Alcohol-preferring AA Rats Research Articles

Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors.

Opioid antagonist treatments reduce alcohol drinking in rodent models and in alcohol-dependent patients, with variable efficacy across different studies. These treatments may suffer from the development of tolerance and opioid receptor supersensitivity, as suggested by preclinical models showing activation of these processes during and after subchronic high-dose administration of the short-acting opioid antagonist naloxone. In the present study, we compared equipotent low and moderate daily doses of naltrexone and nalmefene, two opioid antagonists in the clinical practice for treatment of alcoholism. The antagonists were given here subcutaneously for 7 days either as daily injections or continuous osmotic minipump-driven infusions to alcohol-preferring AA rats having trained to drink 10% alcohol in a limited access protocol. One day after stopping the antagonist treatment, [35 S]GTPγS autoradiography on brain cryostat sections was carried out to examine the coupling of receptors to G protein activation. The results prove the efficacy of repeated injections over infused opioid antagonists in reducing alcohol drinking. Tolerance to the reducing effect on alcohol drinking and to the enhancement of G protein coupling to μ-opioid receptors in various brain regions were consistently detected only after infused antagonists. Supersensitivity of κ-opioid receptors was seen in the ventral and dorsal striatal regions especially by infused nalmefene. Nalmefene showed no clear agonistic activity in rat brain sections or at human recombinant κ-opioid receptors. The findings support the as-needed dosing practice, rather than the standard continual dosing, in the treatment of alcoholism with opioid receptor antagonists.

Different Hypothalamic Nicotinic α7 Receptor Expression and Response to Low Nicotine Dose in Alcohol-Preferring and Alcohol-Avoiding Rats.

The aim of this study was to examine possible differences in nicotinic acetylcholine receptors and responses in rats with genetic preference or avoidance for alcohol. This was done by using 2 rat lines with high alcohol preference (Alko Alcohol [AA]) or alcohol avoidance (Alko Non-Alcohol [ANA]). Locomotor activity was measured following nicotine and histamine H3 receptor (H3R) antagonist treatment. In situ hybridization and receptor ligand binding experiments were used in drug-naïve animals to examine the expression of different α nicotinic receptor subunits. The AA rats were found to be more sensitive to the stimulatory effect of a low dose of nicotine than ANA rats, which were not significantly activated. Combination of histamine H3R antagonist, JNJ-39220675, and nicotine resulted to similar locomotor activation as nicotine alone. To further understand the mechanism underlying the difference in nicotine response in AA and ANA rats, we studied the expression of α5, α6, and α7 nicotinic receptor subunits in specific brain areas of AA and ANA rats. We found no differences in the expression of α5 nicotinic receptor subunits in the medial habenula and hippocampus or in α6 subunit in the ventral tegmental area and substantia nigra. However, the level of α7 nicotinic receptor subunit mRNA was significantly lower in the tuberomamillary nucleus of posterior hypothalamus of alcohol-preferring AA rats than in alcohol-avoiding ANA rats. Also the hypothalamic [125I-α-bungarotoxin binding was lower in AA rats indicating lower levels of α7 nicotinic receptors. The lower expression and receptor binding of α7 nicotinic receptors in the tuberomamillary nucleus of AA rats suggest a difference in the regulation of brain histamine neurons between the rat lines since the α7 nicotinic receptors are located in histaminergic neurons. Stronger nicotine-induced locomotor response, mediated partially via α7 receptors, and previously described high alcohol consumption in AA rats could be explained by the found difference in tuberomamillary α7 receptor levels.

Innate BDNF expression is associated with ethanol intake in alcohol-preferring AA and alcohol-avoiding ANA rats

We have shown recently that acute administration of ethanol modulates the expression of brain-derived neurotrophic factor (BDNF) in several rat brain areas known to be involved in the development of addiction to ethanol and other drugs of abuse, suggesting that BDNF may be a factor contributing to the neuroadaptive changes set in motion by ethanol exposure. The purpose of the present study was to further clarify the role of BDNF in reinforcement from ethanol and in the development of addiction to ethanol by specifying the effect of acute administration of ethanol (1.5 or 3.0g/kg i.p.) on the expression profile of BDNF mRNA in the ventral tegmental area and in the terminal areas of the mesolimbic dopamine pathway in the brain of alcohol-preferring AA and alcohol-avoiding ANA rats, selected for high and low voluntary ethanol intake, respectively. The level of BDNF mRNA expression was higher in the amygdala and ventral tegmental area of AA than in those of ANA rats, and there was a trend for a higher level in the nucleus accumbens. In the amygdala and hippocampus, a biphasic change in the BDNF mRNA levels was detected: the levels were decreased at 3 and 6h but increased above the basal levels at 24h. Furthermore, there was a difference between the AA and ANA lines in the effect of ethanol, the ANA rats showing an increase in BDNF mRNA levels while such a change was not seen in AA rats. These findings suggest that the innate levels of BDNF expression may play a role in the mediation of the reinforcing effects of ethanol and in the control of ethanol intake.

Differences in basal and morphine-induced FosB/ΔFosB and pCREB immunoreactivities in dopaminergic brain regions of alcohol-preferring AA and alcohol-avoiding ANA rats

Besides alcohol, alcohol-preferring AA and alcohol-avoiding ANA rats differ also with respect to other abused drugs. To study the molecular basis of these differences, we examined the expression of two transcription factors implicated in addiction, ΔFosB and pCREB, in brain dopaminergic regions of AA and ANA rats. The effects of morphine and nicotine were studied to relate the behavioral and molecular changes induced by these drugs. Baseline FosB/ΔFosB immunoreactivity (IR) in the nucleus accumbens core and pCREB IR in the prefrontal cortex (PFC) were elevated in AA rats. Morphine increased ΔFosB-like IR more readily in the caudate-putamen of AA rats than in ANA rats. In the PFC morphine decreased pCREB IR in AA rats, but increased it in ANA rats. In addition to enhanced locomotor response, the development of place preference to morphine was enhanced in AA rats. The enhanced nicotine-induced locomotor sensitization found in AA compared with ANA rats seems to depend in addition to dopamine and ΔFosB on other mechanisms. These findings suggest that enhanced sensitivity of AA rats to morphine is related to augmented morphine-induced expression of FosB/ΔFosB and morphine-induced reduction of pCREB levels. Moreover, altered innate expression of FosB/ΔFosB and pCREB in AA rats is likely to affect the sensitivity of these rats to abused drugs.

Ethanol Self‐Administration Is Regulated by CB1 Receptors in the Nucleus Accumbens and Ventral Tegmental Area in Alcohol‐Preferring AA Rats

Endogenous cannabinoids and their receptors, CB1 receptors in particular, have been implicated in mediation of ethanol reinforcement. Previously, suppression of ethanol drinking by CB1 antagonists has been demonstrated in many experimental paradigms. However, the exact mechanism by which CB1 antagonists modulate ethanol drinking remains elusive. In the present study, we assessed the role of CB1 receptors within the key regions of the mesolimbic dopamine pathway, the nucleus accumbens (NAcc) and ventral tegmental area (VTA), in regulation of ethanol self-administration. Adult male alcohol-prefer AA rats were trained to self-administer either 10% (w/v) ethanol or 0.1% (w/v) saccharin under an FR1 schedule during daily 30-minute sessions. Following stable baseline responding, rats were tested after systemic administration of the CB1 antagonist SR141716A (0 to 10 mg/kg) and the agonist WIN55,212-2 (0 to 2 mg/kg). Separate groups of rats were implanted with bilateral cannulas aimed at the NAcc or VTA, and tested after microinjections of SR141716A (0 to 3 microg) and WIN55,212-2 (0 to 5 microg) into the NAcc or VTA. The highest intracerebral doses were tested also in rats responding for a 0.1% saccharin solution. SR141617A dose-dependently suppressed ethanol responding after systemic administration. Microinjections of SR141617A both into NAcc and VTA attenuated ethanol responding. In addition, intra-NAcc injections of SR141617A suppressed saccharin intake. Although low doses of systemically given WIN55,212-2 increased ethanol responding, no effects were seen after WIN55,212-2 microinjections into NAcc or VTA. Bidirectional changes in ethanol self-administration by the systematically administered CB1 agonist and antagonist show that ethanol reinforcement is controlled by CB1 receptors in alcohol-preferring AA rats. Replication of the suppressive effects by CB1 antagonism in the NAcc and VTA suggests that endocannabinoids and their receptors mediate ethanol reinforcement through interaction with the mesolimbic dopamine pathway.

Comparison of deramciclane to benzodiazepine agonists in behavioural activity of mice and in alcohol drinking of alcohol-preferring rats

Interactions between alcohol and traditional benzodiazepine anxiolytics hamper the treatment of alcoholism-related anxiety disorders. Serotonin 5-HT 2 receptor antagonists, such as deramciclane, are anxiolytic, and considering their pharmacological profile, they might benefit alcoholics with comorbid anxiety. We studied the effects of acute deramciclane (1, 3 and 10 mg/kg ip) on alcohol drinking of alcohol-preferring AA rats drinking 10% (vol/vol) ethanol solution in a 4-h limited-access paradigm. Thereafter, a 5-day repeated-treatment experiment was carried out, under corresponding test design, with deramciclane (3 mg/kg ip) as a test drug and midazolam (1 mg/kg ip) as a benzodiazepine reference compound. Deramciclane had no effect on alcohol consumption in either acute or repeated dosing study. Midazolam increased ethanol drinking, as expected, when administered on successive days. A modified functional observational battery (FOB) procedure was applied to study neurological, behavioural and autonomic effects induced by deramciclane (1–30 mg/kg po) and diazepam (1–30 mg/kg po) in mice at 30 min, 2 h and 4 h after dosing. Deramciclane had a mild dopamine D 2 receptor antagonism-like effect at the highest dose. The effects of diazepam were predictable, myorelaxation-induced motor impairment and anxiolysis-related hyperlocomotion in a novel environment being the characteristic features at the two highest doses. Deramciclane appears to be a safe and well-tolerated drug and we suggest that it might be useful in the treatment of anxiety in alcoholics.

Effects of melanocortin receptor ligands on ethanol intake and opioid peptide levels in alcohol-preferring AA rats

Melanocortin (MC) peptides are suggested to play a role in opiate dependence, where they antagonise the addictive properties of opiates. To further study the involvement of the MCs in drug dependence, we analysed the effects of the MC 4-receptor antagonist HS014 (1 nmol/rat), and the non-selective MC-receptor agonist MTII (1 nmol/rat), using i.c.v. administration, on ethanol intake in alcohol-preferring AA rats. The rats had access to ethanol during 40 days, resulting in a mean ethanol intake of 6.6 g/kg/day, before treatment. One group received only artificial cerebrospinal fluid solution. MTII caused a reduction in ethanol intake and ethanol preference, whereas HS014 was without effect. No effect on water intake was observed. A decrease in food intake was detected after MTII, whereas HS014 induced an increase in food intake. Analysis of dynorphin B and Met-enkephalin-Arg 6Phe 7 immunoreactive levels revealed that MTII and HS014 altered opioid peptide levels in several brain areas and the pituitary gland of the rats with an established ethanol intake. This is the first report showing that manipulation of the MC-receptor system changes ethanol intake in chronically ethanol-drinking AA rats. In addition, manipulation of the MC system modulates ethanol-induced changes in opioid peptide levels.

Effect of alcohol abuse on human brain histamine and tele-methylhistamine.

Brain neurotransmitter and receptor systems are altered in animals exhibiting increased ethanol preference; most studies being on brain dopamine and 5-hydroxytryptamine(5HT) systems. The role of histaminergic systems in high ethanol consumption is not well understood. It has been suggested that histaminergic tuberomamillary neurons participate in the inhibitory control of reward functions [1]. Lesions of dopaminergic neurons in the substantia nigra have been shown to disrupt reward-related processes [2]. Thus, it is possible that dopaminergic nigrostriatal and histaminergic tuberomamillary striatal systems may act in a reciprocal fashion to regulate reward functions. Pathophysiological differences in the rat brain histaminergic system have been studied on selectively-bred alcohol-preferring AA rats versus their alcohol-avoiding ANA counterparts. Histamine and its metabolite tele-methylhistamine were measured in brains of these rats. Both have been found in higher concentrations in alcohol-preferring rats [3]. Here we studied if similar changes could be detected in humans abusing alcohol.

Differential Expression of NPY and Its Receptors in Alcohol‐Preferring AA and Alcohol‐Avoiding ANA Rats

Central neuropeptide Y (NPY) is known to control feeding and stress responses. Recently, it has been suggested that NPY also has a role in regulation of alcohol consumption. NPY and NPY receptor expression in genetically selected alcohol-preferring (AA), alcohol-nonpreferring (ANA), and Wistar rats were investigated. Expression was assessed using in situ hybridization histochemistry with riboprobes specific for preproNPY, Y1, and Y2 receptors. Effects of central NPY administration on ethanol self-administration were also examined in AA, ANA, and Wistar rats by using oral operant self-administration. NPY mRNA expression was higher in ANA than in both AA and Wistar rats in the hippocampal CA region and dentate gyrus, whereas AA and Wistar did not differ from each other. No differences in NPY expression were found in the other regions analyzed: cingulate cortex, medial nucleus of the amygdala, arcuate, and paraventricular nuclei of the hypothalamus. Y1 receptor mRNA expression did not differ between the three lines. Y2 expression was higher in the dentate gyrus of both AA and ANA rats than in Wistar subjects. In the medial amygdala, Y2 mRNA was reduced in the AA line, compared to both ANA and Wistar rats. NPY injected intracerebroventricularly (1.5-3.0 nmol) did not affect operant ethanol self-administration in any of the three lines examined. The NPY system seems to differ in several respects between rat lines with different levels of alcohol preference. Differences observed within the hippocampus could be related to behavioral traits other than alcohol intake but it is also possible that elevated hippocampal expression of NPY in the ANA rats contributes to the low alcohol intake of this line. Aberrant NPY expression and/function within the amygdala complex could contribute to alcohol preference and constitute an anatomic substrate of the effects of NPY expression on alcohol intake observed previously in genetically modified animals.

Differential Expression of NPY and Its Receptors in Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats

Differential Expression of NPY and Its Receptors in Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats

Effects of repeated cocaine treatment on striatal dopamine release in alcohol-preferring AA and alcohol-avoiding ANA rats.

Modulation of striatal dopamine (DA) release by acute or repeated cocaine treatment was studied in the nucleus accumbens and caudate-putamen of alcohol-preferring (AA, Alko Alcohol) and alcohol-avoiding (ANA, Alko Non-Alcohol) rats. Cocaine (5-10 mg/kg i.p.) was administered daily for 4 days and the concentrations of extracellular DA measured by in vivo microdialysis on days 1 and 4 in the freely moving rats. The first administration of cocaine increased DA concentration similarly in rats of both lines in both the nucleus accumbens and caudate-putamen. On the 4th day, the effect of cocaine was significantly larger in the nucleus accumbens of AA than in that of ANA rats, whereas no such enhanced effect of cocaine was found in the caudate-putamen of either line. The results suggest that mesolimbic DA release in response to cocaine is sensitized more readily in AA than in ANA rats, which would not only render the former more susceptible to alcohol, but to other drugs of abuse, and might explain our previous findings that AA rats are more susceptible to psychomotor sensitization than ANA rats.

Taste Reactivity in Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats

BADIA-ELDER, N. E. AND S. W. KIEFER. Taste reactivity in alcohol-preferring AA and alcohol-avoiding ANA rats. ALCOHOL 18(2/3) 159–163, 1999.—Alcohol-preferring rats (Alko alcohol or AA) were tested for taste reactivity to water, sucrose, quinine, and a range of alcohol concentrations (5–40%) both before and after a period of continuous alcohol access. The alcohol-avoiding line of rats (Alko nonalcohol or ANA) was also tested for comparison. It was found that AA rats displayed greater ingestive reactivity to alcohol compared to ANA rats both before and after a three-week period of continuous access to 10% alcohol (during which time AA rats drank significantly more alcohol than ANA rats). AA rats also made significantly more ingestive responses to a 0.3 M sucrose solution and a 0.0005 M quinine solution. Differences between AA rats and ANA rats in aversive reactivity appeared only after the alcohol consumption tests; AA rats made significantly fewer aversive responses to the 30% and 40% concentrations after continuous alcohol access. AA rats also made significantly more aversive responses to the quinine solution. The results suggest that line differences between AA rats and ANA rats in the reactivity response to alcohol solutions have been selected in association with the original selection phenotype of alcohol consumption.

Effect of Ethanol on (R)- and (S)-Salsolinol, Salsoline, and THP in the Nucleus Accumbens of AA and ANA Rats

SÄLLSTRÖM BAUM, S., R. HILL, K. KIIANMAA, AND H. ROMMELSPACHER. Effect of ethanol on (R)- and (S)-salsolinol, salsoline and THP in the nucleus accumbens of AA and ANA rats. ALCOHOL 18(2/3) 165–169, 1999.—Tetrahydroisoquinolines (TIQ) are active metabolites of dopamine. Intracerebral application stimulates the voluntary ethanol intake. In the present study, the levels of several TIQ's [(S)- and (R)-salsolinol, salsoline and tetrahydropapaveroline (THP)] were measured in the extracellular space of the nucleus accumbens of alcohol-preferring AA and alcohol-avoiding ANA rats. Ethanol (2 g/kg i.p.) caused an increase in dopamine levels in ANA but not in AA rats. Neither (R)- nor (S)-salsolinol concentrations changed after ethanol application, though (S)-salsolinol concentrations were higher in ANA than in AA rats. Ethanol caused an increase in salsoline concentrations in ANA but not in AA rats. THP increased following ethanol, which tended to be stronger in ANA rats. The study revealed differences in the TIQ levels of the nucleus accumbens between AA and ANA rats. In case of changes following ethanol application (dopamine, salsoline, THP), the AA rats were less sensitive. The findings resemble observations in high-risk sons of alcoholics with reduced sensitivity to ethanol in young age and increased risk to become alcoholic.

Effects of Morphine on Metabolism of Dopamine and Serotonin in Brains of Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats

Morphine induces a larger locomotor stimulation in the alcohol-preferring AA rats than in the alcohol-avoiding ANA rats. We have now studied the acute effects of morphine (1 and 3 mg/kg) on metabolism of dopamine and serotonin (5-HT) in the dorsal and ventral striatum of the AA and ANA rats. The basal level of dopamine release, as reflected by the concentration of dopamine metabolite 3-methoxytyramine (3-MT), was lower in the caudate-putamen and nucleus accumbens of the AA rats than in the ANA rats. In the caudate-putamen, morphine increased dopamine metabolism and release more in the AA than in the ANA rats. In the nucleus accumbens and olfactory tubercle, the effects of morphine on dopamine metabolism and release did not differ between the rat lines. Morphine elevated the metabolism of 5-HT in the caudate-putamen and nucleus accumbens of the AA but not in those of the ANA rats. The results suggest that the larger morphine-induced psychomotor stimulation of the AA rats in comparison with the ANA rats is associated with the larger effect of morphine on dopamine metabolism in the caudate-putamen and 5-HT metabolism in the caudate-putamen and nucleus accumbens. Furthermore, low basal dopamine release may play a role in the high alcohol-preference of AA rats.

Defensive Burying and Stress Gastric Erosions in Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats

The aim of this study was to investigate differences in shock-prod induced defensive burying and vulnerability to stress gastric ulcerations in two lines of rats selectively bred for alcohol-preference (AA) and alcohol-avoidance (ANA). Alcohol-naïve animals from the AA and ANA lines were tested in the shock-prod defensive burying test and (after an interval of approximately 2 months) in a 75 min water-immersion stress ulceratjon-inducing procedure. The AA rats showed longer latencies (327.5 s) for burying after shock-prod compared with the ANA animals (128.0 s). Furthermore, the ANA rats developed more stomach ulcerations (12.35 mm) compared with the AA rats (1.30 mm). Animals also differed based on whether they had been tested for defensive burying or not, with the tested animals showing less ulceration development than the control group. We hypothesize that the difference between AA and ANA rats is controlled by some common biochemical mechanism. One likely candidate is the dopaminergic system, which is involved in both the motivational effects of alcohol, as well as anxiety and stomach ulceration. In addition, the alcohol-preferring strain seems to be less fearful and generally may be less sensitive to aversive stimuli, be it shock prod, the aversive properties of alcohol, or water immersion stress.

P2.19 Differential effects of μ- and δ-opioid receptor agonists on locomotor activity of alcohol-preferring AA, alcohol-avoiding ANA and non-selected wistar rats : A Honkanen ∗, 1, H Ervast 1, E R Korpi 2 & L Ahtee 1, 1Dept of Pharmacy, Univ of Helsinki; 2Dept of Pharmacol & Clin Pharmacol, Univ of Turku, Finland

P2.19 Differential effects of μ- and δ-opioid receptor agonists on locomotor activity of alcohol-preferring AA, alcohol-avoiding ANA and non-selected wistar rats : A Honkanen ∗, 1, H Ervast 1, E R Korpi 2 & L Ahtee 1, 1Dept of Pharmacy, Univ of Helsinki; 2Dept of Pharmacol & Clin Pharmacol, Univ of Turku, Finland

The calcium channel agonist BAY k 8644 reduces ethanol intake and preference in alcohol-preferring AA rats

The calcium channel agonist BAY k 8644 reduces ethanol intake and preference in alcohol-preferring AA rats

Effects of nimodipine and other calcium channel antagonists in alcohol-preferring AA rats

Several lines of evidence suggest that l-type calcium (Ca 2+) channels play a role in excessive ethanol (EtOH) intake. In accordance with this, a considerable amount of antagonists for these ion channels has been found to suppress EtOH intake and preference in various animal models of alcoholism. The aim of the present study was to examine antialcohol effects of l-type Ca 2+ channel antagonists in alcohol-preferring AA rats. These rats, a Wistar line selectively bred for a high 10% v/v EtOH preference in a free-choice situation, have thus far not been subjected to systematic investigations with Ca 2+ channel antagonists. Therefore, effects on EtOH preference and intake, as well as on food and total fluid intake, were evaluated for the 1,4-dihydropyridine (DHP) derivatives nimodipine, felodipine, isradipine, nicardipine, nifedipine, and nitrendipine, as well as for the phenylalkylamine verapamil and the benzothiazepine diltiazem, utilizing a limited access, free-choice procedure. All DHPs were found to be highly effective in reducing both EtOH intake and preference, without affecting total fluid intake. Irrespective of route of application (IP or PO), the effective dose ranges were found to be very similar across compounds (10–30 mg/kg). Nevertheless, because food intake was also reduced, the effects were not completely selective. For nimodipine, the (−)-enantiomer seemed to be more effective as its (+)-enantiomer, possibly reflecting stereoselectivity at central binding sites. Compared to the DHPs, verapamil produced a similar profile of activity, but diltiazem was found to be ineffective. These results confirm and extend previous findings with l-type Ca 2+ channel antagonists obtained in other models of alcoholism and suggest that this class of compounds offers an interesting approach for the pharmacotherapy of alcoholism.

Defective habituation to nociceptive stimulation in alcohol-avoiding ANA rats.

Brain opioidergic mechanisms participate in the regulation of motivational and ingestive behaviours. Since alcohol is believed to activate endogenous opioid systems and to produce opioid-mediated antinociception, the present experiments were performed to find out if alcohol-induced antinociception differs between the alcohol-preferring AA and alcohol-avoiding ANA rat lines. Alcohol doses relevant to the voluntary alcohol intake by the AA rats (0.5-1.0 g/kg, intraperitoneally) failed to alter tail-flick (TF) latency in a 55 degrees C water bath by either rat line. However, repeated measurement of TF latency, even without any alcohol treatment, prolonged tail-flick latencies in AA but not in ANA rats. Prolongation of TF latency was also seen in non-selected Wistar rats, indicating that the ANA rats respond abnormally in this test. The antinociceptive effects of swimming-induced stress (3 min at 15 degrees C) and those of cumulative morphine administration (0.5-16.0 mg/kg, subcutaneously) were similar in both rat lines. Using higher, motor-impairing alcohol doses with repeated baseline TF determinations, it was observed that a dose of 1.5 g/kg induced slight antinociception only in the AA rats, while 2.0 g/kg produced similar effects in both rat lines. It is thus concluded that the alcohol-preferring AA rats do not show any enhanced alcohol-induced antinociception at relevant alcohol doses. However, the alcohol-avoiding ANA rats appear to have a defective ability to habituate to repeated sensory stimuli, which could contribute to their alcohol avoidance by preventing the development of tolerance to aversive effects of alcohol.

Gamma‐Vinyl GABA Decreases Voluntary Alcohol Consumption in Alcohol‐Preferring AA Rats

The effect of a GABA transaminase inhibitor, gamma-vinyl GABA, on the voluntary alcohol consumption of alcohol-preferring AA rats produced by selective breeding for high alcohol preference, was studied. The rats were first trained to voluntarily drink 10% (v/v) ethanol solution until their ethanol consumption stabilized. Gamma-vinyl GABA (100, 200 or 500 mg/kg) was then injected intraperitoneally in three groups of rats, with saline-injected animals serving as a control group. The rats continued to have a free choice between 10% ethanol and plain tap water for five days after the injection, and their ethanol, water and food consumptions were measured daily. Gamma-vinyl GABA decreased ethanol consumption by the rats in a dose-dependent way. The consumption remained significantly decreased for three days in the two groups receiving the highest doses, with only a small concomitant tendency to decreased food intake. The results suggest that an increase in brain GABA concentration decreases alcohol drinking, possibly through potentiation of the pharmacological action of ethanol.