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Recent studies have demonstrated the ability of the positive allosteric modulator (PAM) of the GABA B receptor (GABA B PAM), KK-92A, to suppress operant alcohol self-administration and reinstatement of alcohol seeking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to scrutinize the suppressing effects of KK-92A on alcohol-related behaviors; to this end, four separate experiments were conducted to address just as many new research questions, some of which bear translational value. Experiment 1 found that 7-day treatment with KK-92A (0, 5, 10, and 20 mg/kg, intraperitoneally [i.p.]) effectively reduced alcohol intake in male sP rats exposed to the home-cage 2-bottle "alcohol (10% v/v) vs. water" choice regimen with 1 hour/day limited access, extending to excessive alcohol drinking the ability of KK-92A to suppress operant alcohol self-administration. Experiment 2 demonstrated that the ability of KK-92A to reduce lever-responding for alcohol was maintained also after acute, intragastric treatment (0, 20, and 40 mg/kg) in female sP rats trained to lever-respond for 15% (v/v) alcohol under the fixed ratio 5 schedule of reinforcement. In Experiment 3, acutely administered KK-92A (0, 5, 10, and 20 mg/kg, i.p.) dampened alcohol-seeking behavior in female sP rats exposed to a single session under the extinction responding schedule. Experiment 4 used a taste reactivity test to demonstrate that acute treatment with KK-92A (0 and 20 mg/kg, i.p.) did not alter either hedonic or aversive reactions to a 15% (v/v) alcohol solution in male sP rats, ruling out that KK-92A-induced reduction of alcohol drinking and self-administration could be due to alterations in alcohol palatability. Together, these results enhance the behavioral pharmacological profile of KK-92A and further strengthen the notion that GABA B PAMs may represent a novel class of ligands with therapeutic potential for treating alcohol use disorder., Competing Interests: Declarations of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Exposure of Sardinian alcohol-preferring (sP) rats to an enriched environment (EE) reduced different aspects of operant alcohol self-administration. The present study was aimed at expanding investigation of the effect of EE exposure upon a model of binge drinking composed of daily 1-h drinking sessions with unpredictable access to multiple alcohol concentrations; binge-like alcohol intakes were observed when the drinking session occurred at the last hours of the dark phase of the light/dark cycle. Starting from postnatal day (PND) 21, male sP rats were kept under three different housing conditions: impoverished environment (IE; single housing with no environmental enrichment); standard environment (SE; 3 rats/cage and no environmental enrichment); EE (6 rats/cage and multiple elements of environmental enrichment). From PND 69, rats were exposed daily to a 1-hour drinking session under the 4-bottle "alcohol (10%, 20%, and 30%, v/v) vs. water" choice regimen, during the dark phase, and with timing of alcohol exposure changed each day. In all three rat groups (IE, SE, and EE), alcohol intake increased progressively as the drinking session moved from the first to last hours of the dark phase. The slope of the regression line was steeper in EE than IE and SE rats, suggestive of higher intakes of alcohol in EE than IE and SE rats when the drinking session occurred over the last hours of the dark phase. These results are discussed hypothesizing that the stressful attributes of alcohol expectation were potentiated by the increased "emotionality" that rats living in a comfortable environment (i.e., EE) may experience when facing new, challenging events or environments. Blood alcohol levels, assessed at the end of a final drinking session occurring at the 12th hour of the dark phase, did not differ among the three rat groups and averaged approximately 150 mg%, confirming that this experimental procedure may generate intoxicating levels of alcohol drinking in sP rats., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Living in an enriched environment (EE) produces a notable impact on several rodent behaviors, including those motivated by drugs of abuse. This picture is somewhat less clear when referring to alcohol-motivated behaviors. With the intent of contributing to this research field with data from one of the few rat lines selectively bred for excessive alcohol consumption, the present study investigated the effect of EE on operant oral alcohol self-administration in Sardinian alcohol-preferring (sP) rats. Starting from Postnatal Day (PND) 21, male sP rats were kept under 3 different housing conditions: impoverished environment (IE; single housing in shoebox-like cages with no environmental enrichment); standard environment (SE; small colony cages with 3 rats and no environmental enrichment); EE (large colony cages with 6 rats and multiple elements of environmental enrichment, including 2 floors, ladders, maze, running wheels, and shelter). From PND 60, rats were exposed to different phases of shaping and training of alcohol self-administration. IE, SE, and EE rats were then compared under (i) fixed ratio (FR) 4 (FR4) schedule of alcohol reinforcement for 20 daily sessions and (ii) progressive ratio (PR) schedule of alcohol reinforcement in a final single session. Acquisition of the lever-responding task (shaping) was slower in EE than IE and SE rats, as the likely consequence of a "devaluation" of the novel stimuli provided by the operant chamber in comparison to those to which EE rats were continuously exposed in their homecage or an alteration, induced by EE, of the rat "emotionality" state when facing the novel environment represented by the operant chamber. Training of alcohol self-administration was slower in EE than IE rats, with SE rats displaying intermediate values. A similar ranking order (IE>SE>EE) was also observed in number of lever-responses for alcohol, amount of self-administered alcohol, and breakpoint for alcohol under FR4 and PR schedules of reinforcement. These data suggest that living in a complex environment reduced the reinforcing and motivational properties of alcohol in sP rats. These results are interpreted in terms of the reinforcing and motivational properties of the main components of EE (i.e., social interactions, physical activities, exploration, novelty) substituting, at least partially, for those of alcohol., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alcohol use disorder remains a major health problem. The mesocorticolimbic dopaminergic system, including the nucleus accumbens region and multiple neural circuits, is involved in its complex underlying mechanism. For instance, alcohol intake stimulates the central and peripheral renin-angiotensin system and increases angiotensin II levels, which predominantly affect angiotensin 1 receptors both in the periphery and in the brain. In this study, we aimed to investigate the effects of the intracerebroventricularly-administered angiotensin 1 receptor blocker telmisartan on the alcohol consumption of male Sardinian alcohol-preferring (sP) rats and on the alcohol-induced dopamine levels in the nucleus accumbens region in Wistar rats. Acute intracerebroventricular administration of telmisartan (100 nM) reduced the alcohol intake for 24 hours without affecting food and water consumption in sP rats. Acute intracerebroventricular injection of the opioid receptor antagonist naloxone (75 nM), tested as a reference compound, also reduced the alcohol consumption in sP rats; however, naloxone's effect lasted only for 30 minutes. In microdialysis experiments, telmisartan administered intracerebroventricularly did not change dopamine levels in the nucleus accumbens that had been induced by acute intraperitoneal alcohol administration in Wistar rats. According to these results, further studies are needed to elucidate the role of the renin-angiotensin system on alcohol use disorder pathophysiology., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sardinian alcohol-preferring (sP) rats have been selectively bred, over almost 40 years, for high alcohol preference and consumption. sP rats have served as an animal model for more than 120 published studies. With very few exceptions, however, these studies have always employed male sP rats, and little is known about alcohol-related behaviors in female sP rats. The present study was designed to fill, at least in part, this gap. Accordingly, alcohol self-administration under the fixed ratio 4 schedule of reinforcement was compared among male, intact female, and ovariectomized female sP rats. Additionally, it was investigated whether i) estrous cycle influenced alcohol self-administration, and ii) alcohol self-administration in the three sP rat groups differed in sensitivity to pharmacological manipulation. Lever-responding for alcohol was steadily higher in male than intact and ovariectomized female sP rats; conversely, because of large sex differences in rat body weight, estimated amount of self-administered alcohol (in g/kg) did not differ among the three sP rat groups or occasionally was higher in intact female than male and ovariectomized female sP rats. Blood alcohol levels derived from self-administered alcohol i) did not differ among the three sP rat groups and ii) were positively correlated with the number of lever-responses for alcohol and the estimated amount of self-administered alcohol. Treatment with the opioid receptor antagonist, naloxone (0, 0.3, 1, and 3 mg/kg, i.p. [intraperitoneally]), and the positive allosteric modulator of the GABA B receptor, GS39783 (0, 25, 50, and 100 mg/kg, i.g. [intragastrically]), reduced alcohol self-administration with comparable potency and efficacy in the three sP rat groups. The impact of the estrous cycle on alcohol self-administration was relatively modest, limited to a tendency toward a reduction in the number of lever-responses for alcohol and the estimated amount of self-administered alcohol in estrus and metestrus. Together, these results provide the first characterization of alcohol-seeking and -taking behavior in female sP rats., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Positive allosteric modulators (PAMs) of the GABA B receptor constitute a class of pharmacological agents gaining increasing attention in the alcohol research field because of their ability to suppress several alcohol-related behaviors in rodents. CMPPE is a novel GABA B PAM, still limitedly characterized in vivo. It was therefore of interest to test its ability to affect operant, oral self-administration of alcohol and cue-induced reinstatement of alcohol seeking in alcohol-preferring rats. To this end, female Sardinian alcohol-preferring (sP) rats were trained to lever-respond for alcohol (15% v/v) under the fixed ratio (FR) 5 (FR5) schedule of reinforcement. Once lever-responding had stabilized, rats were exposed to test sessions (under the FR5 [Experiment 1] and progressive ratio [PR; Experiment 2] schedules of reinforcement) preceded by treatment with CMPPE (0, 2.5, 5, and 10 mg/kg; intraperitoneally [i.p.]). In Experiment 3, once lever-responding had stabilized, rats underwent an extinction responding phase and then a single reinstatement session during which lever-responding was resumed by the non-contingent presentation of a complex of alcohol-associated cues; CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) was administered before the reinstatement session. Selectivity of CMPPE action was assessed by evaluating the effect of CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) on self-administration of a chocolate solution in male Wistar rats (Experiment 4). In Experiments 1 and 2, treatment with 5 and 10 mg/kg CMPPE reduced lever-responding and breakpoint for alcohol. In Experiment 3, treatment with 5 and 10 mg/kg CMPPE suppressed reinstatement of alcohol seeking. In Experiment 4, no dose of CMPPE affected lever-responding for the chocolate solution. These results extend to CMPPE the ability of all previously tested GABA B PAMs to affect alcohol-motivated behaviors in rodents and confirm that these effects are a shared feature of the entire class of GABA B PAMs. This conclusion is of relevance in view of the forthcoming transition of GABA B PAMs to clinical testing., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A recent study found that COR659 (methyl 2-[(4-chlorophenyl)carboxamido]-4-ethyl-5-methylthiophene-3-carboxylate) reduced operant alcohol and chocolate self-administration in rats; COR659 also suppressed cue-induced reinstatement of chocolate seeking in rats. COR659 apparently exerts its effects via a composite mechanism, including positive allosteric modulation of the GABA B receptor and an action at the cannabinoid CB 1 receptor. The present study investigated whether the reducing effect of COR659 on alcohol and chocolate self-administration was maintained after repeated treatment and if COR659 affected cue-induced reinstatement of alcohol seeking; additionally, it evaluated the ability of 9 structural analogues of COR659 - designed modifying the substituents on the phenylcarboxamido moiety and replacing the thiophene with the pyridine ring - to affect alcohol and chocolate self-administration. Alcohol self-administration experiments employed Sardinian alcohol-preferring (sP) rats trained to lever-respond for alcohol (15% v/v). Chocolate self-administration experiments employed Wistar rats trained to lever-respond for a chocolate solution (5% w/v Nesquik ® ). In the reinstatement experiment, previously extinguished lever-responding for alcohol in sP rats was reinstated by the non-contingent presentation of an alcohol-associated complex of cues. All drugs were tested at the doses of 0, 2.5, 5, and 10 mg/kg (i.p.). 10-Day treatment with COR659 produced a dose-related reduction of both alcohol and chocolate self-administration, with limited loss of efficacy on continuing treatment. Acute COR659 suppressed reinstatement of alcohol seeking. Among the 9 tested analogues, only COR657 (methyl 2-(benzoylamino)-4-ethyl-5-methylthiophene-3-carboxylate) decreased alcohol self-administration similarly to COR659; all other compounds produced modest, or even no, effect on alcohol self-administration. COR659 excluded, no compound altered chocolate self-administration. These results confirm and extend the ability of COR659 to reduce several behaviors motivated by alcohol and palatable food in rats. Comparison of COR659 to its analogues provided disparate results that do not currently allow any conclusive structure-activity relationship to be hypothesized, as their diverse pharmacological profile apparently does not depend on physicochemical properties., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Previous studies suggested that exposure of Sardinian alcohol-preferring (sP) rats to daily drinking sessions of 1 h, during the dark phase of the light/dark cycle, with multiple alcohol concentrations, and unpredictable access to alcohol, resulted in exceptionally high intakes of alcohol when the drinking session occurred over the last hours of the dark phase. Additionally, higher levels of anxiety-related behaviors were observed at the 12th, rather than 1st, hour of the dark phase, suggesting that uncertainty of time of alcohol access and expectation of alcohol availability produced an emotional "distress". The present study was designed to provide pharmacological support to the hypothesis that high alcohol intake under this drinking procedure is secondary to exacerbation of the anxiety-like state of sP rats. To this end, sP rats were initially exposed to daily 1-h drinking sessions during the dark phase and with multiple alcohol concentrations (0%, 10%, 20%, and 30%; v/v); time of alcohol exposure was changed each day and was unpredictable to rats. Rats were then treated acutely with non-sedative doses of diazepam (0, 1, 2, and 3 mg/kg; intraperitoneally [i.p.]) before two drinking sessions occurring at the 1st and 12th hour of the dark phase, respectively. Treatment with diazepam was ineffective at the 1st hour; conversely, it selectively reduced alcohol intake (up to 50% at the dose of 3 mg/kg) at the 12th hour. The preferential effectiveness of diazepam in reducing alcohol intake when the drinking session occurred at the 12th hour of the dark phase is consistent with the hypothesis that uncertainty of time of alcohol access and expectation of alcohol availability generated an emotional "distress" that rats counterbalanced with high alcohol drinking; the results of the present study are interpreted as the anxiolytic effects of diazepam substituting for those of alcohol, resulting in the observed reduction in alcohol intake., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent research found that exposure of selectively bred, Sardinian alcohol-preferring (sP) rats to multiple alcohol concentrations (10%, 20%, and 30%, v/v), under the 4-bottle "alcohol vs. water" choice regimen, in daily 1-h drinking sessions with an unpredictable time schedule, promoted high intakes of alcohol (≥2 g/kg) when the drinking session occurred over the final hours of the dark phase of the light/dark cycle. The present study investigated whether these high intakes of alcohol (a) were associated with alterations in rats' emotional state (Experiment 1) and (b) were pharmacologically manipulable (Experiment 2). In both experiments, over a period of 12 days, sP rats were initially exposed daily to a 1-h drinking session during the dark phase; time of alcohol exposure was changed each day and was unpredictable to rats. The day after this 12-day drinking phase, rats were (a) exposed to the Social Interaction (SI) test at the 1st or 12th hour of the dark phase with no alcohol available (Experiment 1) or (b) treated with the positive allosteric modulator of the GABAB receptor, GS39783 (0, 25, 50, and 100 mg/kg, intragastrically [i.g.]), and exposed to a drinking session at the 12th hour of the dark phase (Experiment 2). In Experiment 1, rats exposed to the SI test during the 12th hour spent approximately 35% less time in "social" behaviors than rats exposed to the SI test during the 1st hour. No difference in "social" behaviors was observed between alcohol-naive sP rats exposed to the SI test at the 1st and 12th hour. In Experiment 2, all doses of GS39783 selectively reduced alcohol intake. These results suggest that (a) expectation of alcohol availability likely exacerbated the anxiety-like state of sP rats and (b) the GABAB receptor is part of the neural substrate underlying these exceptionally high intakes of alcohol in sP rats., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The dried roots of Salvia miltiorrhiza are highly valued in Chinese folk medicine for use in the prevention and treatment of a series of ailments. Previous studies have demonstrated that administration of standardized extracts of S. miltiorrhiza selectively reduced excessive alcohol drinking and relapse-like drinking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to extend these findings on the "anti-alcohol" properties of S. miltiorrhiza extracts to operant procedures of oral alcohol self-administration. Two independent groups of sP rats were trained to lever-respond on an FR4 schedule of reinforcement for alcohol (15%, v/v) or sucrose (1-3%, w/v) in daily 30 min sessions. Once responding had stabilized, rats were tested under the fixed ratio 4 (FR4) schedule of reinforcement (index of alcohol reinforcing properties) and the progressive ratio (PR) schedule of reinforcement (index of alcohol motivational properties). Treatment with S. miltiorrhiza extract (0, 50, 100, and 200 mg/kg, intragastrically [i.g.]) markedly reduced lever responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol (defined as the lowest response requirement not achieved in the PR experiment). No dose of S. miltiorrhiza extract altered any parameter of sucrose self-administration. These results a) demonstrate that treatment with S. miltiorrhiza extract selectively reduced the reinforcing and motivational properties of alcohol in sP rats and b) extend to operant procedures of alcohol self-administration previous data on the "anti-alcohol" effects of S. miltiorrhiza extracts. These data strengthen the notion that novel pharmacological approaches for treatment of alcohol use disorders may stem from natural substances., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Sardinian alcohol-preferring (sP) and -non preferring (sNP) rats have been selectively bred for opposite ethanol preference and consumption; sP rats represent a validated experimental tool to model several aspects of excessive ethanol drinking in humans. Phosphorylated Extracellular signal-Regulated Kinase (pERK) in dopamine-rich terminal areas plays a critical role in several psychopharmacological effects of addictive drugs, including ethanol. This study was aimed at investigating whether ethanol-elicited ERK activation may differ in key brain areas of ethanol-naïve sP and sNP rats. To this end, the effects of ethanol (0, 0.5, 1, and 2 g/kg, administered intra-gastrically [i.g.]) on ERK phosphorylation were assessed by pERK immunohistochemistry in the shell (AcbSh) and core (AcbC) of the nucleus accumbens (Acb) as well as in the prelimbic (PrL) and infralimbic (IL) prefrontal cortex (PFCx), in the bed nucleus of stria terminalis (BSTL) and in the central nucleus of the amygdala (CeA). Ethanol (1 g/kg) significantly increased pERK immunoreactivity in AcbSh and AcbC of sP but not sNP rats. Conversely, ethanol failed to affect pERK expression in PrL and IL PFCx as well as in BSTL and CeA of both sP and sNP rats. These results suggest that selective breeding of these rat lines results in differential effects of acute ethanol on ERK phosphorylation in brain regions critical for the psychopharmacological effects of ethanol., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Sardinian alcohol-preferring (sP) rats have been selectively bred for high alcohol preference and consumption. When exposed to the standard, home cage 2-bottle "alcohol (10%, v/v) vs. water" choice regimen with continuous access, male sP rats consume daily approximately 6 g/kg alcohol. Conversely, when exposed to the intermittent (once every other day) access to 2 bottles containing alcohol (20%, v/v) and water, respectively, male sP rats display marked increases in daily alcohol intake and signs of alcohol intoxication and "behavioral" dependence. The present study was designed to assess alcohol intake in female sP rats exposed, under the 2-bottle choice regimen, to (a) 10% (v/v) alcohol with continuous access (CA10%), (b) 10% (v/v) alcohol with intermittent access (IA10%), (c) 20% (v/v) alcohol with continuous access (CA20%), and (d) 20% (v/v) alcohol with intermittent access (IA20%). Male sP rats (exposed to CA10% and IA20% conditions) were included for comparison. Over 20 daily drinking sessions, daily alcohol intake in female CA10% and IA20% rats averaged 7.0 and 9.6 g/kg, respectively. The rank of alcohol intake was IA20% > IA10% = CA20% > CA10%. Conversely, daily alcohol intake in male CA10% and IA20% rats averaged 6.0 and 8.2 g/kg, respectively. Comparison of female and male rats yielded the following rank of alcohol intake: female IA20% > male IA20% > female CA10% ≥ male CA10%. An additional experiment found that alcohol drinking during the first hour of the drinking session produced mean blood alcohol levels of 35-40 mg% and 85-100 mg% in the CA10% and IA20% rats, respectively. These results (a) extend to female sP rats previous data demonstrating the capacity of the IA20% condition to markedly escalate alcohol drinking, and (b) demonstrate that female sP rats consume more alcohol than male sP rats. This sex difference is more evident under the IA20% condition, suggesting that female sP rats are highly sensitive to the promoting effect of the IA20% condition on alcohol drinking. These data contribute to the characterization of sP rats as a model of excessive alcohol consumption., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Sardinian alcohol-preferring (sP) rats have been selectively bred for high alcohol preference and consumption using the standard 2-bottle "alcohol (10%, v/v) vs. water" choice regimen with unlimited access; under this regimen, sP rats daily consume 6-7 g/kg alcohol. The present study assessed a new paradigm of alcohol intake in which sP rats were exposed to the 4-bottle "alcohol (10%, 20%, and 30%, v/v) vs. water" choice regimen during one of the 12 h of the dark phase of the daily light/dark cycle; the time of alcohol exposure was changed daily in a semi-random order and was unpredictable to rats. Alcohol intake was highly positively correlated with the time of the drinking session and averaged approximately 2 g/kg when the drinking session occurred during the 12th hour of the dark phase. Alcohol drinking during the 12th hour of the dark phase resulted in (a) blood alcohol levels averaging approximately 100 mg% and (b) severe signs of alcohol intoxication (e.g., impaired performance at a Rota-Rod task). The results of a series of additional experiments indicate that (a) both singular aspects of this paradigm (i.e., unpredictability of alcohol exposure and concurrent availability of multiple alcohol concentrations) contributed to this high alcohol intake, (b) alcohol intake followed a circadian rhythm, as it decreased progressively over the first 3 h of the light phase and then maintained constant levels until the beginning of the dark phase, and (c) sensitivity to time schedule was specific to alcohol, as it did not generalize to a highly palatable chocolate-flavored beverage. These results demonstrate that unpredictable, limited access to multiple alcohol concentrations may result in exceptionally high intakes of alcohol in sP rats, modeling - to some extent - human binge drinking. A progressively increasing emotional "distress" associated to rats' expectation of alcohol might be the neurobehavioral basis of this drinking behavior., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The objectives of this study were to determine innate differences in gene expression in 2 regions of the extended amygdala between 5 different pairs of lines of male rats selectively bred for high or low ethanol consumption: a) alcohol-preferring (P) vs. alcohol-non-preferring (NP) rats, b) high-alcohol-drinking (HAD) vs. low-alcohol-drinking (LAD) rats (replicate line-pairs 1 and 2), c) ALKO alcohol (AA) vs. nonalcohol (ANA) rats, and d) Sardinian alcohol-preferring (sP) vs. Sardinian alcohol-nonpreferring (sNP) rats, and then to determine if these differences are common across the line-pairs. Microarray analysis revealed up to 1772 unique named genes in the nucleus accumbens shell (AcbSh) and 494 unique named genes in the central nucleus of the amygdala (CeA) that significantly differed [False Discovery Rate (FDR) = 0.10; fold-change at least 1.2] in expression between the individual line-pairs. Analysis using Gene Ontology (GO) and Ingenuity Pathways information indicated significant categories and networks in common for up to 3 or 4 line-pairs, but not for all 5 line-pairs. However, there were almost no individual genes in common within these categories and networks. ANOVAs of the combined data for the 5 line-pairs indicated 1014 and 731 significant (p < 0.01) differences in expression of named genes in the AcbSh and CeA, respectively. There were 4-6 individual named genes that significantly differed across up to 3 line-pairs in both regions; only 1 gene (Gsta4 in the CeA) differed in as many as 4 line-pairs. Overall, the findings suggest that a) some biological categories or networks (e.g., cell-to-cell signaling, cellular stress response, cellular organization, etc.) may be in common for subsets of line-pairs within either the AcbSh or CeA, and b) regulation of different genes and/or combinations of multiple biological systems may be contributing to the disparate alcohol drinking behaviors of these line-pairs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Previous research has demonstrated that treatment with the positive allosteric modulator (PAM) of the GABA(B) receptor (GABA(B) PAM), rac-BHFF, suppressed lever-responding for alcohol and amount of self-administered alcohol in Sardinian alcohol-preferring (sP) rats. The present study was designed to extend the investigation on the anti-alcohol effects of rac-BHFF to alcohol drinking behavior. To this end, sP rats were exposed to the homecage, 2-bottle "alcohol (10%, v/v) vs water" choice regimen, with unlimited access for 24 h/day. rac-BHFF was administered once daily and for 7 consecutive days at the doses of 0, 50, 100, and 200 mg/kg (i.g.). Treatment with rac-BHFF resulted in an immediate, stable, and dose-related reduction in daily alcohol intake; the overall magnitude of reduction in alcohol intake averaged approximately 25%, 40%, and 65% in 50, 100, and 200 mg/kg rac-BHFF-treated rat groups, respectively. An increase in daily water intake fully compensated the reduction in alcohol intake, so that daily total fluid intake was unaffected by treatment with rac-BHFF. Daily food intake tended to be reduced only by the highest dose of rac-BHFF. These results complement closely with previous data indicating that (a) rac-BHFF suppressed operant, oral alcohol self-administration in sP rats and (b) the prototypic GABA(B) PAMs, CGP7930 and GS39783, reduced alcohol drinking in sP rats. However, while the reducing effect of CGP7930 and GS39783 on the daily alcohol intake tended to vanish after the first 2-3 days of treatment, the reducing effect of rac-BHFF on daily alcohol intake remained unchanged over the entire 7-day treatment period. These data strengthen the hypothesis that GABA(B) PAMs may represent a step forward in the search for GABA(B) receptor ligands with therapeutic potential for alcoholism., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The present paper summarizes experimental data demonstrating the reducing effect of direct agonists and positive allosteric modulators (PAMs) of the gamma-aminobutyric acid(B) (GABA(B)) receptor on different alcohol-related behaviors. Different lines of evidence indicate that direct agonists, including baclofen, effectively suppress acquisition and maintenance of alcohol drinking behavior, relapse-like drinking, and alcohol's reinforcing, rewarding, stimulating, and motivational properties in rats and mice. More recently, the discovery of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, opened a new avenue of research in GABA(B) pharmacology. Accumulating lines of evidence suggest that PAMs retain baclofen's capcity to suppress alcohol consumption and alcohol's reinforcing and motivational properties in rats; these effects occur at doses far from those producing behavioral toxicity.

New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB(1) receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB(1) receptor, with K(i) concentrations comparable to the reference compounds 1, 4 and 5, and exhibited CB(1) selectivity comparable to 1 and 2. Docking experiments and molecular dynamics (MD) simulations explained the potent hCB(1) binding affinity of compounds 31 and 37. According to our previous studies, 31 and 37 formed a H-bond with K3.28(192), which accounted for the high affinity for the receptor inactive state and the inverse agonist activity. The finding of inhibition of food intake following their acute administration to rats, supported the concept that the CB(1) selective compounds 4 and 52 act as antagonists/inverse agonists.

gamma-Hydroxybutyric acid (GHB) reduces alcohol drinking, promotes abstinence from alcohol, suppresses craving for alcohol, and ameliorates alcohol withdrawal syndrome in alcoholics. At preclinical level, GHB suppresses alcohol withdrawal signs and alcohol intake in rats. The present study was designed to investigate whether GHB administration was capable of affecting alcohol's motivational properties (the possible animal correlate of human craving for alcohol) in selectively bred Sardinian alcohol-preferring rats. To this aim, rats were initially trained to lever press for alcohol (15%, vol/vol) under a procedure of operant, oral alcohol self-administration (fixed ratio 4 in 30-min daily sessions). Once responding for alcohol had stabilized, rats were divided into two groups and allocated to two independent experiments. Experiment 1 assessed the effect of GHB (0, 25, 50, and 100mg/kg, i.p.) on breakpoint for alcohol, defined as the lowest response requirement not achieved by each rat when exposed to a single-session progressive ratio schedule of reinforcement. Experiment 2 assessed the effect of GHB (0, 25, 50, and 100mg/kg, i.p.) on single-session extinction responding for alcohol (alcohol was absent and unreinforced responding was recorded). Breakpoint and extinction responding for alcohol are reliable indexes of alcohol's motivational strength. In Experiment 1, all doses of GHB reduced--by approximately 20% in comparison to saline-treated rats--breakpoint for alcohol. In Experiment 2, administration of 25, 50, and 100mg/kg GHB reduced--by approximately 25%, 40%, and 50%, respectively, in comparison to saline-treated rats--extinction responding for alcohol. Conversely, no dose of GHB altered breakpoint and extinction responding for sucrose (3%, wt/vol) in two independent subsets of Sardinian alcohol-preferring rats. Together, these data suggest that GHB administration specifically suppressed alcohol's motivational properties in Sardinian alcohol-preferring rats. These results are consistent with the anticraving properties of GHB observed in clinical studies.

The purpose of the present study was to characterize cue-induced reinstatement of ethanol seeking in selectively bred Sardinian alcohol-preferring (sP) rats trained to lever press for ethanol in 30-min self-administration sessions. Four responses on an "active" lever led to presentation of 0.1 ml of 15% (vol/vol) ethanol by a liquid dipper and concurrent activation of a set of discrete light and auditory cues. In a 70-min extinction/reinstatement session, responding was first extinguished for 60 min. Subsequently, different stimuli were delivered in a noncontingent manner and reinstatement of nonreinforced responding was assessed. Fifteen presentations of the ethanol-predictive stimulus complex, including the dipper cup containing 5 or 15% ethanol, potently reinstated responding on the previously active lever. The magnitude of reinstatement increased with the number of stimulus presentations and concentration of ethanol presented by the dipper cup. Fifteen presentations of the ethanol-predictive stimulus complex, including the dipper cup filled with water (0% ethanol), did not produce any reinstatement. These results indicate that (1) noncontingent presentations of the ethanol-predictive stimulus complex may reinstate ethanol seeking in sP rats and (2) the orosensory properties of ethanol may play an important role in reinstatement of ethanol seeking in sP rats. The latter finding concurs with clinical observations that odor and taste of alcoholic beverages elicit immediate craving responses in abstinent alcoholics.

This study investigated the effect of the gamma-aminobutyric acid(B) (GABA(B)) receptor agonist, baclofen, on alcohol deprivation effect (the transient increase in alcohol intake occurring after a period of alcohol abstinence) in Sardinian alcohol-preferring (sP) rats exposed to 4 bottles containing water and 10%, 20%, and 30% (v/v) alcohol, respectively. Acute administration of baclofen (1 mg/kg, i.p.) suppressed both aspects of alcohol deprivation effect: the extra-intake of alcohol and the selection of the highest concentrated alcohol solution. These results suggest that the GABA(B) receptor is part of the neural substrate mediating alcohol deprivation in sP rats.

The gamma-aminobutyric acidB (GABA(B)) receptor full agonists, baclofen and CGP44532, have been found to suppress different aspects of alcohol drinking behavior, including acquisition and maintenance, in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to assess whether this capability extends to the recently synthesized, positive allosteric modulators of the GABA(B) receptor, 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783). In the "acquisition" experiments, CGP7930 (0, 25, 50 and 100 mg/kg; i.g.) and GS39783 (0, 6.25, 12.5 and 25 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-naive sP rats. In the "maintenance" experiments, (0, 50 and 100 mg/kg; i.g.) and GS39783 (0, 50 and 100 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-experienced sP rats. Alcohol intake was evaluated under the standard, homecage 2-bottle "alcohol (10%, v/v) vs water" regimen with unlimited access for 24 h/day. Both CGP7930 and GS39783 dose-dependently suppressed the acquisition of alcohol drinking behavior. In the "maintenance" experiments, CGP7930 and GS39783 reduced daily alcohol intake by 30-40% only at the highest dose when compared to vehicle-treated rats; this effect tended to vanish on continuing treatment. The results of the present study suggest that positive allosteric modulation of the GABA(B) receptor produced an effect on alcohol drinking behavior similar to that produced by GABA(B) receptor full agonists. These data also suggest that positive allosteric modulation of the GABA(B) receptor may constitute a potential strategy for developing new drugs for treating alcohol dependence.

The function of the gamma-aminobutyric acid(B) (GABAB) receptor, measured as baclofen-stimulated [35S]GTPgammaS binding, was evaluated in some brain regions of Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) rats. EC50 value of baclofen-stimulated [35S]GTPgammaS in limbic areas was approximately 125% higher in alcohol-naive sP than sNP rats; voluntarily consumed alcohol reduced the EC50 value to a level similar to that of alcohol-naive sNP rats. These results suggest the presence of a genetically determined lower function of the GABAB receptor in limbic areas of sP than sNP rats; this differential functioning of the GABAB receptor may contribute to the opposite preference for alcohol in these rat lines.

Recent studies have demonstrated that treatment with the gamma-aminobutyric acid (GABA(B)) receptor agonist, baclofen, reduces alcohol intake in selectively bred Sardinian alcohol-preferring rats tested under the homecage two-bottle "alcohol versus water" choice regimen. This study was designed to investigate whether baclofen also reduces alcohol-reinforcing effects in Sardinian alcohol-preferring rats. To this aim, sP rats were trained to lever press for oral alcohol (15%, vol/vol) or sucrose (0.3%, wt/vol; included as alternative reinforcer to evaluate the specificity of baclofen effect on alcohol reinforcement) under a fixed ratio schedule of 4. Once steady levels of alcohol or sucrose self-administration behavior were established, the effects of acutely administered baclofen (0, 1.7, and 3 mg/kg, intraperitoneal [ip]) and naloxone (0, 1, and 3 mg/kg, ip; included as reference compound) on alcohol- or sucrose-reinforced responding were evaluated. Baclofen administration dose dependently, although not specifically, reduced alcohol-reinforced responding to an extent comparable to that of naloxone. Baclofen also produced a dose-dependent and specific delay in the onset of alcohol-reinforced responding, suggesting that it suppressed the rats' motivation to start drinking alcohol. These data are discussed in terms of adding further support to the hypothesized involvement of the GABA(B) receptor in the neural system mediating alcohol reinforcement. These data are also in agreement with the results of recent preliminary clinical studies suggesting that baclofen may have therapeutic efficacy in the treatment of alcohol dependence.

In the current study, we investigated the effect of the concurrent presentation of saccharin on the acquisition of alcohol-drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats. Alcohol-naive rats were given access to saccharin [0%, 0.01%, 0.1%, 1%, or 3% (weight/volume) in water], alcohol [10% (volume/volume) in water], and water under the home cage, three-bottle, free-choice regimen, with unlimited access for 24 h/day for 10 consecutive days. Intake of saccharin solution resulted as an inverted-U function of saccharin concentration, reaching polydipsic-like values at the 0.1% concentration. In contrast, alcohol intake was a U function of saccharin concentration, being virtually suppressed in the groups of rats exposed to the highly accepted 0.1% and 1% concentrations of saccharin. These results indicate that (1) the concurrent presentation of highly palatable solutions of saccharin suppresses acquisition of alcohol-drinking behavior in sP rats and (2) the suppressive effect of saccharin solutions on the acquisition of alcohol-drinking behavior in sP rats was positively related to their degree of acceptability. We hypothesize that an immediate and continuous access to the highly palatable saccharin solution may have distracted the rat, preventing it from consuming the amounts of alcohol solution needed to disclose and experience the psychopharmacologic effects of alcohol on which alcohol-drinking behavior in sP rats is based.

In the current study, we investigated the effect of the concurrent presentation of saccharin on the maintenance of alcohol-drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially given access to alcohol [10% (volume/volume) in water] and water under the home cage, two-bottle, free-choice regimen, with unlimited access for 24 h/day for eight consecutive weeks. Next, a third bottle, containing saccharin [0%, 0.01%, 0.1%, 1%, or 3% (weight/volume) in water], was concomitantly offered for an additional 10 consecutive days. Intake of saccharin solution resulted as an inverted-U function of saccharin concentration, with the 0.1% saccharin solution being the highest accepted. Alcohol intake was a U function of saccharin concentration, being reduced by 65%-95% in the group of rats exposed to the 0.1% saccharin solution. These results indicate that (1) the concurrent presentation of highly palatable solutions of saccharin markedly reduced alcohol intake in alcohol-experienced sP rats and (2) the reducing effect of saccharin solutions on the alcohol intake in sP rats was positively related to their degree of acceptability. We hypothesized that saccharin solutions may have functioned as a reinforcer, partially substituting for alcohol reinforcement and rendering alcohol drinking less urgent.

The present study was aimed at assessing the in vivo effectiveness of the positive allosteric modulator of the gamma-aminobutyric acidB (GABAB) receptor, CGP7930 [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol]. The synergistic potentiation of GABAB receptor functioning, previously observed in different in vitro assays, has been confirmed in the present work, where pretreatment with CGP7930 (10-170 mg/kg, i.p.) resulted in a marked potentiation of the sedative/hypnotic effect of the GABAB receptor agonists, baclofen (40 mg/kg, i.p.) and gamma-hydroxybutyric acid (500 mg/kg, i.p.), in DBA mice. Pretreatment with the GABAB receptor antagonist, SCH 50911 [(S)-5,5-dimethyl-2-morpholine acetic acid; 100 mg/kg, i.p.], resulted in a complete blockade of the sedative/hypnotic effect of the combination of CGP7930 with either baclofen or gamma-hydroxybutyric acid. These results confirm that CGP7930 may constitute an interesting tool for pharmacological studies in the GABAB receptor field.

Different effects of moderate to high doses of gamma-hydroxybutyric acid, including sedation/hypnosis, have been found to be blocked by gamma-aminobutyric acidB (GABAB) receptor antagonists. The present study investigated whether the protective effect of GABAB receptor antagonists extends also to gamma-hydroxybutyric acid-induced mortality. To this aim, the present study investigated the effect of the GABAB receptor antagonist, (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911; 100 mg/kg, ip), on mortality induced by gamma-hydroxybutyric acid (1-6 g/kg, ip) in DBA mice. Pretreatment with SCH 50911 resulted in a significant shift to the right of the dose-response curve of gamma-hydroxybutyric acid-induced mortality. Accordingly, the LD50 in SCH 50911-pretreated mice was significantly higher than that obtained in water-pretreated mice. The results of the present study support the hypothesis that (a) the GABAB receptor is a relevant site of action of gamma-hydroxybutyric acid, and (b) GABAB receptor antagonists may constitute potentially effective therapeutic interventions for gamma-hydroxybutyric acid intoxication.

Administration of the cannabinoid CB(1) receptor antagonist, SR 141716 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide], has been reported to reduce alcohol intake and alcohol self-administration in different models of excessive alcohol consumption, including the selectively bred Sardinian alcohol-preferring (sP) rats. The present study investigated whether SR 141716 was also capable of decreasing, in this rat line, alcohol's motivational properties. Extinction responding for alcohol, defined as the maximal number of lever responses reached in the absence of alcohol in rats trained to lever-press for alcohol, was used as index of alcohol's motivational properties. Rats were initially trained to lever-press for oral alcohol (15%, v/v) under a fixed ratio (FR) schedule of FR4. Once self-administration behavior was established, extinction sessions were conducted. SR 141716 (0, 0.3, 1 and 3 mg/kg; i.p.) was acutely administered before extinction sessions. In order to assess the specificity of SR 141716 action on extinction responding for alcohol, a separate group of sP rats was trained to lever-press for a 3% (w/v) sucrose solution under an FR4 schedule. SR 141716 administration produced a dose-dependent, virtually complete suppression of extinction responding for alcohol. In contrast, extinction responding for sucrose was not significantly altered by treatment with SR 141716. Further to the consummatory aspects, these results also extend the suppressing effect of SR 141716 to the appetitive aspects of alcohol drinking behavior in sP rats. The results also implicate the cannabinoid CB1 receptor in the neural substrate mediating alcohol's motivational properties in this rat line.

The cannabinoid CB(1) receptor antagonist, SR 141716 (Rimonabant), has been reported to stimulate, when acutely administered, intestinal motility in mice. The present study was aimed at determining whether tolerance develops to its repeated administration. Mice were treated twice a day for up to 8 consecutive days with 0, 3 and 5.6 mg/kg SR 141716 (i.p.). On days 1, 3, 5 and 8, separate groups of mice were treated intragastrically with a non-absorbable colored marker (carmine). The distance traveled by the head of the marker in the small intestine was recorded. On day 1, SR 141716 markedly activated intestinal peristalsis, but complete tolerance to this effect developed within the third day of treatment. The results may have some relevance to the proposed future clinical use of SR 141716.

Administration of morphine and cannabinoids stimulates alcohol intake in rats. The present study investigated whether the promoting effect of morphine and of the cannabinoid receptor agonist, WIN 55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone], on alcohol intake was prevented by the gamma-aminobutyric (GABA)(B) receptor agonist, baclofen. Sardinian alcohol-preferring (sP) rats were given alcohol (10%, v/v) and water under the standard homecage two-bottle-free choice regimen with unlimited access for 24 h/day. Baclofen (0, 0.5 and 1 mg/kg; i.p.) was administered acutely 30 min before lights off. Morphine (0 and 1 mg/kg, s.c.) or WIN 55,212-2 (0 and 2 mg/kg, i.p.) was administered acutely 10 min after baclofen. Alcohol intake was recorded 60 min after lights off. As predicted, both morphine and WIN 55,212-2 produced a specific and marked increase in alcohol intake. Pretreatment with baclofen, which failed to alter alcohol intake when given alone, dose-dependently suppressed morphine- and WIN 55,212-2-induced promotion of alcohol drinking. These results suggest the involvement of the GABA(B) receptor in the neural circuitry mediating the stimulating effect of morphine and cannabinoids on alcohol consumption in sP rats.

Results of a recent investigation revealed that selectively bred Indiana ethanol-nonpreferring (NP) rats could be "environmentally" conditioned to consume high amounts of ethanol. Specifically, a long-term exposure to a sucrose-plus-ethanol solution resulted, when sucrose was faded out, in an ethanol intake that was equivalent to that recorded in the counterpart ethanol-preferring (P) rats. The current study was designed to extend the above investigation to the selectively bred Sardinian alcohol-nonpreferring (sNP) rats. To this aim, rats of the sNP and Sardinian alcohol-preferring (sP) lines were exposed to a 108-day sucrose-fading procedure, which was virtually identical to that previously used with NP and P rats. Results indicated that intake of the sucrose-plus-ethanol solution in sNP rats was maintained predominantly by sucrose, as negligible intakes of ethanol were observed when sucrose was faded out. In contrast, sP rats maintained high levels of ethanol intake both during and after the induction procedure. These results support the suggestion that an environmental manipulation such as a long-term exposure to a sucrose-fading procedure did not overcome the genetically determined predisposition to avoid ethanol in sNP rats.

Results of a recent study have demonstrated that exposure to multiple ethanol concentrations and repeated ethanol deprivation periods in Indiana ethanol-preferring (P) rats resulted in the development of an alcohol deprivation effect (ADE; the temporary increase in voluntary ethanol intake after a period of deprivation from ethanol) characterized by consumption of intoxicating amounts of ethanol. The current study was designed to possibly extend these results to Sardinian alcohol-preferring (sP) rats, generated with the same selective program previously used for P rats. To this aim, ethanol-naive sP rats were exposed initially to the home cage four-bottle choice [10%, 20%, and 30% (vol./vol.) ethanol solutions and water] for eight consecutive weeks. Subsequently, rats were divided into two groups: The first group had continuous access to the four-bottle regimen (nondeprived rats), and the second group was exposed to five cycles of 14-day periods of deprivation from ethanol and 14-day periods of reexposure to the four-bottle regimen. An ADE developed after each deprivation period. However, the extra intake of ethanol was limited to the first hour of each reaccess period. Magnitude of ADE did not change with repeated periods of deprivation. However, a shift in preference toward the two highest concentrations of ethanol solutions was evident from the first reexposure to ethanol and was maintained throughout the study. These results provide further evidence on the heterogeneity of ethanol-drinking behavior among rat lines selectively bred for high ethanol preference and consumption.

The present study investigated the effect of the GABA(B) receptor antagonist, SCH 50911 [(2S)(+)-5,5-dimethyl-2-morpholineacetic acid], on the occurrence of seizures in ethanol-dependent rats undergoing ethanol withdrawal syndrome. The acute administration of nonconvulsive doses of SCH 50911 (0, 100, 170 and 300 mg/kg, i.p.) resulted in a dramatic facilitation of spontaneous seizure occurrence. This finding, together with the reported ability of the GABA(B) receptor agonist, baclofen, to suppress seizures associated to ethanol withdrawal syndrome, suggests that the GABA(B) receptor may be part of the neural substrate underlying the hyperexcitability of ethanol withdrawal syndrome.

The present study investigated the effect of the cannabinoid CB(1) receptor antagonist, SR 141716 (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide), on the ability of low and high doses of morphine to, respectively, augment and suppress voluntary alcohol intake in selectively bred Sardinian alcohol-preferring rats. Acute administration of a low dose of morphine (1 mg/kg, s.c.) produced a specific and marked increase in alcohol intake, which correlated with an increase in blood alcohol levels and was prevented by either SR 141716 (0.3 mg/kg, i.p.) or naloxone (0.1 mg/kg, i.p.). A higher dose (10 mg/kg, s.c.) of morphine reduced both alcohol and food intakes and produced sedation and hypomotility. The suppressant effect of morphine on alcohol intake was blocked by naloxone (0.1 mg/kg, i.p.) but not by SR 141716 (0.3 mg/kg, i.p.). These results are in agreement with those showing the ability of SR 141716 to antagonize the appetitive and positive reinforcing properties of morphine and add further support to the hypothesis of the existence of a functional link between the action of opioids and of cannabinoids.

The present study investigated the effect of the cannabinoid CB(1) receptor antagonist, SR 141716 (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide), on alcohol deprivation effect (i.e. the temporary increase in alcohol intake after a period of alcohol withdrawal) in Sardinian alcohol-preferring (sP) rats. As expected, alcohol-deprived rats virtually doubled voluntary alcohol intake during the first hour of re-access. Acute administration of SR 141716 (0, 0.3, 1 and 3 mg/kg, i.p.) completely abolished the alcohol deprivation effect. These results suggest that the cannabinoid CB(1) receptor is part of the neural substrate mediating the alcohol deprivation effect and that SR 141716 may possess anti-relapse properties.

The aliphatic alcohol 1,4-butanediol in converted into gamma-hydroxybutyric acid (GHB) via two enzymatic steps: first, it is oxidised by alcohol dehydrogenase in gamma-hydroxybutyraldehyde; second, the latter is transformed, likely by aldehyde dehydrogenase, into GHB. Initially, the present study compared the sedative/hypnotic effect of GHB and 1,4-butanediol, measured as loss of righting reflex. 1,4-Butanediol was more potent than GHB, presumably because of a more rapid penetration of the blood brain barrier. Further alcohol dehydrogenase inhibitors, 4-methylpyrazole and ethanol, totally prevented the sedative/hypnotic effect of 1,4-butanediol; the aldehyde dehydrogenase inhibitor disulfiram partially blocked the sedative/hypnotic effect of 1,4-butanediol. Finally, the sedative/hypnotic effect of 1,4-butanediol was antagonised by the GABA(B) receptor antagonists, SCH 50911 [(2S)(+)-5,5-dimethyl-2-morpholineacetic acid] and CGP 46381 [(3-aminopropyl)(cyclohexylmethyl)phosphinic acid], but not by the putative GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid), indicating that it is mediated by GABA(B) but not GHB receptors. Taken together, these results suggest that the sedative/hypnotic effect of 1,4-butanediol is mediated by its conversion in vivo into GHB which, in turn, binds to GABA(B) receptors. Accordingly 1,4-butanediol, unlike GHB, failed to displace [(3)H]GHB and [(3)H]baclofen in brain membranes.

In the present study, we investigated whether aversion to the pharmacological effects of ethanol developed to a differential extent in selectively bred Sardinian alcohol-preferring (sP) and Sardinian alcohol-nonpreferring (sNP) rats, and whether this different response was consistent with their genetically determined differences in ethanol preference and consumption. To this purpose, a conditioned taste aversion paradigm was used. Male sP and sNP rats were exposed to five sessions in which a 20-min availability of a saccharin solution (1 g/l) was paired to the injection of ethanol (0, 0.5, or 1 g/kg, i.p.), delivered immediately after removal of the saccharin bottle (conditioning phase). Subsequently, the choice between saccharin solution and water was offered for 18 consecutive daily 20-min sessions (postconditioning phase). Ethanol at 1g/kg produced a marked aversion to saccharin in sNP rats: The reduction in saccharin intake was already evident on the second day of the conditioning phase and lasted for 15 days of the postconditioning phase. In contrast, this dose of ethanol elicited a modest, if any, conditioned taste aversion in sP rats, although blood ethanol levels were comparable to those assessed in sNP rats. These results indicate the existence of a differential degree of aversion to the postingestional effects of ethanol between sP and sNP rats, and support the suggestion that it may contribute, at least in part, to the opposite preference for and consumption of ethanol monitored in these rat lines.