The protective effects of the melanocortin receptor (MCR) agonist, melanotan-II (MTII), against binge-like ethanol drinking are facilitated by deletion of the MC3 receptor in mice.

Recent data have implicated the melanocortin (MC) system in modulating voluntary ethanol consumption. Administration of melanotan-II (MTII), a nonselective melanocortin receptor (MCR) agonist, reduces voluntary ethanol consumption in C57BL/6J mice. Previous studies have demonstrated that central infusion of MTII effectively reduced voluntary ethanol drinking in mutant mice lacking normal expression of MC3R (MC3R-/- mice) but failed to alter ethanol drinking in mice lacking expression of MC4R, demonstrating that central MTII administration reduces voluntary ethanol drinking by signaling through the MC4R. However, evidence shows that the neurocircuitry recruited during excessive binge-like ethanol drinking versus moderate ethanol drinking are not identical. Thus the present study sought to investigate the potential role of the MC3R in binge-like ethanol intake. To this end, the "drinking in the dark" (DID) procedure, a commonly used animal model of binge-like ethanol drinking, was employed. Wild-type MC3R+/+ and MC3R-/- mice were given intracerebroventricular (i.c.v.) infusion of MTII (0.0, 0.25, 0.50, or 1.0 µg) prior to the onset of a 4-h testing period in which mice were given access to 20% (v/v) ethanol. Immediately after the 4-h testing period, tail blood samples were collected from each animal in order to assess blood ethanol concentrations (BECs). Consistent with previous findings, central administration of MTII blunted binge-like ethanol drinking in both MC3R+/+ and MC3R-/- mice. Interestingly, all doses of MTII blunted binge-like ethanol drinking in MC3R-/- mice during the first hour of testing, while only the 1.0 µg dose reduced binge-like drinking in MC3R+/+ mice. Thus, MC3R-/- mice were more sensitive to the protective effects of MTII. These data suggest that MC3Rs oppose the protective effects of MTII against binge-like ethanol drinking, and thus selective MC3R antagonists may have potential therapeutic roles in treating excessive ethanol drinking.

Deletion of agouti-related protein blunts ethanol self-administration and binge-like drinking in mice.

The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). Recent pharmacological and genetic evidence suggests that melanocortin receptor (MCR) signaling modulates neurobiological responses to ethanol and ethanol intake. Agouti-related protein (AgRP) is synthesized by neurons in the arcuate nucleus of the hypothalamus and is a natural antagonist of MCRs. Because central administration of the functionally active AgRP fragment AgRP-(83-132) increases ethanol intake by C57BL/6 J mice, we determined if mutant mice lacking normal production of AgRP (AgRP(-/-)) and maintained on a C57BL/6 J genetic background would show reduced self-administration of ethanol relative to littermate wild-type (AgRP(+/+)) mice. AgRP(-/-) mice showed reduced 8% (v/v) ethanol-reinforced lever-pressing behavior relative to AgRP(+/+) mice in daily 2-h sessions, but normal sucrose-, saccharin- and water-reinforced lever-pressing. Similarly, AgRP(-/-) mice showed reduced consumption of 8% ethanol in a two-bottle limited access test (2 h/day), although this effect was largely sex-dependent. Using drinking-in-the-dark (DID) procedures, AgRP(-/-) mice showed blunted binge-like drinking of 20% (v/v) ethanol which was associated with lower blood ethanol levels (85 mg/dl) relative to AgRP(+/+) mice (133 mg/dl) after 4 h of intake. AgRP(-/-) mice showed normal ethanol metabolism and did not show altered sensitivity to the sedative effects of ethanol. These observations with genetically altered mice are consistent with previous pharmacological data and suggest that endogenous AgRP signaling modulates the reinforcing properties of ethanol and binge-like ethanol drinking.

Corticotropin releasing factor-1 receptor antagonist, CP-154,526, blocks the expression of ethanol-induced behavioral sensitization in DBA/2J mice.

RATIONALE: Manipulation of glucocorticoid receptor signaling has been shown to alter the acquisition and expression of ethanol-induced locomotor sensitization in mice. It is unknown if other components of the hypothalamic-pituitary-adrenal (HPA)-axis modulate locomotor sensitization resulting from repeated ethanol administration. In the present investigation, we determined if pretreatment with an i.p. injection of CP-154,526, a selective corticotropin releasing factor (CRF) type-1 receptor antagonist, would block the acquisition and/or expression of ethanol-induced locomotor sensitization in male DBA/2J mice. METHODS: To assess the role of the CRF1 receptor in the acquisition of behavioral sensitization, mice were pretreated with an i.p. injection of CP-154,526 30 min before each of 10 sensitizing i.p. injections of ethanol. To determine the role of the CRF1 receptor in modulating the expression of ethanol-induced sensitization, mice that had previously been sensitized to the locomotor stimulant effects of ethanol were pretreated with CP-154,526 30 min before an i.p. injection of ethanol on the test day. In a third study, ethanol-naïve mice were pretreated with CP-154,526 30 min before an initial i.p. injection of ethanol to determine the combined effects of the CRF1 receptor antagonist and ethanol on locomotor activity. Blood ethanol concentrations were assessed at the termination of sensitization studies. RESULTS: Pretreatment with CP-154,526 blocked the expression of ethanol-induced locomotor sensitization in DBA/2J mice but did not prevent the acquisition of sensitization. The ability of CP-154,526 to block the expression of ethanol-induced locomotor sensitization was not attributable to alterations in blood ethanol levels or possible sedative effects produced by the combined administration of CP-154,526 and ethanol. CONCLUSIONS: These data provide novel evidence that CRF1 receptor signaling modulates the expression of ethanol-induced locomotor sensitization, and add to a growing literature suggesting a role for neurochemicals and hormones associated with the HPA-axis in behavioral sensitization resulting from repeated exposure to drugs of abuse.

Involvement of protein kinase A in ethanol-induced locomotor activity and sensitization.

RATIONALE: Mutant mice lacking the RIIbeta subunit of protein kinase A (regulatory subunit II beta(-/-)) show increased ethanol preference. Recent evidence suggests a relationship between heightened ethanol preference and susceptibility to ethanol-induced locomotor sensitization. It is currently unknown if protein kinase A signaling modulates the stimulant effects and/or behavioral sensitization caused by ethanol administration. To address this question, we examined the effects of repeated ethanol administration on locomotor activity RIIbeta(-/-) and littermate wild-type (RIIbeta(+/+)) mice on multiple genetic backgrounds. METHODS: Over three consecutive days, mice were given single i.p. saline injections and immediately placed in a locomotor activity apparatus to establish a composite baseline for locomotor activity. Next, mice maintained on a hybrid 129/SvEvxC57BL/6J or pure C57BL/6J genetic background were given 10 i.p. ethanol injections before being placed in the activity apparatus. Each ethanol injection was separated by 3-4 days. To determine if changes in behavior were specific to ethanol injection, naïve mice were tested following repeated daily saline injections. The effects of ethanol injection on locomotor behavior were also assessed using an alternate paradigm in which mice were given repeated ethanol injections in their home cage environment. RESULTS: Relative to RIIbeta(+/+) mice, RIIbeta(-/-) mice, regardless of genetic background, consistently showed significantly greater ethanol-induced locomotor activation. RIIbeta(-/-) mice also showed increased sensitivity to ethanol-induced locomotor sensitization resulting from repeated administration, an effect that was dependent on genetic background and testing paradigm. Increased locomotor activity by RIIbeta(-/-) mice was specific to ethanol injections, and was not related to altered blood ethanol levels. CONCLUSIONS: These data provide novel evidence implicating an influence of protein kinase A signaling on ethanol-induced locomotor activity and behavioral sensitization. The observation that RIIbeta(-/-) mice are more sensitive to the effects of repeated ethanol administration suggests that normal protein kinase A signaling limits, or is protective against, the stimulant effects of ethanol and the plastic alterations that underlie behavioral sensitization.

Dopamine mediation of the feeding response to violations of spatial and temporal expectancies.

The present studies were aimed at further characterizing the role of DA in motivation. Rats, conditioned to expect food in one environment and no food in another, all received food on the test night. Those in the environment in which food was unexpected ate four times as much as those eating where food was expected. The overeating was eliminated by administration of the D2 antagonist raclopride. Another expectancy, timing of light offset in rats entrained to a fixed light--dark cycle, was violated by unexpectedly turning the lights off 1 h early. This provoked an elevation in food intake, which was also eliminated by the administration of raclopride. Feeding in two other situations not involving violation of expectancies (food deprivation; normal light offset) was unaffected by DA antagonism. These findings support the idea that DA signals errors in expectancy and that DA signaling is necessary for certain behavioral responses to unexpected events.

Approaches to understanding the neurobiological regulation of ethanol self-administration: a young investigators forum.

The article represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The co-chairs were Cristine L. Czachowski and Craig J. Slawecki. The presentations were (1) Behavioral assessment of ethanol seeking and self-administration, by Cristine L. Czachowski; (2) Electrophysiological measures of ethanol preference and reinforcing efficacy, by Craig J. Slawecki; (3) Genetic differences in locomotor sensitization and reward phenotypes associated with bidirectional selection for alcohol preference in mice, by Nicholas J. Grahame; (4) Transgenic and knockout mouse models: Powerful tools for investigating the neurobiology of alcoholism, by Todd E. Thiele; and (5) Neurochemical characteristics that may predict ethanol preference in selected P and NP rats: A quantitative microdialysis study, by Simon N. Katner.

Ethanol-induced c-fos expression in catecholamine- and neuropeptide Y-producing neurons in rat brainstem.

BACKGROUND: Previous studies have used c-Fos-like immunoreactivity (cFLI) to examine the neuroanatomical location of cells that are activated in response to ethanol administration. However, the use of cFLI alone fails to reveal the phenotypical identity of cells. In the present study we used double-labeling procedures to identify the neurochemical phenotype of neurons that showed ethanol-induced cFLI in the rat brainstem. METHODS: Individual groups of rats received intraperitoneal injection of ethanol (1.5 g/kg or 3.5 g/kg) or isotonic saline (23 ml/kg). To assess the specificity of cFLI induced by ethanol, we injected other rats with the drug lithium chloride (LiCl; 76 mg/kg). Two hours after injection, rats were killed and their brains were processed for immunohistochemistry. RESULTS: Both doses of ethanol promoted cFLI in several brainstem regions, including the nucleus of the solitary tract (NTS), the locus coeruleus (LC), and the ventrolateral medulla (VLM). Although LiCl caused significant cFLI in the NTS, this drug promoted only minimal cFLI in the VLM and no significant activation in the LC. We found that a significant proportion of tyrosine hydroxylase (TH)-positive neurons coexpressed ethanol-induced cFLI in the VLM (approximately 75-85%), the NTS (approximately 65-75%), and the LC (approximately 30-65%). Additionally, a significant proportion of neuropeptide Y (NPY)-producing neurons in the VLM coexpressed ethanol-induced cFLI (approximately 60-75%). On the other hand, LiCl promoted activation of TH-positive neurons in the VLM and the NTS but failed to stimulate cFLI in TH-producing neurons in the LC or in NPY-producing neurons of the VLM. CONCLUSIONS: Neurons in the rat brainstem that show ethanol-induced c-Fos expression produce catecholamines and NPY. This research demonstrates the usefulness of double-labeling immunohistochemistry procedures for identifying the neurochemical identity of neurons that are activated after ethanol administration.

Comparison of central administration of corticotropin-releasing hormone and urocortin on food intake, conditioned taste aversion, and c-Fos expression.

Corticotropin-releasing hormone (CRH) is a potent regulator of the hypothalamic-pituitary-adrenal axis, and reduces food intake when administered into the third cerebral ventricle (i3vt). However, CRH also promotes conditioned taste aversion (CTA) learning which indicates that its anorectic effects are accompanied by aversive consequences that would reduce food intake independently of energy regulation. Urocortin (Ucn) is a closely related mammalian peptide that binds to both identified CRH receptor subtypes and also reduces food intake when administered i3vt. The present experiments compared the aversive consequences of i3vt administration of CRH and Ucn at doses that produced comparable decrements in food intake. Experiment 1 found that 1.0 microg Ucn and 2.0 microg CRH produced similar reductions in food intake. Experiment 2 demonstrated that, at these doses, CRH but not Ucn promoted robust and reliable CTA learning. A third experiment showed comparable increased c-Fos-like immunoreactivity after Ucn and CRH in forebrain and hindbrain structures associated with food intake. It is concluded that Ucn, at doses that reduce food intake to levels like that observed after administration of CRH, do not produce similarly aversive consequences.

High ethanol consumption and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice.

Both in vitro and in vivo evidence indicate that cAMP-dependent protein kinase (PKA) mediates some of the acute and chronic cellular responses to alcohol. However, it is unclear whether PKA regulates voluntary alcohol consumption. We therefore studied alcohol consumption by mice that completely lack the regulatory IIbeta (RIIbeta) subunit of PKA as a result of targeted gene disruption. Here we report that RIIbeta knockout mice (RIIbeta-/-) showed incr eased consumption of solutions containing 6, 10, and 20% (v/v) ethanol when compared with wild-type mice (RIIbeta+/+). On the other hand, RIIbeta-/- mice showed normal consumption of solutions containing either sucrose or quinine. When compared with wild-type mice, the RIIbeta-/- mice were found to be less sensitive to the sedative effects of ethanol as measured by more rapid recovery from ethanol-induced sleep, even though plasma ethanol concentrations did not differ significantly from those of controls. Finally, both RIbeta- and catylatic subunit beta1-deficient mice showed normal voluntary consumption of ethanol, indicating that increased ethanol consumption is not a general characteristic associated with deletion of PKA subunits. These data demonstrate a role for the RIIbeta subunit of PKA in regulating voluntary consumption of alcohol and sensitivity to the intoxication effects that are produced by this drug.

The induction of c-Fos in the NTS after taste aversion learning is not correlated with measures of conditioned fear.

The induction of c-Fos-like immunoreactivity (c-FLI) in the nucleus of the solitary tract (NTS) has been shown to be correlated with behavioral expression of a conditioned taste aversion (CTA). However, because this cellular response is also dependent on an intact amygdala, it may represent the activation of a stress-related autonomic response. The present experiments addressed this possibility by evaluating the correlation between c-FLI in the intermediate division of the NTS (iNTS) and 2 measures of conditioned fear: freezing and changes in mean arterial pressure (MAP) and heart rate (HR). Exposure to the taste conditioned stimulus (CS) resulted in a marked induction of c-FLI in the iNTS, whereas exposure to a fear CS did not. Further, exposure to a taste CS did not selectively lead to increases in MAP or HR. Results suggest that induction of c-FLI in the iNTS may reflect the activation of a cell population whose function is unique to the CTA paradigm.

Neurobiological responses to ethanol in mutant mice lacking neuropeptide Y or the Y5 receptor.

We have previously shown that voluntary ethanol consumption and resistance are inversely related to neuropeptide Y (NPY) levels in NPY-knockout (NPY -/-) and NPY-overexpressing mice. Here we report that NPY -/- mice on a mixed C57BL/6Jx129/SvEv background showed increased sensitivity to locomotor activation caused by intraperitoneal (ip) injection of 1.5 g/kg of ethanol, and were resistant to sedation caused by a 3.5-g/kg dose of ethanol. In contrast, NPY -/- mice on an inbred 129/SvEv background consumed the same amount of ethanol as wild-type (WT) controls at 3%, 6%, and 10% ethanol, but consumed significantly more of a 20% solution. They exhibited normal locomotor activation following a 1.5-g/kg injection of ethanol, and displayed normal sedation in response to 2.5 and 3.0 g/kg of ethanol, suggesting a genetic background effect. Y5 receptor knockout (Y5 -/-) mice on an inbred 129/SvEv background showed normal ethanol-induced locomotor activity and normal voluntary ethanol consumption, but displayed increased sleep time caused by 2.5 and 3.0 g/kg injection of ethanol. These data extend previous results by showing that NPY -/- mice of a mixed C57BL/6Jx129/SvEv background have increased sensitivity to the locomotor activation effect caused by a low dose of ethanol, and that expression of ethanol-related phenotypes are dependent on the genetic background of NPY -/- mice.

cFos induction during conditioned taste aversion expression varies with aversion strength.

Fos-like immunoreactivity (FLI) can indicate the location of neurons activated following expression of conditioned taste aversion (CTA). After one conditioning trial FLI has been identified in the intermediate nucleus of the solitary tract (iNTS) with little expression in other brain regions. The present study assessed the effect of increasing aversion strength on the magnitude and anatomical distribution of FLI during CTA expression. When animals received three rather than one conditioning trial, significant FLI was seen not only in the iNTS but also in the parabrachial nucleus (PBN), and the central nucleus of the amygdala (CNA), regions thought to be important in taste aversion learning.

Insular cortex lesions and taste aversion learning: effects of conditioning method and timing of lesion.

The specific role of insular cortex in acquisition and expression of a conditioned taste aversion was assessed using two different conditioning methods, which vary mode of taste delivery. Involvement of insular cortex in the induction of c-Fos-immunoreactivity in the nucleus of the solitary tract, a cellular correlate of the behavioral expression of a conditioned taste aversion, was also assessed. Electrolytic lesions of insular cortex blocked behavioral expression of a conditioned taste aversion and this was evident not only when lesions were placed prior to conditioning, but also when they were made after conditioning but before testing. In contrast to the effects on behavior, lesions did not completely block the c-Fos-immunoreactivity which accompanies re-exposure to the aversive taste. In addition, the blocking of behavioral evidence of aversion conditioning by cortical lesions was seen both in animals trained under an intraoral acquisition procedure and those trained with bottle-conditioning. This contrasts with previous work with amygdala lesions which showed that amygdala was absolutely necessary for taste aversions conditioned with the intraoral method but not for those conditioned using bottle presentation of the taste. Overall, these findings imply that the details of the neural circuitry involved in taste aversion learning, including its anatomical distribution, complexity and degree of redundancy, vary with the type of conditioning method employed.

Metabolic, gastrointestinal, and CNS neuropeptide effects of brain leptin administration in the rat.

To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 micrograms) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (-8%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (-15%) and gastrointestinal fill (-50%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptin's anorexigenic action.

Glucagon-like peptide-1 (7-36) amide: a central regulator of satiety and interoceptive stress.

Glucagon-like peptide-1 (7-36) amide (GLP-1) is processed from proglucagon in the distal ileum as well as in the CNS. In the periphery, GLP-1 acts as an incretin factor and profoundly inhibits upper gastrointestinal motility ('ileal brake'), the latter presumably involving the CNS. Within the CNS, GLP-1 has a satiating effect, since administration of GLP-1 into the third cerebral ventricle reduces short-term food intake (and meal size), while administration of GLP-1 antagonists have the opposite effect. In addition, activation of GLP-1 receptors in certain brain regions elicits strong taste aversions. Similarities between toxin- and GLP-1-induced neuronal activity in the CNS (brain stem) suggest a role for central GLP-1 receptors in relaying interoceptive stress. Thus, regionally distinct GLP-1 receptor populations in the CNS may be involved in satiety or malaise. It is argued that the satiating and aversive aspects of GLP-1 serve homeostatic and nonhomeostatic functions with respect to maintenance of nutrient balance.

Ethanol consumption and resistance are inversely related to neuropeptide Y levels.

Genetic linkage analysis of rats that were selectively bred for alcohol preference identified a chromosomal region that includes the neuropeptide Y (NPY) gene. Alcohol-preferring rats have lower levels of NPY in several brain regions compared with alcohol-non-preferring rats. We therefore studied alcohol consumption by mice that completely lack NPY as a result of targeted gene disruption. Here we report that NPY-deficient mice show increased consumption, compared with wild-type mice, of solutions containing 6%, 10% and 20% (v/v) ethanol. NPY-deficient mice are also less sensitive to the sedative/hypnotic effects of ethanol, as shown by more rapid recovery from ethanol-induced sleep, even though plasma ethanol concentrations do not differ significantly from those of controls. In contrast, transgenic mice that overexpress a marked NPY gene in neurons that usually express it have a lower preference for ethanol and are more sensitive to the sedative/hypnotic effects of this drug than controls. These data are direct evidence that alcohol consumption and resistance are inversely related to NPY levels in the brain.

Ethanol consumption in rats selectively bred for differential saccharin intake.

Rat lines selectively bred for high ethanol consumption consume more saccharin solution than do their low-ethanol-consuming counterparts. The present study utilized the technique of reciprocal selection to examine the reliability of the saccharin/ethanol relationship; specifically, consumption of 1-10% ethanol solution was measured in rats selectively bred for high vs. low saccharin consumption (Occidental HiS and LoS lines). HiS rats consumed more ethanol than did LoS rats. These results support the idea that individual differences in ethanol and saccharin consumption share some common mechanism(s).

Effects of third intracerebroventricular injections of corticotropin-releasing factor (CRF) on ethanol drinking and food intake.

Corticotropin releasing factor (CRF), a neuropeptide secreted by hypothalamic and extrahypothalamic neurons, is thought to mediate stress-related behaviors. The tension reduction hypothesis suggests that ethanol drinking reduces stress; that drinking is reinforced by this reduced stress; and that the probability of drinking therefore subsequently increases. CRF also decrease food intake, and might decrease ethanol drinking similarly. We addressed these hypotheses directly by assessing the effects of intracerebroventricular (i.c.v.) CRF upon ethanol drinking (1 h/day). Rats were provided drinking tubes containing ethanol solutions that were gradually incremented in concentration (from 2% to 8% w/v, over 38 days). Ethanol intakes remained stable, ranging from 0.4 to 0.5 g/kg per hour on average, and a two-bottle choice test revealed that ethanol was preferred reliably to water. Third-i.c.v. cannulae were surgically implanted and CRF or vehicle was acutely injected immediately prior to the sessions. CRF dose-dependently reduced ethanol intake by 31% (0.5 microg) and 64% (5.0 microg), and reduced 24-h food by 9% and 21%, respectively, but did not alter body weights. I.c.v. CRF reduced ethanol drinking despite any acute stress-like effects that may have been present. Hence, these data are inconsistent with the tension reduction hypothesis. On the other hand, our results support the concept that food intake and ethanol drinking may be mediated by similar mechanisms.

Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) receptor antagonist attenuates lithium chloride-induced c-Fos induction in rat brainstem.

Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) and intraperitoneal (i.p.) injection of lithium chloride (LiCl) produce similar patterns of c-Fos induction in the rat brain. These similarities led us to assess the hypothesis that neuronal activity caused by i.p. injection of LiCl involves activation of central GLP-1 pathways. We therefore determined if third-ventricular (i3vt) infusion of a GLP-1 receptor antagonist would block LiCl-induced c-Fos expression in the brainstem. Relative to rats pretreated with i3vt infusion of vehicle, pretreatment with the potent GLP-1 receptor antagonist, des His1 Glu9 exendin-4 (10.0 microgram), significantly attenuated LiCl-induced (76 mg/kg; i.p.) c-Fos expression in several brainstem regions, including the area postrema, the nucleus of the solitary tract, and the lateral parabrachial nucleus. While central infusion of des His1 Glu9 exendin-4 also blocked GLP-1-induced (10.0 microgram) anorexia and c-Fos expression, the antagonist produced no independent effects on food intake or c-Fos expression. These results suggest that LiCl-induced c-Fos expression in the rat brainstem is mediated, at least in part, by GLP-1 receptor signaling.

Effects of food deprivation on conditioned taste aversions in rats.

Food deprivation increases the rewarding effects of self-administered drugs such as psychomotor stimulants and benzodiazepines. These drugs also possess aversive properties and can produce conditioned taste aversions (CTA). Because drug-seeking behavior is most likely affected by both the rewarding and aversive properties of drugs, we hypothesize that food deprivation might also attenuate a drug's aversive consequences. The CTAs induced by three different drugs (amphetamine, chlordiazepoxide, and LiCl) were assessed separately. Male Long-Evans rats were assigned to one of two feeding conditions: restricted (maintained at 80% of free-feeding body weight), or nonrestricted (with ad lib food). Both groups received CTA training, consisting of an intraoral infusion of a novel saccharin solution (10 min) followed immediately by one of two i.p. injections: paired rats received drug, and unpaired rats received a similar volume of saline. After 10 days of ad lib food access, saccharin was presented to all rats again, and the latency to reject the tastant was used as an index of CTA learning. The rats that had been food restricted at the time of conditioning exhibited attenuated CTAs relative to those that had not been deprived. These differences were seen only when a rewarding drug (amphetamine or chlordiazepoxide) and not when a nonrewarding drug (LiCl) was used as the unconditioned stimulus. In a separate experiment, we established that this effect is apparent only when the deprivation period precedes conditioning rather than precedes testing. The present results indicate that food deprivation modulates the acquisition of a CTA induced by amphetamine or chlordiazepoxide, but not LiCl.