Nicotine-induced conditioned taste aversion in the rat: effects of ethanol

It has been shown that small doses of ethanol antagonise the discriminative stimulus properties of nicotine in the rat. The aim of the present study was to evaluate whether ethanol could antagonise the aversive stimulus effects of nicotine. Wistar rats were trained to associate nicotine injections with a novel tasting fluid (0.1% saccharin) in the conditioned taste aversion procedure. Nicotine (0.3 mg/kg, s.c.) was injected 5 min after the end of a 20-min exposure to the saccharin solution. Ethanol (0.25-0.5 g/kg, i.p.) was administered 5 or 50 min before nicotine. In general, ethanol did not inhibit nicotine-induced conditioned taste aversion. Contrary to the findings in drug discrimination studies, a slight but significant enhancement of nicotine-induced taste aversion conditioning was observed after ethanol pre-treatment. Blood ethanol levels were measured in a separate group of rats. Maximal blood ethanol levels after i.p. administration of 0.25 or 0.5 g/kg ethanol exceeded 20 and 80 mg%, respectively. Concluding, the present results may indicate that ethanol does not attenuate nicotine-induced conditioned taste aversion in the rat.     

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     

Ethanol-induced conditioned place preference, but not aversion, is blocked by treatment with d-penicillamine, an inactivation agent for acetaldehyde

Rationale There is evidence to suggest that acetaldehyde is involved in the control of ethanol-seeking behavior and reward. d-penicillamine, a thiol amino acid, is a highly selective agent for the inactivation of acetaldehyde. Previous studies from our laboratory have demonstrated that d-penicillamine prevents both behavioral stimulation induced by ethanol and acetaldehyde-produced locomotor depression in mice. Objectives The contribution of ethanol-derived acetaldehyde to the affective effects of ethanol (preference and aversion) was assessed using an unbiased place conditioning design. Methods Male mice received four pairings of a distinctive floor stimulus (CS+: GRID+ or HOLE+) with injections of saline and ethanol (2 g/kg) given before (preference) or after (aversion) the 5-min exposure to the place conditioning apparatus. A different floor stimulus (CS−: GRID− or HOLE−), associated with saline-saline injections on alternate days, was presented. For a different group of animals, the pairings with the CS+ were associated with saline and ethanol injections, but on alternate days, they received d-penicillamine (50 or 75 mg/kg) and ethanol injections paired with the CS−floor stimulus. A 60-min preference test was carried out 24 h after the last conditioning trial. A similar procedure was followed to test the effect of d-penicillamine on morphine (16 mg/kg) and cocaine-induced (20 mg/kg) conditioned place preference (CPP). Results CPP and conditioned place aversion (CPA) were observed for ethanol, but d-penicillamine only blocked CPP. d-penicillamine, by itself, did not produce either rewarding or aversive effects. CPP observed for morphine and cocaine was unaffected by d-penicillamine pretreatment. Conclusions The results of the present study suggest that the selective inactivation of acetaldehyde blocked the rewarding, but not aversive, effects of ethanol and support the role of this ethanol metabolite in the affective properties of ethanol.     

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.     

Non-specific enhancement of ethanol-induced taste aversion by naloxone

The conditioned taste aversion paradigm (CTA) was used to examine the effects of naloxone on ethanol-induced aversion towards a saccharine solution (3 conditioning and 11 extinction trials). Six groups of rats received conditioning trials consisting of two IP injections after saccharine presentation of different combinations of either ethanol (E: 1.75 g/kg), LiCl (L: 12 mEq/kg, 0.1 M), naloxone (N: 10 mg/kg) or saline (S); S-S, S-N, E-S, E-N, L-S and L-N. Naloxone by itself produced no aversion to the saccharin flavor. Based on the onset and extinction of aversion, naloxone significantly enhanced ethanol but also LiCl-induced CTA. The comparative data argues in favor of different mechanisms of action (1) between the aversive central effects of ethanol and morphine and (2) between ethanol's acute behavioral effects and negatively reinforcing properties. Enhancement of ethanol and LiCl-induced CTA by naloxone is compatible with hypernociceptive action of the opiate-antagonist and with the pain-modulating role of opiates in the CNS.     

Differences in response to the aversive properties of ethanol in rats selectively bred for oral ethanol preference

A conditioned taste aversion (CTA) paradigm was used to determine whether aversion to the pharmacological effects of ethanol, apart from orosensory cues, can contribute to genetic differences in voluntary ethanol consumption. Four doses of ethanol, administered IP, were paired with the consumption of a 0.1% saccharin solution in rats from the alcohol-preferring (P) and alcohol-nonpreferring (NP) lines. Repeated pairing of saccharin and ethanol in a dose of 1.0 g/kg produced stronger and more prolonged aversion to saccharin in NP rats, compared with P rats, at comparable blood ethanol levels. A low dose of ethanol (0.25 g/kg) produced transient conditioned facilitation of saccharin consumption in P rats, but not in NP rats, at comparable blood ethanol levels. The results suggest that rats of the NP line find the postingestional effects of high-dose ethanol more aversive, and low-dose ethanol less reinforcing, than do rats of the P line. Genetic differences in voluntary ethanol consumption may be due, in part, to differences in aversion to the postingestional effects of ethanol.     

Discriminative stimulus effects of ethanol with a conditioned taste aversion procedure: lack of acetaldehyde substitution

Acetaldehyde has been suggested to mediate a number of the pharmacological and behavioural effects of ethanol. Recently, several studies investigated the role of acetaldehyde in the subjective effects of ethanol, but obtained conflicting results. With the discriminative taste aversion (DTA) procedure, high acetaldehyde doses were shown to substitute for the discriminative stimulus effects of ethanol. In contrast, the operant drug discrimination protocol failed to show any substitution effect of acetaldehyde. Several methodological differences between the two procedures could explain these discrepancies, and particularly the absence of an individual discrimination criterion in the DTA procedure. In the present study, the DTA procedure was adapted to introduce such a criterion. In addition, the effects of acetaldehyde were compared with those of other drugs, for which the substitution effects for ethanol are well known. Rats were trained to discriminate 1.0 g/kg ethanol from saline in a DTA protocol. When the rats met the criterion of ethanol discrimination, various doses of several drugs were tested for their ethanol stimulus substitution effects: ethanol, acetaldehyde, dizocilpine, diazepam and nicotine. The results showed a clear dose-dependent discrimination of ethanol stimulus effects. In addition, dizocilpine fully substituted for ethanol, while diazepam only partially substituted. In contrast, both acetaldehyde and nicotine failed to substitute for ethanol. These results show that acetaldehyde is not significantly involved in the subjective and discriminative stimulus effects of ethanol. Acetaldehyde up to toxic doses did not substitute for the ethanol discriminative stimulus in the DTA protocol, when non-specific effects were carefully controlled.     

Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats.

Conditioned place aversion in rats has face validity as a measure of the aversive stimulus effects of opiate withdrawal that reflects an important motivational component of opiate dependence. The purpose of the present study was to validate conditioned place aversion as sensitive to medications that will alleviate the aversive stimulus effects of opiate withdrawal in humans, and to extend this model to the exploration of the neuropharmacological basis of the motivational effects of opiate withdrawal. Male Sprague-Dawley rats were implanted with two subcutaneous morphine pellets and 5 days later began place conditioning training following subcutaneous administration of a low dose of naloxone. Animals were subjected to three pairings of a low dose of naloxone (15 microg/kg, s.c.) to one arm of a three-chambered place conditioning apparatus. Buprenorphine administered prior to each pairing dose-dependently blocked the place aversion produced by precipitated opiate withdrawal. A corticotropin-releasing factor-1 (CRF1) receptor antagonist (antalarmin) also reversed the place aversion produced by precipitated opiate withdrawal. Antalarmin did not produce a place preference or place aversion by itself in morphine-dependent rats. No effect was observed with pretreatment of the dopamine partial agonist terguride or the selective serotonin reuptake inhibitor fluoxetine. Also, chronic pretreatment with acamprosate (a glutamate receptor modulator used to prevent relapse in alcohol dependence) did not alter naloxone-induced place aversion. Buprenorphine by itself in dependent rats produced a mild place preference at low doses and a mild place aversion at higher doses. These results suggest that buprenorphine blocks the aversive stimulus effects of precipitated opiate withdrawal in rats and provides some validity for the use of place conditioning as a measure that is sensitive to potential opiate-dependence medications. In addition, these results suggest that CRF1 antagonists can block the aversive stimulus effects of opiate withdrawal and may be potential therapeutic targets for opiate dependence.     

Motivational properties of ethanol in naive rats as studied by place conditioning

The reinforcing properties of ethanol were examined in naive adult male rats by means of a place conditioning paradigm that has previously demonstrated the positive reinforcing properties of food, water and some drugs, and the aversive properties of punishers such as electric shock and lithium chloride. Only doses of 0.8-1.0 g/kg and higher produced clear place conditioning, and this was only conditioned place aversion; rats spent significantly more time on the side of the place conditioning box in which they received the vehicle than on the side in which they received ethanol. Doses between 0.1 g/kg and 0.8 g/kg produced increases in general activity, but did not produce any place conditioning. Control experiments indicated that the pattern of effects was not specific to the route of ethanol administration (intravenous or intragastric), rate of infusion, concentration, or vehicle. It was concluded that ethanol, in the doses used here, has only punishing or neutral motivational effects in naive rats and does not serve as a primary positive reinforcer in this model. The conclusions are discussed in relation to the relative difficulty encountered in attempts to produce ethanol self-administration, and the findings are viewed as consistent with a proposal that prolonged training and experience with ethanol are important for ethanol self-administration by the rat.     

An acetaldehyde-sequestering agent inhibits appetitive reinforcement and behavioral stimulation induced by ethanol in preweanling rats

Ethanol's motivational consequences have been related to the actions of acetaldehyde, a metabolic product of ethanol oxidation. The present study assessed the role of acetaldehyde in the motivational effects of ethanol on preweanling rats. In Experiment 1 pups (postnatal days 13-14, PD 13-14) were given systemic administration of d-penicillamine (DP, a drug that sequesters acetaldehyde: 0, 25, 50 or 75 mg/kg) before pairings of 1.0 g/kg ethanol and a rough surface (sandpaper, conditioned stimulus, CS). At test, pups given sandpaper-ethanol pairings exhibited greater preference for the CS than unpaired controls, but this preference was not expressed by pups given DP. Pre-training administration of 25 or 50 mg/kg DP completely blocked the expression of ethanol-mediated appetitive conditioning. d-penicillamine did not alter blood ethanol levels. Subsequent experiments revealed that ethanol-induced activation was blocked by central (intra-cisterna magna injections, volume: 1 μl, dose: 0 or 75 μg) but not systemic treatment with DP (0, 25, 50 or 75 mg/kg; ip). These results indicate that: (a) preweanling rats are sensitive to the reinforcing effect of ethanol, and (b) that this effect is associated with the motor activating effect of the drug. These effects seem to be mediated by the first metabolite of ethanol, acetaldehyde.     

Distal and proximal pre-exposure to ethanol in the place conditioning task: tolerance to aversive effect,sensitization to activating effect,but no change in rewarding effect

RATIONALE: The literature offers many examples of tolerance to ethanol's inhibitory/depressant effects and sensitization to its activating effects. There are also many examples of tolerance to ethanol's aversive effects as measured in the conditioned taste aversion and conditioned place aversion (CPA) procedures. However, there are very few demonstrations of either tolerance or sensitization to ethanol's rewarding or reinforcing effects. OBJECTIVE: The present studies were designed to examine effects of two forms of ethanol pre-exposure (distal or proximal) on ethanol's rewarding and aversive effects as indexed by the place conditioning procedure. METHOD: Male inbred (DBA/2J) mice were exposed to ethanol (2 g/kg IP) in an unbiased place conditioning procedure that normally produces either conditioned place preference (CPP) (ethanol injection before CS exposure) or CPA (ethanol injection after CS exposure). In the distal pre-exposure studies (experiments 1 and 2), mice initially received a series of four ethanol injections (0, 2, or 4 g/kg) in the home cage at 48-h intervals during the week before place conditioning. In the proximal pre-exposure studies (experiments 3-4), mice were injected with ethanol 65 min before (experimental groups) or 65 min after (control groups) each paired ethanol injection on CS+ trials. RESULTS: Distal pre-exposure produced a robust sensitization to ethanol's activating effect, whereas proximal pre-exposure generally reduced the activation normally produced by the paired ethanol injection. Both forms of pre-exposure interfered with CPA, but had no effect on CPP. CONCLUSIONS: These studies suggest that both forms of pre-exposure reduced ethanol's aversive effect, but had no impact on ethanol's rewarding effect. In general, the detrimental effects of pre-exposure on CPA are explained best in terms of a reduction in ethanol's efficacy as an aversive unconditioned stimulus (i.e. tolerance), although explanations based on other types of associative interference are also possible. The failure to affect CPP with pre-exposure treatments that reduced or eliminated CPA suggests that these behaviors are mediated by independent, motivationally opposite effects of ethanol. Moreover, these results indicate dissociation between sensitization to ethanol's locomotor activating effect and changes in its rewarding effect. To the extent that motivational processes measured by CPP and CPA normally contribute to ethanol drinking, the present findings suggest that increases in ethanol intake seen after chronic ethanol exposure are more likely caused by tolerance to ethanol's aversive effect rather than sensitization to its rewarding or reinforcing effect.     

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.     

PCP and conditioned place preferences

Phencyclidine (PCP), in doses of 0.25, 0.35, and 0.45 mg/kg, was administered systemically to male Sprague-Dawley rats in order to determine if a positive conditioned place preference (CPP) could be achieved. Other subjects received systemic injections of morphine, 4.0 mg/kg, as a standard for comparison. At testing, rats receiving 0.45 mg/kg PCP showed a positive CPP compared to controls, as did rats receiving morphine. Previous research had shown that larger doses of PCP and prolonged times after PCP administration produced aversion as indexed by CPP testing. The narrow dose range and short time span in which PCP's positively reinforcing properties are apt to emerge may be related to PCP's psychotomimetic potential and to its ability to sustain its own intake even though aversive effects are often manifest.     

Stimulation of serotonin1B receptors induces conditioned place aversion and facilitates cocaine place conditioning in rats

RATIONALE: Changes in serotonin(1B) (5-HT(1B)) receptor function appear to modify the reinforcing properties of cocaine, but the direction of this effect is not completely clear. Pharmacological stimulation of 5-HT(1B) enhanced the rewarding properties of self-administered cocaine while attenuating the threshold-reducing effect of cocaine in the intracerebral brain stimulation procedure. OBJECTIVE: The present study investigates how pharmacological modification of 5-HT(1B) receptor-mediated neurotransmission influence cocaine motivational properties in the conditioned place preference paradigm in rats. METHODS: In separate groups of rats the motivational properties of CP 94,253, a selective 5-HT(1B) agonist, or GR 127935, a 5-HT(1B/D) receptor partial agonist, given alone or in combination, were determined. To evaluate their influence on cocaine-induced place conditioning, CP 94,253, that was found to be aversive, was given every day before each conditioning session, while GR 127935, which given alone had no effect, was administered only before cocaine conditioning sessions. RESULTS: CP 94,253, injected IP at 2.5 and 10 (but not 0.5) mg/kg produced place aversion in the place conditioning paradigm. The aversive effect of 2.5 mg/kg CP 94,253 was completely reversed by 10 mg/kg SC GR 127935. Given before every conditioning session, CP 94,253 did not modify place conditioning by four injections of 10 mg/kg cocaine but at 2.5 mg/kg it potentiated a sub-threshold dose of cocaine. The place preference caused by these two drugs was completely reversed by 10 mg/kg GR 127935. The antagonism by GR 127935 of CP 94,253's effects was shown not to be due to the induction of state-dependent effects. CONCLUSION: The results suggest that stimulation of 5-HT(1B) receptors causes place aversion, and enhances the effect of low doses of cocaine in the conditioned place preference paradigm.     

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.     

Taurine and ethanol preference: a microdialysis study using Sardinian alcohol-preferring and non-preferring rats.

Recent intracerebral microdialysis studies of different rat brain regions have shown that an acute ethanol injection induced a rapid dose-dependent increase in taurine microdialysate content during the first 60-min period. In taurine-supplemented rats, a reduced aversion for high ethanol doses was observed in a place conditioning paradigm, suggesting that taurine may be implicated in the regulation of some adverse effects of ethanol. The present study compares the effects of acute ethanol injections (1.0 and 2.0 g/kg, i.p.) on taurine nucleus accumbens microdialysate content in Sardinian ethanol-preferring (sP) and Sardinian ethanol-non-preferring (sNP) rats. While neither saline nor 1.0 g/kg ethanol injections had significant effect on taurine microdialysate concentration, 2.0 g/kg ethanol administration induced a rapid and significant increase in taurine microdialysate content in both sP and sNP rats. However, this ethanol-induced taurine release was significantly reduced in sP rats by comparison to sNP rats. As taurine is suggested to be released by brain cells to modulate different ethanol adverse effects, this lower taurine responsiveness to ethanol in sP rats by comparison to both sNP and Wistar rats may be a relevant indicator of reduced ethanol aversive effects in such animals and therefore be related to their higher alcohol consumption.     

Effect of acetaldehyde on acute tolerance and ethanol consumption in drinker and nondrinker rats

OBJECTIVE: Acetaldehyde (AcH) has been shown to have aversive or reinforcing actions in relation to ethanol consumption. We have previously observed that a pharmacological dose of AcH (50-150 mg/kg) administered intraperitoneally (i.p.) produced a dose-dependent flavor aversion in low-ethanol drinker (UChA) rats, whereas high-ethanol drinker (UChB) rats appeared to be insensitive to AcH. Both strains of rats differ innately in their brain aldehyde dehydrogenase (ALDH) activity and in their capacity to develop acute tolerance to ethanol. The present study evaluates the effects of AcH, in UChA and UChB rats, on rats' behavior, their voluntary ethanol consumption and the development of acute functional tolerance to motor impairment induced by a dose of ethanol. METHOD: Subjects were rats selectively bred for high (UChB; n = 48) and low (UChA; n = 40) voluntary ethanol consumption. Rats were treated with either saline or doses of AcH (50 or 100 mg/kg, i.p.), and examined for effects on motor activity, on voluntary alcohol consumption with free access to a 10% alcohol solution and on acute tolerance to motor impairment induced by an ethanol dose (2.3 g/kg, i.p.), using the tilting plane test. RESULTS: AcH, 50 or 100 mg/kg, caused a dose-dependent loss of the righting reflex in UChA rats, whereas in UChB rats with same dose, a slight excitement was observed. There was significant increase of voluntary ethanol consumption in UChB rats (p < .001) 17 hours after the AcH injection, compared with saline-treated and control rats; in UChA rats, no change in voluntary ethanol consumption was produced. AcH produced a faster acute tolerance-to-ethanol development in UChB rats (p < .001) as compared with saline-treated and control rats, and no change in acute tolerance in UChA rats. Acetaldehyde injection did not change total mitochondrial ALDH2 activity. CONCLUSIONS: These results show that, 17 hours later, treatment of rats with pharmacological doses of acetaldehyde alters the voluntary ethanol consumption and acute tolerance development in UChB but not UChA rats. One of the factors involved may be a different sensitivity to AcH in these rat strains.     

Moderate doses of ethanol partially reverse avoidance learning deficits in high-alcohol-drinking rats

We previously reported that ethanol-naive high-alcohol-drinking (HAD1 and HAD2) rats exhibited selective deficits in active avoidance learning, as compared to low-alcohol-drinking (LAD1 and LAD2) rats, in a signaled bar-pressing task [Alcohol. Clin. Exp. Res. 24 (2000) 1778]. In the current study, we used appetitive and aversive learning tasks to assess whether administration of ethanol influences approach and avoidance learning in HAD and LAD rats. Rats were administered 0.0, 0.5, 1.0, or 1.5 g ethanol/kg body weight during appetitive and aversive conditioning sessions. We found that ethanol impaired acquisition of the appetitive conditioned response in a dose-dependent manner in both HAD and LAD rats, with 1.5 g/kg ethanol producing the greatest deficits. Notably, moderate doses of ethanol (0.5 and 1.0 g/kg) partially reversed avoidance learning deficits in HAD rats, but only when appetitive conditioning preceded aversive conditioning. The highest dose (1.5 g/kg EtOH) abolished avoidance responding altogether in HAD rats. Avoidance responding in LAD rats was not affected by any dose of ethanol. These results are consistent with previous studies suggesting that alcohol preference may be associated with increased fear or anxiety, but the conditions under which ethanol produces a reduction of fear and anxiety in HAD rats appear to be relatively complex.     

Early maternal separation affects ethanol-induced conditioning in a nor-BNI insensitive manner, but does not alter ethanol-induced locomotor activity

Early environmental stress significantly affects the development of offspring. This stress has been modeled in rats through the maternal separation (MS) paradigm, which alters the functioning of the HPA axis and can enhance ethanol intake at adulthood. Infant rats are sensitive to ethanol's reinforcing effects, which modulate ethanol seeking and intake. Little is known about the impact of MS on sensitivity to ethanol's appetitive and aversive effects during infancy. The present study assessed ethanol-induced conditioned place preference established through second-order conditioning (SOC), spontaneous or ethanol-induced locomotor activity and ethanol intake in preweanling rats that experienced normal animal facility rearing (AFR) or daily episodes of maternal separation (MS) during postnatal days 1-13 (PDs 1-13). Low-ethanol dose (0.5 g/kg) induced appetitive conditioned place preference (via SOC) in control rats given conventional rearing but not in rats given maternal separation in early infancy, whereas 2.0 g/kg ethanol induced aversive conditioned place preference in the former but not the latter. The administration of a kappa antagonist at PD 1 or immediately before testing did not alter ethanol-induced reinforcement. High (i.e., 2.5 and 2.0 g/kg) but not low (i.e., 0.5 g/kg) ethanol dose induced reliable motor stimulation, which was independent of early maternal separation. Ethanol intake and blood alcohol levels during conditioning were unaffected by rearing conditions. Pups given early maternal separation had lower body weights than controls and showed an altered pattern of exploration when placed in an open field. These results indicate that, when assessed in infant rats, earlier maternal separation alters the balance between the appetitive and aversive motivational effects of ethanol but has no effect on the motor activating effects of the drug.     

DBA/2J mice develop stronger lithium chloride-induced conditioned taste and place aversions than C57BL/6J mice

Genetic differences in lithium-induced conditioned aversion were examined using both place- and taste-conditioning procedures. In the place-conditioning procedure, adult male C57BL/6J (B6) and DBA/2J (D2) mice were exposed to a differential conditioning procedure in which each mouse received four 30-min pairings of a distinctive floor cue immediately after IP injections of either 0.75, 1.5, or 3. 0 mEq/kg LiCl. A different floor cue was paired with saline injections. A separate group of control mice received saline injections paired with both floor types. Subsequent floor preference testing revealed greater conditioned aversion in D2 mice compared to B6 mice in groups receiving 3.0 mEq/kg LiCl. Lower LiCl doses did not produce conditioning in either strain. In a conditioned taste-aversion procedure, fluid-restricted mice received four trials in which access to 0.2 M NaCl solution was followed by IP injection of either 0.75, 1.5, 3.0, or 6.0 mEq/kg LiCl. D2 mice showed stronger conditioned taste aversion than B6 mice at all doses, suggesting that taste conditioning may be a more sensitive index of aversive drug sensitivity than place conditioning. These findings are not well explained by strain differences in general learning ability or by strain differences in stimulus salience or innate preference. Rather, these data appear more consistent with previous studies showing strain differences in lithium pharmacokinetics and in general sensitivity to aversive events.