Time-dependent retrograde amnesic effects of muscimol on conditioned taste aversion extinction

We explored how stimulation of GABA_A receptors at different times during conditioned taste aversion (CTA) acquisition or extinction influenced extinction. In Experiment 1, rats acquired a CTA to 0.3% saccharin-flavored water (SAC) when it followed an injection of lithium chloride (LiCl; 81.0 mg/kg, i.p.). Following conditioning, rats received extinction training in which the GABA_A agonist muscimol (1.0 mg/kg, i.p.), or control (saline) injections, were administered either before or after each extinction trial. Muscimol hindered extinction when administered after extinction trials. Muscimol's inhibitory effects may have impeded extinction learning by disrupting synaptic mechanisms required to consolidate information experienced during extinction training. In Experiment 2, we studied the effects of muscimol on CTA acquisition and subsequent extinction. Rats received muscimol (1.0 mg/kg, i.p.) either before or after CTA conditioning trials. Following CTA acquisition, all rats were given CTA extinction training without muscimol administration. All groups developed CTA, but the group that received muscimol before CTA conditioning trials extinguished rapidly in comparison to other treatment groups. Differences between muscimol's effects on CTA conditioning and CTA extinction indicate that fear conditioning and extinction involve, to some degree, different neuronal mechanisms.     

Extinction of ethanol-induced conditioned place preference and conditioned place aversion: effects of naloxone

 Four experiments examined the effect of naloxone pretreatment on the expression and extinction of ethanol-induced conditioned place preference (experiments 1, 2, 4) or conditioned place aversion (experiments 1, 3). DBA/2 J mice received four pairings of a distinctive tactile (floor) stimulus (CS) with injection of ethanol (2 g/kg) given either immediately before or after 5-min exposure to the CS. A different stimulus was paired with injection of saline. Pre-CS injection of ethanol produced conditioned place preference, whereas post-CS injection of ethanol produced conditioned place aversion. Both behaviors extinguished partially during repeated choice testing after vehicle injection. Naloxone (10 mg/kg) had little effect on the initial expression of conditioned place preference, but facilitated its extinction. Moreover, repeated naloxone testing resulted in the expression of a weak conditioned place aversion to the CS that initially elicited a place preference. In contrast, naloxone (1.5 or 10 mg/kg) enhanced expression of conditioned place aversion, thereby increasing its resistance to extinction. A control experiment (experiment 4) indicated that repeated testing with a different aversive drug, lithium chloride, did not affect rate of extinction or produce an aversion to the CS previously paired with ethanol. These findings do not support the suggestion that naloxone facilitates the general processes that underlie extinction of associative learning. Also, these data are not readily explained by the conditioning of place aversion at the time of testing. Rather, naloxone’s effects appear to reflect a selective influence on maintenance of ethanol’s conditioned rewarding effect, an effect that may be mediated by release of endogenous opioids. Overall, these findings encourage further consideration of the use of opiate antagonists in the treatment of alcoholism. Received: 4 December 1997 / Final version: 16 February 1998     

Suppression of feeding by naloxone in rat: a dose-response comparison of anorexia and conditioned taste aversion suggesting a specific anorexic effect

The dose-related suppression of feeding by naloxone (0.25-15.0 mg/kg), either by injection before feeding, or by conditioning taste aversion (CTA), was compared. The weaker suppression found for CTA at low (below 0.75 mg/kg) and high (above 5.0 mg/kg) doses suggests that the aversive sequelae of naloxone injection cannot account fully for its suppressive effects. In turn, this suggests that naloxone exerts a specific anorexic effect. Comprehensive dose-response curves for naloxone anorexia (15 doses) and CTA (nine doses) are presented.     

GABAA receptors modulate ethanol-induced conditioned place preference and taste aversion in mice

  Rationale: GABA_A receptor antagonists have been shown to reduce ethanol self-administration and ethanol-induced conditioned taste aversion (CTA) in rats, suggesting a role for the GABA_A receptor in modulating ethanol’s motivational effects. Objectives: The present experiments examined the effects of the GABA_A receptor antagonists, bicuculline and picrotoxin, on the acquisition of ethanol-induced conditioned place preference (CPP) and CTA in male DBA/2J mice. Methods: Mice in the CPP experiments received four pairings of ethanol (2 g/kg) with a distinctive floor stimulus for a 5-min conditioning session (CS+ sessions). During CS+ sessions, mice also received bicuculline (0, 1.0, 3.0, or 5.0 mg/kg) or picrotoxin (2.0 mg/kg) before an injection of ethanol. On intervening days (CS– sessions), the pretreatment injection was always vehicle followed by saline injections that were paired with a different floor type. For the preference test, all mice received saline injections and were placed on a half grid and half hole floor for a 60-min session. For the CTA experiments, mice were adapted to a 2-h per day water restriction regimen followed by five conditioning trials every 48 h. During conditioning trials, subjects received an injection of vehicle, bicuculline (0.5 and 2.0 mg/kg), or picrotoxin (0.75 and 2.5 mg/kg) before injection of 2 g/kg ethanol or saline following 1-h access to a saccharin solution. Results: Both picrotoxin and the lowest dose of bicuculline (1.0 mg/kg) significantly increased the magnitude of CPP relative to vehicle-treated controls. Picrotoxin alone did not produce place conditioning. Ethanol-stimulated locomotor activity was significantly reduced during conditioning trials with picrotoxin and the higher doses of bicuculline (3.0 and 5.0 mg/kg). Bicuculline did not alter ethanol-induced CTA; however, picrotoxin dose-dependently increased the magnitude of ethanol-induced CTA. Bicuculline and picrotoxin did not produce CTA when administered alone. Conclusions: Overall, these results suggest that blockade of GABA_A receptors with bicuculline and picrotoxin enhances ethanol’s motivational effects in the CPP paradigm; however, only picrotoxin enhances ethanol’s motivational effects in the CTA paradigm. Received: 12 September 1998 / Final version: 21 December 1998     

Baclofen alters ethanol-stimulated activity but not conditioned place preference or taste aversion in mice.

The present experiments examined the effects of the GABA(B) receptor agonist, baclofen, on the acquisition of ethanol-induced conditioned place preference (CPP) and conditioned taste aversion (CTA) in male DBA/2J mice. Mice in the CPP experiment received four pairings of ethanol (2g/kg) with a distinctive floor stimulus for a 5-min conditioning session (CS+ sessions). On intervening days (CS- sessions), mice received saline injections paired with a different floor type. On CS+ days, mice also received one of four doses of baclofen (0.0. 2.5, 5.0, or 7.5 mg/kg) 15 min before an injection of ethanol. For the preference test, all mice received saline injections, and were placed on a half-grid and half-hole floor for a 60-min session. Baclofen dose dependently reduced ethanol-stimulated activity, but did not alter the magnitude of ethanol-induced CPP at any dose. For the CTA experiment, mice were adapted to a 2-h per day water restriction regimen followed by five conditioning trials every 48 h. During conditioning trials, subjects received an injection of saline or baclofen (2.0 and 6.0 mg/kg) 15 min before injection of 2 g/kg ethanol or saline following 1-h access to a saccharin solution. Baclofen did not alter the magnitude of ethanol-induced CTA at any dose. In addition, baclofen alone did not produce a CTA. Overall, these studies show that activation of GABA(B) receptors with baclofen reduces ethanol-induced locomotor activation, but does not alter ethanol's rewarding or aversive effects in the CPP and CTA paradigms in DBA/2J mice.     

Genetic differences in naloxone enhancement of ethanol-induced conditioned taste aversion

The influence of the opioid system on acquisition of an ethanol-induced conditioned taste aversion was examined in alcohol-preferring and avoiding inbred strains of mice (C57BL/6J and DBA/2J). Fluid-deprived mice from each strain received either ethanol alone, naloxone alone, or both ethanol and naloxone immediately after access to a novel tasting fluid. Naloxone alone (1 or 3 mg/kg) did not induce a conditioned taste aversion in either strain of mice. Administration of ethanol (1.5 g/kg) to DBA/2J mice produced a moderate taste aversion that was not affected by co-administration of naloxone. Although ethanol administered alone (3 g/kg) did not cause a taste aversion in C57BL/6J mice, the combination of ethanol and the higher dose of naloxone produced a significant taste aversion that increased across trials. A second experiment addressed the possibility that naloxone failed to enhance the ethanol-induced condition taste aversion in DBA/2J mice due to a floor effect on consumption. A lower ethanol dose (1 g/kg) was given alone or in combination with naloxone (1 or 3 mg/kg). Again, ethanol produced a moderate conditioned taste aversion that was not potentiated by naloxone. Subsequent conditioning with a high ethanol dose produced further suppression of intake, confirming that naloxone's failure to enhance aversion on earlier trials was not due to a floor effect. These data demonstrate a strain specific interaction between the aversive effect of ethanol and naloxone. More specifically, the results indicate that blockade of opioid receptors enhances the aversive effect of ethanol in C57BL/6J but not DBA/2J mice, suggesting that genetically determined differences in the endogenous opioid system of alcohol-preferring mice may mitigate ethanol's aversive effect.     

Conditioned taste aversion and alcohol drinking: strain and gender differences

OBJECTIVE: The present study examined the relationship between ethanol-induced conditioned taste aversion (CTA) and ethanol oral self-administration (OSA) in male and female rats (N = 183) from three related strains not genetically selected for their ethanol preference and differing in their emotional reactivity profile. The strains used were the Wistar Kyoto (WKY), Spontaneously Hypertensive (SHR) and Wistar Kyoto Hyperactive (WKHA). We hypothesized that differences between strains in sensitivity to the aversive properties of alcohol could explain the different propensities to drink alcohol solutions. METHOD: All animals were given three conditioning trials consisting of 20-minute access to saccharin solution followed by saline or ethanol injections (0.5, 1 or 1.5 g/kg, intraperitoneally). Animals subsequently had free access to ethanol OSA for 3 weeks, followed by two CTA trials. RESULTS: Ethanol injections produce a dose-dependent reduction of saccharin consumption in all animals; moreover, the strength of the CTA is gender- and strain-dependent. Taste avoidance induced by ethanol injections disturbed the initiation of ethanol OSA in two strains (WKY and WKHA) but did not change subsequent long-term ethanol consumption in either strain. In addition, voluntary alcohol drinking experience does not attenuate ethanol-induced CTA, and no association was found between ethanol-induced CTA and ethanol OSA. CONCLUSIONS: The data confirm the large variation among strains and between genders in alcohol drinking and taste-aversion learning, but suggest that there is no relationship between the sensitivity to the aversive properties of alcohol and alcohol drinking.     

Dose response effects of lithium chloride on conditioned place aversions and locomotor activity in rats

The present study examined the multi-variable locomotor activity effects of lithium chloride (LiCl) treatment in male rats. Of interest was a determination of which variables might show a dose-response relationship in LiCl-induced conditioned place aversions. Automated open-fields were partitioned into two chambers distinct in tactile and visual cues. A control group [n=8] received saline (NaCl; 0.15 M) paired with both chambers while three LiCl groups (0.15 M; 32 mg/kg [n=7], 95 mg/kg [n=7], 127 mg/kg [n=7]) received LiCl paired with the normally preferred chamber and saline paired with the non-preferred chamber. During extinction trials, rats were allowed to choose between the two chambers to provide an index of conditioned place aversions. Locomotor activity and its distribution within the chambers were also assessed during both conditioning and extinction trials. Dose-dependent decreases occurred in all measures of locomotor activity following LiCl administration during conditioning. During extinction trials, place aversions developed in animals conditioned with LiCl. LiCl-treated rats spent significantly less time in the LiCl-paired chamber relative to controls but not in a dose-dependent manner. Animals that had been conditioned with 95 or 127 but not 32 mg/kg LiCl, displayed significantly more vertical activity in the LiCl-paired chamber than controls during extinction trials. These findings indicate that, in addition to producing dose-dependent unconditioned effects on locomotor activity, LiCl also produces dose-dependent conditioned effects on vertical activity. These conditioned rearing response effects provide a valid measure of the conditioned avoidance response that provides evidence for dose-dependent LiCl-induced conditioned place aversions.     

Conditioning tastant and the acquisition of conditioned taste avoidance to drugs of abuse in DBA/2J mice

RATIONALE: Conditioned taste aversion (CTA) produced by drugs of abuse such as morphine and cocaine has been interpreted as representing the rewarding actions of these drugs. Evidence for this interpretation is based, in part, on findings in rats indicating saccharin is a more effective conditioning flavor compared to salt (NaCl). However, our studies with ethanol have found salt to be a highly effective conditioning flavor in mice. OBJECTIVES: The present series of studies examined the acquisition of CTA to morphine, ethanol, lithium chloride, and cocaine. Further, saccharin and salt were utilized in each experiment in order to determine effectiveness of each flavor to serve as a conditioning stimulus. METHODS: In four separate experiments, adult male DBA/2J mice were acclimated to a 2 h/day water restriction regimen. Subsequently they received four conditioning trials consisting of 1 h access to either 0.15% w/v saccharin or 0.1 M salt followed by 0, 10 or 20 mg/kg morphine (experiment 1), 0, 2, or 4 g/kg ethanol (experiment 2), 0, 1.5 or 3.0 milliequivalents/kg lithium chloride (experiment 3) or 0, 10 or 20 mg/kg cocaine (experiment 4). A fifth flavor access period (trial 5) was not followed by drug exposure. Following trial 5, each subject received 24-h access to the conditioning flavor and water (two-bottle test 1). Control subjects (0 dose groups from each experiment) received a second two-bottle test with 24-h access to both saccharin and salt flavors. RESULTS: Reduced flavor intake and reduced flavor preference was noted in all drug-paired groups in each experiment. However, more rapid development of CTA was seen with the saccharin flavor in morphine- or cocaine-paired groups. In contrast, ethanol-induced CTA appeared more rapidly with the salt flavor. Lithium-induced CTA was modest, and emerged equally with either flavor. CONCLUSIONS: CTA induced by morphine or cocaine in mice occurs in a similar pattern to that seen in rats, and these findings agree with an interpretation based on drug reward. In contrast, ethanol-induced CTA is more likely attributable to aversive effects.     

Genetic and early environmental contributions to alcohol's aversive and physiological effects

Genetic and early environmental factors interact to influence ethanol's motivational effects. To explore these issues, a reciprocal cross-fostering paradigm was applied to Fischer and Lewis rats. The adult female offspring received vehicle or the kappa opioid antagonist nor-BNI (1 mg/kg) followed by assessments of conditioned taste aversion (CTA), blood alcohol concentrations (BACs) and hypothermia induced by 1.25 g/kg intraperitoneal ethanol. CTA acquisition in the in-fostered Fischer and Lewis animals did not differ; however, the Fischer maternal environment produced stronger acquisition in the cross-fostered Lewis rats versus their in-fostered counterparts. CTAs in the Fischer rats were not affected by cross-fostering. In extinction, the in-fostered Lewis animals displayed stronger aversions than the Fischer groups on two trials (of 12) whereas the cross-fostered Lewis differed from the Fischer groups on nine trials. Despite these CTA effects, Lewis rats exhibited higher BACs and stronger hypothermic responses than Fischer with no cross-fostering effects in either strain. No phenotypes were affected by nor-BNI. These data extend previous findings dissociating the aversive and peripheral physiological effects of ethanol in female Fischer and Lewis rats, and highlight the importance of genetic and early environmental factors in shaping subsequent responses to alcohol's motivational effects in adulthood.     

Role of catalase in ethanol-induced conditioned taste aversion: a study with 3-amino-1,2,4-triazole

Recent studies involved acetaldehyde, the first ethanol metabolite, in both the rewarding and aversive effects of ethanol consumption. Brain acetaldehyde is believed to originate mainly from local brain metabolism of ethanol by the enzyme catalase. Therefore, the inhibition of catalase by 3-amino-1,2,4-triazole (aminotriazole) may help to clarify the involvement of acetaldehyde in ethanol's hedonic effects. In the present study, multiple doses of both ethanol and aminotriazole were used to investigate the effects of catalase inhibition on ethanol-induced conditioned taste aversion (CTA). A separate microdialysis experiment investigated the effects of aminotriazole pretreatment on the time course of brain ethanol concentrations. Ethanol induced a dose-dependent CTA with a maximal effect after conditioning with 2.0 g/kg ethanol. Aminotriazole pretreatments dose-dependently potentiated the CTA induced by 1.0 g/kg ethanol. However, aminotriazole pretreatments did not alter the CTA induced by higher ethanol doses (1.5 and 2.0 g/kg) probably because a maximal aversion for saccharin was already obtained without aminotriazole. The results of the microdialysis experiment confirmed that the effects of aminotriazole cannot be attributed to local alterations of brain ethanol levels. The present study argues against a role for brain acetaldehyde in ethanol's aversive effects but in favor of its involvement in ethanol rewarding properties.     

Second-order (environmental) conditioning of a taste aversion in rats

Four groups of rats (n = 10/group) were conditioned in a taste aversion task using a second-order reinforcer associated with precipitated morphine withdrawal. Rats in CS+, CS- and CS(random) groups were exposed to a chronic morphine (morphine sulfate, MS) dosing regimen. A control group received equivalent volumes of saline. All rats then received daily i.p. injections of naloxone HCI (1.0-3.2mg/kg), inducing precipitated morphine withdrawal in group-dependent unique environments. The 4-h withdrawal trials were terminated by a 20mg/kg MS injection (MS treatment groups only) and returned to their home cage. After a 1-week wash-out was imposed, all subjects were exposed to a conditioned taste aversion (CTA) task using environmental stimuli (CSI) from Phase 1 paired with saccharin (CS2) in a second-order conditioning procedure. The CS+ group developed a significant CTA; the CS- and CS(random) groups increased their consumption of saccharin. The saline group was unaffected by the treatment conditions. The data demonstrate the salience and importance of environmental stimuli and suggest a role for such conditioning in drug relapse phenomena.     

Learned taste aversion to saccharin following intraventricular or intraperitoneal administration of d,1-amphetamine

The effects of intracerebroventricular (ICV—160, 250, 500 μg) and intraperitoneal (IP—3,5 mg/kg) administration of d,1-amphetamine were compared using a multiple-bottle CTA procedure. After one conditioning trial animals receiving IP amphetamine exhibited a marked aversion to saccharin. This effect was dose-dependent. With cannulated animals receiving ICV saline the effectiveness of amphetamine at 5 mg/kg IP was equivalent to that of 3 mg/kg IP with unoperated rats. After one conditioning trial amphetamine at 160 μg ICV was ineffective in inducing an aversion to saccharin. Animals receiving 250 or 500 μg ICV exhibited a marked aversion to saccharin after one trial. The 160 μg ICV dose was effective after two conditioning trials. This differential potency of centrally and peripherally administered amphetamine after one conditioning trial indicates that the aversive stimulus properties of amphetamine may not simply be centrally mediated. It is proposed that both central and peripheral amphetamine effects may be necessary for the induction of a CTA with this drug.     

Conditioned place aversion is a highly sensitive index of acute opioid dependence and withdrawal

Rationale Conditioned place aversion (CPA) is known to be a sensitive measure of the aversive motivational state produced by opioid withdrawal in rats made chronically dependent on opioids. Objective The purpose of the present study was to examine the sensitivity of the CPA model in detecting a possible aversive state associated with naloxone-precipitated withdrawal from acute treatment with morphine. Methods Doses of morphine and naloxone, as well as number of conditioning trials, were systematically varied to determine the minimum conditions that would result in a detectable CPA in male Wistar rats. Naloxone (0.003–16.7 mg/kg) was administered 4 h after an injection of vehicle or morphine (1.0, 3.3, or 5.6 mg/kg) and immediately prior to confinement to one compartment of the conditioning apparatus; rats received either one or two such naloxone-conditioning trials (separate by 48 h). Results Morphine (5.6 mg/kg) followed 4 h later by vehicle produced no significant preference or aversion. In morphine-naive rats, 10 mg/kg naloxone was required to produce a significant CPA with two cycles of conditioning. When increasing doses of morphine were administered (1.0, 3.3, 5.6 mg/kg), significant increases in naloxone potency to elicit a CPA were observed (16-, 211-, and 1018-fold potency shifts, respectively). Naloxone potency after two pretreatments with 5.6 mg/kg morphine was comparable to its potency to elicit a CPA after chronic exposure to morphine. Although naloxone was still effective in producing a CPA after a single conditioning cycle (and hence a single morphine exposure), its effects were dramatically reduced relative to those seen with two conditioning cycles. Conclusions CPA is a reliable and sensitive index of the aversive motivational state accompanying withdrawal from acute opioid dependence.     

Role of acetaldehyde in ethanol-induced conditioned taste aversion in rats

Rationale. In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. Objectives. The present study reexamined the role of acetaldehyde in ethanol-induced conditioned taste aversion (CTA). A first experiment compared ethanol- and acetaldehyde-induced CTA. In a second experiment, cyanamide, an aldehyde dehydrogenase inhibitor, was administered before conditioning with either ethanol or acetaldehyde to investigate the effects of acetaldehyde accumulation. Methods. A classic CTA protocol was used to associate the taste of a saccharin solution with either ethanol or acetaldehyde injections. In experiment 1, saccharin consumption was followed by injections of either ethanol (0, 0.5, 1.0, 1.5 or 2.0 g/kg) or acetaldehyde (0, 100, 170 or 300 mg/kg). In experiment 2, the rats were pretreated with either saline or cyanamide (25 mg/kg) before conditioning with either ethanol or acetaldehyde. Results. Both ethanol and acetaldehyde induced significant CTA. However, ethanol produced a very strong CTA relative to acetaldehyde that induced only a weak CTA even at toxic doses. Cyanamide pretreatments significantly potentiated ethanol- but not acetaldehyde-induced CTA. Conclusions. The present results indicate that ethanol-induced CTA does not result from brain acetaldehyde effects. In contrast, it is suggested that the reinforcing effects of brain acetaldehyde might actually reduce ethanol-induced CTA. Our results also suggest that the inhibition of brain catalase activity may contribute to the potentiating effects of cyanamide on ethanol-induced CTA. Electronic Publication     

Asymmetric serial interactions between ethanol and cocaine in taste aversion learning

Although the interaction between ethanol and cocaine is well documented, it has generally been limited to situations in which the two drugs are given concurrently. Little exists on the interaction between ethanol and cocaine when one drug is given prior to the other. In Experiment 1, female Long-Evans rats were given five exposures to ethanol (2 g/kg ip) or vehicle prior to taste aversion conditioning with cocaine (32 mg/kg sc) for a total of five conditioning trials. In Experiment 2, rats were given five exposures to cocaine (32 mg/kg sc) or vehicle prior to taste aversion conditioning with ethanol (2 g/kg ip) for a total of five conditioning trials. Ethanol-preexposed, cocaine-conditioned animals (Experiment 1) displayed attenuated aversions to the cocaine-associated solution, drinking significantly greater amounts of saccharin than vehicle-preexposed, conditioned subjects. Conversely, cocaine-preexposed, ethanol-conditioned animals (Experiment 2) displayed robust aversions to the ethanol-associated solution, drinking levels comparable to those consumed by vehicle-preexposed, conditioned subjects and drinking significantly less than controls. Although the basis for these asymmetric effects is not known, they may have implications for abuse vulnerability in that drug history may impact subsequent drug toxicity that, in turn, may alter drug acceptability.     

Ethanol-induced CTA mediated by acetaldehyde through central catecholamine activity

The possible involvement of catecholamines (CA) in the mediation of acetaldehyde's conditioned taste aversion (CTA) was examined by testing the effects of alpha-methyl-para-tyrosine (AMPT, a tyrosine hydroxylase inhibitor) on the CTAs produced by acetaldehyde. AMPT blocked the acquisition of the CTA normally produced by a low dose of acetaldehyde (0.2 g/kg), but had no significant effect on CTA produced by a high dose of acetaldehyde (0.3 g/kg). In a second study, acetaldehyde's role in the CTA produced by ethanol was investigated using the pre-exposure conditioned taste aversion paradigm. Pre-exposure to acetaldehyde (both doses) blocked the ethanol CTAs but when pre-exposure with acetaldehyde was coupled with AMPT, only the larger dose of acetaldehyde blocked the ethanol aversion. These results suggest that while the CTA to the low dose of acetaldehyde may be primarily central and catecholamine-mediated, the mechanism underlying the high dose CTA is probably peripheral and emetic in nature. These findings support the conclusion that acetaldehyde may be mediating many of the actions of ethanol.     

Failure of Ro15-4513 to alter an ethanol-induced taste aversion.

The ability of Ro15-4513, an imidazobenzodiazepine inverse benzodiazepine agonist, to attenuate/block the acquisition of an ethanol (ETOH)-induced conditioned taste aversion (CTA) was investigated in two experiments. Experiment 1 examined the effects of Ro15-4513 (3 mg/kg) on rats' consumption of a novel saccharin solution under a traditional CTA paradigm. Experiment 2 examined the effects of Ro15-4513 (3 mg/kg) on rats' consumption of a novel saccharin solution under a preexposure CTA paradigm. Under the preexposure paradigm, rats were given Ro15-4513 immediately before each of five daily consecutive preexposure treatments prior to the initial conditioning day. To obtain maximal preexposure and unconditioned stimulus effects, a 2-g/kg dose of ETOH (20% v/v) was used in the present study. As previously reported, animals given ETOH following 20-min access to a novel saccharin solution established moderate to strong aversions, with the degree of aversion being directly related to the number of conditioning days. Experiment 1 showed that Ro15-4513 failed to alter the CTA induced by ETOH. Experiment 2 further showed that Ro15-4513 failed to block the preexposure effect exerted on the ETOH-mediated CTA. The results confirm previous reports regarding the failure of Ro15-4513 to disrupt an ETOH-induced CTA. These data are in agreement with a number of behavioral studies demonstrating the failure of Ro15-4513 to antagonize certain actions of ETOH. Moreover, the present study along with a previous report suggests that ETOH-induced CTA's do not appear to be mediated via actions at the GABA-BDZ receptor complex.     

Lithium-chloride-induced conditioned taste aversions in the Lewis and Fischer 344 rat strains

Conditioned taste aversions (CTAs) are differentially induced by cocaine and morphine in the Lewis and Fisher 344 (LEW and F344, respectively) rat strains. Although the acquisition of LiCl-induced aversions has recently been reported to be comparable between the two strains, these aversions were induced by the oral consumption of LiCl, and the possibility exists that, given their different weights, that differential doses were functionally administered. To address the issue of LiCl-induced aversions in LEW and F344 rats (and to control for this possible confound), the present study assessed the ability of intraperitoneally (ip) administered LiCl to induce aversions in the two strains. Specifically, rats from both strains were given 20-min access to saccharin and injected immediately, thereafter, with 0.3, 0.6, 0.9 or 1.2 mEq/kg, 0.15 M LiCl (or its distilled water vehicle). Under these conditions, both strains acquired dose-dependent aversions that increased over repeated trials. Although there was no overall strain difference in LiCl-induced aversions, LEW rats displayed a stronger aversion at the 0.3 mEq/kg dose (on Trial 3) and acquired the aversion at this dose more rapidly than the F344 rats did (by Trial 2 vs. Trial 3). Although evident, this strain difference with LiCl does not parallel that reported with morphine (in which F344 rats are more sensitive than LEW rats) or with cocaine (in which the differences between LEW and F344 rats are larger and occur at more doses and on more trials). These cross-drug comparisons suggest that strain differences in aversion learning are drug dependent. Because drug acceptability has been reported to be a function of the balance between the reinforcing and aversive effects of various compounds, the examination of possible strain differences in aversion learning with a range of such compounds may provide insight into drug acceptability (and use) in these strains.     

Chronic alcohol consumption in alcohol-preferring P rats attenuates subsequent conditioned taste aversion produced by ethanol injections

Rats of the P line were tested for the development of tolerance to the aversive effects of ethanol during 33 days of continuous availability of food, water and a 10% (v/v) ethanol solution. Beginning on the day following the removal of ethanol, five daily conditioned taste aversion (CTA) trials were administered to the ethanol-drinking P rats and an ethanol-naive control group. The CTA trials consisted of a 20-min access to a Polycose solution, followed by IP injection of saline, 0.5, 1.0, or 1.5 g ethanol/kg. The ethanol-drinking rats developed a preference for the Polycose solution when it was paired with 0.5 g ethanol injections, but the control rats did not. Both control and ethanol groups had similar CTAs at the 1.5 g dose. However, at the 1.0 g dose, the ethanol group had an attenuated CTA compared with the water control group. The results suggest that P rats develop tolerance to aversive effects of ethanol during chronic drinking. This tolerance could contribute to the high ethanol intake in these selectively-bred rats.