 64, no. 2, pp. 337– ioral Neuroscience, vol. 99, pp. 1031–1039, 1985. 345, 1999. [302] P. Rozin, S. Dow, M. Moscovitch, and S. Rajaram, “What [287] J. H. Porter and A. J. Prus, “Discriminative stimulus proper- causes humans to begin and end a meal? A role for memory ties of atypical and typical antipsychotic drugs: a review of for what has been eaten, as evidenced by a study of multiple preclinical studies,” Psychopharmacology, vol. 203, pp. 279– meal eating in amnesic patients,” Psychological Science, 294, 2009. vol. 9, pp. 392–396, 1998. [288] J. R. Troisi and N. L. Michaud, “Can the discriminative stim- [303] S. Higgs, A. C. Williamson, P. Rotshtein, and G. W. Hum- ulus effects of nicotine function concurrently as modulatory phreys, “Sensory-specific satiety is intact in amnesics who opponents in operant and Pavlovian occasion setting para- eat multiple meals: research report,” Psychological Science, digms in rats?,” Behavioural Processes, vol. 158, pp. 144– vol. 19, pp. 623–628, 2008. 150, 2019. [304] T. L. Davidson and L. E. Jarrard, “A role for hippocampus in [289] R. A. Glennon, T. U. Järbe, and J. Frankenheim, Drug Dis- the utilization of hunger signals,” Behavioral and Neural Biol- crimination: Applications to Drug Abuse Research. US ogy, vol. 59, pp. 167–171, 1993. Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administra- [305] T. L. Davidson, S. E. Kanoski, K. Chan, D. J. Clegg, S. C. tion, National Institute on Drug Abuse, Rockville, MD, 1991. Benoit, and L. E. Jarrard, “Hippocampal lesions impair reten- tion of discriminative responding based on energy state [290] A. L. Riley, “Use of drug discrimination learning in behav- cues,” Behavioral Neuroscience, vol. 124, pp. 97–105, 2010. ioral toxicology: classification and characterization of toxins,” in Neurotoxicology: Approaches and Methods, L. Chang and [306] Y. O. Henderson, G. P. Smith, and M. B. Parent, “Hippocam- W. Slikker, Eds., pp. 309–321, Academic Press, San Diego, pal neurons inhibit meal onset,” Hippocampus, vol. 23, CA, 1995. pp. 100–107, 2013. Behavioural Neurology 27 [307] R. Hannapel, J. Ramesh, A. Ross, R. T. Lalumiere, A. G. Rose- berry, and M. B. Parent, “Postmeal optogenetic inhibition of dorsal or ventral hippocampal pyramidal neurons increases future intake,” Eneuro, vol. 6, pp. 1–16, 2019. [308] S. B. Briggs, R. Hannapel, J. Ramesh, and M. B. Parent, “Inhi- biting ventral hippocampal NMDA receptors and arc increases energy intake in male rats,” Learning & Memory, vol. 28, pp. 187–194, 2021. [309] T. L. Davidson, K. Chan, L. E. Jarrard, S. E. Kanoski, D. J. Clegg, and S. C. Benoit, “Contributions of the hippocampus and medial prefrontal cortex to energy and body weight reg- ulation,” Hippocampus, vol. 19, pp. 235–252, 2009. [310] C. H. Sample, S. Jones, S. L. Hargrave, L. E. Jarrard, and T. L. Davidson, “Western diet and the weakening of the interocep- tive stimulus control of appetitive behavior,” Behavioural Brain Research, vol. 312, pp. 219–230, 2016. [311] S. D. Glick and R. D. Cox, “Changes in morphine self- administration after tel-diencephalic lesions in rats,” Psycho- pharmacology, vol. 57, pp. 283–288, 1978. [312] R. M. Karlsson, D. M. Kircher, Y. Shaham, and P. O’Donnell, “Exaggerated cue-induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia,” Psychopharmacology, vol. 226, pp. 45–51, 2013. [313] R. A. Chambers and D. W. Self, “Motivational responses to natural and drug rewards in rats with neonatal ventral hippo- campal lesions: an animal model of dual diagnosis schizo- phrenia,” Neuropsychopharmacology, vol. 27, pp. 889–905, [314] S. K. Conroy, Z. Rodd, and R. A. Chambers, “Ethanol sensiti- zation in a neurodevelopmental lesion model of schizophre- nia in rats,” Pharmacology Biochemistry and Behavior, vol. 86, pp. 386–394, 2007. [315] A. M. Brady, R. D. Saul, and M. K. Wiest, “Selective deficits in spatial working memory in the neonatal ventral hippocampal lesion rat model of schizophrenia,” Neuropharmacology, vol. 59, pp. 605–611, 2010. [316] S. A. Berg, A. M. Sentir, B. S. Cooley, E. A. Engleman, and R. A. Chambers, “Nicotine is more addictive, not more cogni- tively therapeutic in a neurodevelopmental model of schizo- phrenia produced by neonatal ventral hippocampal lesions,” Addiction Biology, vol. 19, pp. 1020–1031, 2014. [317] T. L. Davidson, S. L. Hargrave, D. N. Kearns et al., “Cocaine impairs serial-feature negative learning and blood-brain bar- rier integrity,” Pharmacology Biochemistry and Behavior, vol. 170, pp. 56–63, 2018.

Journal

Behavioural NeurologyHindawi Publishing Corporation

Published: Apr 20, 2022

There are no references for this article.