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Background Positive allosteric modulators (PAMs) of the GABAB receptor constitute a new class of GABAB-receptor ligands. GABAB PAMs reproduce several pharmacological effects of the orthosteric GABAB receptor agonist, baclofen, although displaying a better safety profile. Aims This paper reviews the reducing or, frequently, even suppressing effects of all GABAB PAMs tested to date on multiple alcohol-related behaviours in laboratory rodents exposed to validated experimental models of human alcohol use disorder. Results Acute or repeated treatment with CGP7930, GS39783, BHF177, rac -BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669 reduced excessive alcohol drinking, relapse- and binge-like drinking, operant alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced conditioned place preference in rats and mice. Conclusions These effects closely mirrored those of baclofen; notably, they were associated to remarkably lower levels of tolerance and toxicity. The recent transition of ASP8062 to clinical testing will soon prove whether these highly consistent preclinical data translate to AUD patients. [ABSTRACT FROM AUTHOR]

An editorial is presents the retirement of Professor Jonathan Chick as one of the Editors-in-Chief of Alcohol and Alcoholism, highlighting his significant contributions to the field of alcohol and addiction over several decades, including his clinical, academic, and research endeavors. It emphasizes his instrumental role in advancing addiction psychiatry, his leadership in clinical guidelines development, research on treatments for alcohol use disorder.

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 GABAB receptor and an action at the cannabinoid CB1 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. [ABSTRACT FROM AUTHOR]

The orthosteric γ-aminobutyric acidB (GABAB) receptor agonist baclofen is currently considered a therapeutic option for alcohol use disorder (AUD); however, the safety profile of baclofen is a concern, thus arousing interest in the positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs), a new class of ligands expected to possess a better safety profile. The present paper summarizes the several lines of experimental evidence indicating the ability of GABAB PAMs to inhibit multiple alcohol-motivated behaviors in rodents. All GABAB PAMs tested to date have invariably been reported to reduce, or even suppress, excessive alcohol drinking, relapse- and binge-like drinking, operant oral alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced locomotor stimulation and conditioned place preference in rats and mice. The use of validated animal models of several aspects of AUD confers translational value to these findings. The reducing effects of GABAB PAMs on alcohol-motivated behaviors (1) occurred at doses largely lower than those inducing sedation, suggesting that GABAB PAMs may possess, if compared with baclofen, a higher therapeutic index and a more favorable safety profile, and (2) were often not associated with reductions on other non-drug consummatory behaviors. Additional findings with therapeutic potential were (1) the lack of tolerance, after repeated treatment, to the reducing effect of GABAB PAMs on alcohol drinking and self-administration; (2) the efficacy of GABAB PAMs after intragastric administration; and (3) the ability of GABAB PAMs to selectively potentiate the suppressing effect of baclofen on alcohol self-administration. The recent transition of the first GABAB PAMs to the initial steps of clinical testing makes investigation of the efficacy of GABAB PAMs in AUD patients a feasible option. [ABSTRACT FROM AUTHOR]

Rationale and objectives: COR659 [methyl2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate] is a new, positive allosteric modulator (PAM) of the GABA receptor. This study evaluated whether COR659 shared with previously tested GABA PAMs the capacity to reduce alcohol self-administration in rats. Results: Treatment with non-sedative doses of COR659 (2.5, 5, and 10 mg/kg; i.p.) suppressed lever-responding for alcohol (15% v/ v) in Sardinian alcohol-preferring (sP) rats under the fixed ratio (FR) 4 (FR4) and progressive ratio (PR) schedules of reinforcement; COR659 was more potent and effective than the reference GABA PAM, GS39783. Treatment with COR659, but not GS39783, suppressed (a) lever-responding for a sucrose solution (1-3% w/ v) in sP rats under the FR4 and PR schedules, (b) lever-responding for a chocolate solution [5% ( w/ v) Nesquik®] in Wistar rats under the FR10 and PR schedules, and (c) cue-induced reinstatement of chocolate seeking in Wistar rats. Treatment with COR659 was completely ineffective on lever-responding (FR10) for regular food pellets in food-deprived Wistar rats. Pretreatment with the GABA receptor antagonist, SCH50911, partially blocked COR659-induced reduction of alcohol self-administration, being ineffective on reduction of chocolate self-administration. Pretreatment with the cannabinoid CB receptor antagonist, AM4113, fully blocked COR659-induced reduction of chocolate self-administration, being ineffective on reduction of alcohol self-administration. Conclusions: COR659 might exert its behavioral effects via a composite mechanism: (i) positive allosteric modulation of the GABA receptor, responsible for a large proportion of reduction of alcohol self-administration; (ii) an action at other receptor system(s), including the cannabinoid CB receptor, through which COR659 affects seeking and consumption of highly palatable foods. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aims: Salvia miltiorrhiza Bunge (Labiatae) is a Chinese medicinal plant, the dried roots of which (known as Dan-Shen) have been used for hundreds of years in the treatment of a series of ailments, including hyperglycemia. This study was designed to evaluate the hypoglycemic effect of a new, standardized extract of S. miltiorrhiza. Materials and Methods: S. miltiorrhiza extract (containing 21% total tanshinones and 3.7% tanshinone IIA) was administered acutely and intragastrically at the doses of 0, 50, 100, and 200 mg/kg to male, healthy, fasted Wistar rats 60 min before the intragastric infusion of a bolus of starch (3 g/kg; a semi-naturalistic experimental condition) (Experiment 1) or glucose (2 g/kg) (Experiment 2). Results: In both experiments, treatment with S. miltiorrhiza extract produced a dose-related decrease in glycemia, evidenced in terms of reduction of peak value and/or area under the curve of the time-course of glycemia. The effect of S. miltiorrhiza extract occurred at doses devoid of any behavioral toxicity in rats. Conclusion: The results of this study suggest that the hypoglycemic effect of S. miltiorrhiza extract was likely secondary to an action on carbohydrate metabolism. These results are consistent with several preclinical and clinical data and add further support to the hypothesis that S. miltiorrhiza extracts may act as effective anti-hyperglycemic remedies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aims: Salvia miltiorrhiza Bunge (Labiatae) is a Chinese medicinal plant, the dried roots of which (known as Dan-Shen) have been used for hundreds of years in the treatment of a series of ailments, including hyperglycemia. This study was designed to evaluate the hypoglycemic effect of a new, standardized extract of S. miltiorrhiza. Materials and Methods: S. miltiorrhiza extract (containing 21% total tanshinones and 3.7% tanshinone IIA) was administered acutely and intragastrically at the doses of 0, 50, 100, and 200 mg/kg to male, healthy, fasted Wistar rats 60 min before the intragastric infusion of a bolus of starch (3 g/kg; a semi-naturalistic experimental condition) (Experiment 1) or glucose (2 g/kg) (Experiment 2). Results: In both experiments, treatment with S. miltiorrhiza extract produced a dose-related decrease in glycemia, evidenced in terms of reduction of peak value and/or area under the curve of the time-course of glycemia. The effect of S. miltiorrhiza extract occurred at doses devoid of any behavioral toxicity in rats. Conclusion: The results of this study suggest that the hypoglycemic effect of S. miltiorrhiza extract was likely secondary to an action on carbohydrate metabolism. These results are consistent with several preclinical and clinical data and add further support to the hypothesis that S. miltiorrhiza extracts may act as effective anti-hyperglycemic remedies. Key words: Rats, standardized extract of S. miltiorrhiza roots, starch-and glucose-induced rise in glycemia, type-2 diabetes [ABSTRACT FROM AUTHOR]

Background. There is a growing consensus that similar neural mechanisms are involved in the reinforcing properties of natural rewards, like food and sex, and drugs of abuse. Rat lines selectively bred for high and low oral alcohol intake and preference have been useful for understanding factors contributing to excessive alcohol intake and may constitute proper animal models for investigating the neurobiological basis of natural rewarding stimuli. Methods. The present study evaluated copulatory behavior in alcohol and sexually naïve Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) male rats in three consecutive copulatory behavior tests. Results. The main finding was that, under the conditions used in this study, sNP rats were sexually inactive relative to sP rats. To gain more information about the sexual behavior in sP rats, Wistar rats were included as an external reference strain. Only minor differences between sP and Wistar rats were revealed. Conclusions. The reason behind the low copulatory activity of sNP rats remains to be elucidated, but may in part be mediated by innate differences in brain transmitter systems. The comparison between sP and Wistar rats may also suggest that the inherent proclivity to excessive alcohol drinking in sP rats may mainly be dependent on its anxiolytic properties, as previously proposed, and not changes in the reward system. [ABSTRACT FROM AUTHOR]

Background Recent experimental data indicate that treatment with the selective dopamine β-hydroxylase inhibitor, nepicastat, suppressed different reward-related behaviors, including self-administration of chocolate and reinstatement of cocaine and chocolate seeking, in rats. This study was designed to extend to different alcohol-related behaviors the investigation on the ' anti-addictive' properties of nepicastat. Methods Sardinian alcohol-preferring (sP) rats, selectively bred for excessive alcohol consumption, were exposed to different procedures of alcohol drinking and self-administration. Results Repeated treatment with nepicastat (0, 25, 50, and 100 mg/kg, intraperitoneally [i.p.], once daily for 10 consecutive days) produced a stable and dose-related reduction in daily alcohol intake in sP rats exposed to the homecage 2-bottle 'alcohol (10% v/v) versus water' choice regimen with unlimited access. Acute treatment with nepicastat (0, 25, 50, and 100 mg/kg, i.p.) completely suppressed the 'alcohol deprivation effect' (i.e., the temporary increase in alcohol intake occurring after a period of abstinence; model of alcohol relapse episodes) in sP rats exposed to the 2-bottle choice regimen. Acute treatment with nepicastat (0, 25, 50, and 100 mg/kg, i.p.) dose dependently and selectively reduced oral alcohol self-administration in sP rats trained to lever respond for alcohol (15% v/v) on a fixed ratio 4 schedule of reinforcement. Finally, combination of nepicastat (0, 50, and 100 mg/kg, i.p.) and alcohol (2 g/kg, intragastrically) did not alter spontaneous locomotor activity in sP rats. Conclusions Together, these data extend to alcohol the capacity of nepicastat to suppress different behaviors motivated by natural stimuli and drugs of abuse. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 35e40 mg% and 85e100 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. [ABSTRACT FROM AUTHOR]

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 6e7 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. [ABSTRACT FROM AUTHOR]

Highlights: [•] Effects of voluntary alcohol drinking on CRF and ppDyn gene expression. [•] Genetically determined high basal CRF mRNA levels in CeA of sP rats. [•] Alcohol drinking decreased CRF, but increased ppDyn mRNA levels in CeA. [ABSTRACT FROM AUTHOR]

Background Evidence obtained in humans and rodents indicates that beta-endorphin (encoded by the proopiomelanocortin [ POMC] gene) is critical in the regulation of alcohol drinking behavior. However, the alcohol effect on POMC gene expression has not been studied in rodent mesolimbic regions, such as the nucleus accumbens ( NAc). Methods In this study, we first utilized POMC-enhanced green fluorescent protein ( EGFP) transgenic mice to visualize POMC neurons and found that POMC- EGFP cells were modestly distributed throughout the NAc shell and core, in addition to the hypothalamic arcuate nucleus. POMC m RNA expression in the NAc of mice and rats was confirmed using reverse transcriptase-polymerase chain reaction and solution hybridization assays. We then investigated whether there are genetically determined differences in basal m RNA levels of POMC and mu opioid receptor ( MOP-r) between selectively bred Sardinian alcohol-preferring (s P) and nonpreferring (s NP) rats, and whether these m RNA levels are altered in s P rats after alcohol drinking (10%, unlimited access) for 17 days. Results Alcohol-naïve s P rats had higher basal POMC m RNA levels than s NP rats only in hypothalamus. Alcohol drinking increased POMC m RNA levels in both the NAc shell (by 100%) and the hypothalamus (by 50%) of s P rats. Although s P rats had lower basal levels of MOP-r m RNA and GTPγ S binding in NAc shell than s NP rats, voluntary alcohol consumption had no effect on MOP-r m RNA levels in the NAc shell. Conclusions Our results define the distribution of POMC-expressing neurons in the NAc of mice and rats. Higher POMC expression at basal levels in s P rats (genetically determined), along with increases after drinking (alcohol-induced) in the NAc shell and hypothalamus, suggests that the POMC systems play a role in high alcohol preference and consumption. [ABSTRACT FROM AUTHOR]

Background: Recent animal studies have shown that the level of stress-responsive arginine vasopressin (AVP) gene expression in the amygdala is increased during early withdrawal from long-term heroin or cocaine administration. The selective AVP V1b receptor antagonist SSR149415 (capable of exerting antidepressant-like and anxiolytic effects in animal models) also blocked stress-induced reinstatement of drug-seeking behavior. This study was undertaken to investigate the effects of alcohol and to determine whether (i) there are genetically determined differences in basal AVP mRNA levels in the medial/central amygdala (Me/CeA) and medial hypothalamus (MH) between selectively bred Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats; (ii) the AVP mRNA levels are altered by long-term alcohol drinking in sP rats; and (iii) the V1b receptor antagonist SSR149415 alters alcohol drinking in sP rats. Methods: In Experiment 1, AVP mRNA levels were measured in the Me/CeA and MH of alcohol-naïve sP and sNP rats, and sP rats exposed to the standard, homecage 2-bottle 'alcohol versus water' choice regimen 24 h/d for 17 days. In Experiment 2, SSR149415 (0, 3, 10, or 30 mg/kg; intraperitoneal) was acutely administered 30 minutes before lights off to alcohol-experienced sP rats. Alcohol, water, and food intake were monitored 6 and 24 hours later. Results: We found higher basal AVP mRNA levels in both Me/CeA and MH of alcohol-naïve sP than sNP rats; alcohol consumption decreased AVP mRNA levels in both brain regions of sP rats, suggesting genetically determined differences between the 2 rat lines and in the effects of alcohol drinking in sP rats. Acute treatment with SSR149415 significantly reduced alcohol intake of sP rats. Conclusion: The stress-responsive AVP/V1b receptor system is 1 component of the neural circuitry underlying high alcohol drinking in sP rats. [ABSTRACT FROM AUTHOR]

Abstract: The present investigation continues previous behavioral profiling studies of selectively bred alcohol-drinking and alcohol non-drinking rats. In this study, alcohol-naïve adult Sardinian alcohol-preferring (sP) and non-preferring (sNP) rats were tested in the multivariate concentric square field™ (MCSF) test. The MCSF test has an ethoexperimental approach and measures general activity, exploration, risk assessment, risk taking, and shelter seeking in laboratory rodents. The multivariate design enables behavioral profiling in one and the same test situation. Age-matched male Wistar rats were included as a control group. Five weeks after the first MCSF trial, a repeated testing was done to explore differences in acquired experience. The results revealed distinct differences in exploratory strategies and behavioral profiles between sP and sNP rats. The sP rats were characterized by lower activity, lower exploratory drive, higher risk assessment, and lower risk taking behavior than in sNP rats. In the repeated trial, risk-taking behavior was almost abolished in sP rats. When comparing the performance of sP and sNP rats with that of Wistar rats, the principal component analysis revealed that the sP rats were the most divergent group. The vigilant behavior observed in sP rats with low exploratory drive and low risk-taking behavior is interpreted here as high innate anxiety-related behaviors and may be related to their propensity for high voluntary alcohol intake and preference. We suggest that the different lines of alcohol-preferring rats with different behavioral characteristics constitute valuable animal models that mimic the heterogeneity in human alcohol dependence. [Copyright &y& Elsevier]

Abstract: The present paper summarizes experimental data demonstrating the reducing effect of direct agonists and positive allosteric modulators (PAMs) of the γ-aminobutyric acidB (GABAB) 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 GABAB 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. [Copyright &y& Elsevier]

Abstract: This study investigated the effect of the γ-aminobutyric acidB (GABAB) 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 GABAB receptor is part of the neural substrate mediating alcohol deprivation in sP rats. [Copyright &y& Elsevier]

A severe and life-threatening γ-hydroxybutyric acid (GHB) withdrawal syndrome, clinically similar to the alcohol withdrawal syndrome, is increasingly being reported in GHB addicts. We investigated for the occurrence of withdrawal in Wistar and Sprague-Dawley rats, and in the selectively bred lines of GHB-sensitive (GHB-S) and Sardinian alcohol-preferring (sP) rats, following chronic administration of GHB, γ-butyrolactone (GBL), and/or 1,4-butanediol (1,4-BD). Using validated rodent alcohol withdrawal scoring scales, little to no spontaneous or pharmacologically precipitated withdrawal effects were observed in Wistar, Sprague-Dawley, or GHB-S rats. Conversely, sP rats displayed both spontaneous and precipitated audiogenic seizures following abrupt cessation of chronic GHB or 1,4-BD administration and following pharmacological challenge with the GABAB receptor-selective antagonist, SCH 50911, respectively. [ABSTRACT FROM AUTHOR]

Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats are one of the pairs of rat lines selectively bred for high and low alcohol preference and consumption, respectively, under the homecage, continuous two-bottle choice regimen. sP rats meet most of the fundamental criteria for an animal model of alcoholism, in that they voluntarily consume sufficient amounts of alcohol to achieve significant blood alcohol levels and produce psychopharmacological effects, including anxiolysis and motor stimulation. sP rats are also willing to ‘work’ (such as lever-pressing) for alcohol. Chronic alcohol drinking in sP rats results in the development of tolerance to a given effect of alcohol (specifically, motor incoordination) and relapse-like drinking (the alcohol deprivation effect). Conversely, sNP rats avoid alcohol virtually completely; their avoidance for alcohol being resistant even to an environmental manipulation such as long-term exposure to alcohol plus sucrose. sP and sNP rats have been characterized for different phenotypes, possibly associated to their different alcohol preference and consumption. In comparison with sNP rats, alcohol-naive sP rats displayed (1) more anxiety-related behaviors; (2) higher initial sensitivity to the locomotor stimulating and sedative/hypnotic effects of alcohol; and (3) lower sensitivity to the aversive effects of alcohol. The present paper reviews the data collected to date on alcohol drinking behavior and other alcohol-related behaviors in sP and sNP rats. The behavioral profile of sP rats is also compared with that of other lines of selectively bred alcohol-preferring rats and the heterogeneity resulting from this comparison is discussed in terms of different animal models for the different forms of alcoholism. [ABSTRACT FROM AUTHOR]

This study investigated whether (a) cannabinoid CB1 receptor knockout (CB1−/−) mice displayed altered gastrointestinal transit and (b) cannabinoid CB1 and opioid receptors functionally interact in the regulation of gastrointestinal transit.Gastrointestinal transit was assessed by the Whole Gastrointestinal Transit, measuring the excretion time of an intragastrically administered marker (whole intestine), and the Upper Gastrointestinal Transit, measuring the distance covered by the marker in the small intestine.CB1−/− and homozygous CB1+/+ (CB1+/+) mice did not differ in both whole gut and small intestine transit. CB1−/− and CB1+/+ mice were equally responsive to the inhibitory effect of morphine (10 mg kg−1) and loperamide (3 mg kg−1) on whole gut transit.Additionally, in CD1 mice the cannabinoid CB1 receptor antagonist, rimonabant (0–0.5 mg kg−1), failed to block the inhibitory effect of morphine (0–1.25 mg kg−1) and loperamide (0–0.5 mg kg−1) on transit in small and whole intestine. Similarly, the opioid receptor antagonists, naloxone (0–1 mg kg−1) and naltrexone (0–10 mg kg−1), failed to block the inhibitory effect of the cannabinoid WIN 55,212-2 (0–3 mg kg−1) on transit in small and whole intestine.These results suggest that (a) compensatory mechanisms likely developed in CB1−/− mice to overcome the lack of inhibitory function of endocannabinoid system; (b) cannabinoid and opioid receptor systems did not interact in regulating gastrointestinal transit in mice.British Journal of Pharmacology (2006) 148, 1043–1050. doi:10.1038/sj.bjp.0706824; published online 17 July 2006 [ABSTRACT FROM AUTHOR]

The present paper focuses on the different lines of evidence indicating that cannabinoid CB1 receptor antagonists, including the prototype rimonabant, reduce food intake and body weight in laboratory animals. Recent clinical surveys demonstrated that rimonabant significantly reduced body weight also in overweight/obese humans. Treatment with rimonabant was associated with a beneficial effect on different metabolic parameters and cardiovascular risk factors linked to overweight. The data reviewed in this paper suggest that cannabinoid CB1 receptor antagonists may constitute a novel class of drugs potentially effective in the treatment of obesity-related disorders. [ABSTRACT FROM AUTHOR]

Background: Previous work found that extracts from the roots of Salvia miltiorrhiza, a Chinese medicinal herb, reduced alcohol intake in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to evaluate whether miltirone, one of the possible active constituents of S. miltiorrhiza, might be responsible for the reducing effect of the extracts on alcohol intake. Methods: An initial experiment assessed the effect of 100 mg/kg (intragastric, i.g.) of 4 extracts of S. miltiorrhiza, differing in miltirone content (0, 2, 3, and 7%, respectively), on alcohol intake in alcohol-experienced sP rats exposed to the 2-bottle “alcohol (10%, volume in volume) versus water” choice regimen. Subsequently, the effect of pure miltirone (2.5–10 mg/kg, i.g., i.e., a dose range comparable to its content in the effective doses of the active extracts) on acquisition and maintenance of alcohol-drinking behavior was evaluated in alcohol-naive and alcohol-experienced sP rats exposed to the 2-bottle choice regimen. The effect of miltirone (10 mg/kg, i.g.) on blood alcohol levels was assessed after the i.g. and intraperitoneal (i.p.) administration of alcohol. Finally, the effect of miltirone (30–100 mg/kg, i.g.) on the severity of alcohol withdrawal syndrome was evaluated in Wistar rats made physically dependent on alcohol by the repeated administration of intoxicating doses of alcohol. Results: The reducing effect of 4 different extracts of S. miltiorrhiza on alcohol intake was positively and significantly correlated with their miltirone content. Pure miltirone reduced alcohol intake in alcohol-experienced rats and delayed acquisition of alcohol-drinking behavior in alcohol-naive rats. Similar to S. miltiorrhiza extracts, miltirone markedly reduced blood alcohol levels when alcohol was administered i.g. but not i.p., suggesting that miltirone hampered alcohol absorption from the gastrointestinal system. Finally, miltirone failed to affect the severity of alcohol withdrawal syndrome in alcohol-dependent rats. Conclusions: The results of the present study suggest that miltirone is the likely active constituent of S. miltiorrhiza responsible for the reducing effect of its extracts on alcohol intake in different experimental models of excessive alcohol consumption. [ABSTRACT FROM AUTHOR]

Abstract: The present paper synthetically reviews the multiple experimental lines of evidence indicating the ability of the prototypic cannabinoid CB1 receptor antagonist, rimonabant (also known as SR 141716), to suppress the reinforcing/rewarding properties of different drugs of abuse, including cocaine, heroin, nicotine and alcohol, in laboratory rodents. This paper also reviews the data demonstrating that rimonabant reduces food intake and body weight in laboratory animals and humans. Taken together, the data reviewed here suggest that rimonabant may constitute a new and potentially effective medication for the treatment of drug addiction and obesity-related disorders. [Copyright &y& Elsevier]

Abstract: The present paper describes the results of recent pharmacological studies implicating the cannabinoid CB1 receptor in the neural circuitry regulating alcohol consumption and motivation to consume alcohol. Cannabinoid CB1 receptor agonists have been found to specifically stimulate alcohol intake and alcohol''s motivational properties in rats. Conversely, the cannabinoid CB1 receptor antagonist, SR 141716, has been reported to specifically suppress acquisition and maintenance of alcohol drinking behavior, relapse-like drinking and alcohol''s motivational properties in rats. More recent data indicate that opioid receptor antagonists a) blocked the stimulatory effect of cannabinoids on alcohol intake, and b) synergistically potentiated the suppressing effect of SR 141716 on alcohol intake and alcohol''s motivational properties. Consistently, SR 141716 blocked the stimulatory effect of morphine on alcohol intake. These results suggest a) the existence of a functional link between the cannabinoid and opioid receptor systems in the control of alcohol intake and motivation to consume alcohol, and b) that novel and potentially effective therapeutic strategies for alcoholism may come from the combination of cannabinoid and opioid receptor antagonists. [Copyright &y& Elsevier]

Abstract: γ-Hydroxybutyric acid (GHB)-sensitive (GHB-S) and GHB-resistant (GHB-R) rats have been selectively bred for their opposite sensitivity to the sedative/hypnotic effect of GHB. This opposite sensitivity has been found to generalize to the GABAB receptor agonist, baclofen. A control line [named GHB-control (GHB-C)] has been derived from the foundation stock of GHB-S and GHB-R rats. GHB-C rats have been bred without any evaluation of their sensitivity to GHB. The experiments described here were designed to evaluate the sensitivity of GHB-C rats, from the 13th generation, to the sedative/hypnotic effect of GHB (1 g/kg, i.p.) and baclofen (20 mg/kg, i.p.). All measures (onset, sleep time and r = sleep time/onset) of sensitivity to GHB- and baclofen-induced sedation/hypnosis in GHB-C rats were significantly different from and intermediate to those recorded in GHB-S and GHB-R rats. Furthermore, these values were similar to those recorded in the foundation stock. These results suggest that GHB-C rats may constitute a valid control line for GHB-S and GHB-R rats, representing the “general population” from which GHB-S and GHB-R rats were derived. Furthermore, the relative equidistance of sensitivity to GHB- and baclofen-induced sedation/hypnosis of GHB-C rats from those of GHB-S and GHB-R rats suggests that genetic factors contributes to the development of both sensitivity in GHB-S rats and resistance in GHB-R rats. [Copyright &y& Elsevier]

Abstract: The present study investigated whether the differential sensitivity of selectively bred γ-hydroxybutyric acid (GHB)-sensitive (GHB-S) and GHB-resistant (GHB-R) rats to GHB- and baclofen-induced sedation/hypnosis generalized to the motor incoordinating effect of the two drugs. To this aim, GHB-S and GHB-R rats were tested on a Rota-Rod after the acute administration of GHB (100–500 mg/kg, i.p.) and baclofen (1.25–5 mg/kg, i.p.). Significant line differences were observed in the dose–response curves for both GHB and baclofen, with GHB-S rats displaying a greater sensitivity to the motor incoordinating effects of both drugs than GHB-R rats. No line difference was observed in diazepam (1.25–5 mg/kg, i.p.), pentobarbital (5–15 mg/kg, i.p.), and ethanol (1–1.5 g/kg, i.p.) dose–response curves. These results suggest that the differential sensitivity of GHB-S and GHB-R rats to GHB and baclofen extends to the effects produced by doses of the two drugs which are 5–10 times lower than those for which rats have been selectively bred. These results are discussed in terms of the GABAB receptor being the likely neural substrate on which the differential sensitivity of GHB-S and GHB-R rats resides. [Copyright &y& Elsevier]

Abstract: Recent surveys suggest that positive outcomes in the pharmacotherapy of alcoholism may be obtained through drug combinations. The present study evaluated the effect of the combination of the opioid receptor antagonist, naltrexone, with the GABAB receptor agonist, baclofen, on the acquisition of alcohol drinking behavior in Sardinian alcohol-preferring (sP) rats. Rats were treated with either saline, 0.5mg/kg naltrexone, 1mg/kg baclofen, or 0.5mg/kg naltrexone plus 1mg/kg baclofen once a day for 10 days. Alcohol was offered immediately after the first drug injection under the 2-bottle regimen. Alcohol intake in saline-treated rats rose to 5–6g/kg/day within a few days, indicative of a rapid acquisition of alcohol drinking behavior. Neither naltrexone nor baclofen, when given alone, affected alcohol drinking behavior. In contrast, the drug combination resulted in a significant reduction in daily alcohol intake and retardation in the acquisition of alcohol drinking behavior. These results suggest that combination of naltrexone plus baclofen may result in a synergistic reduction in alcohol intake in sP rats. These results are discussed in terms of naltrexone and baclofen exerting a concomitant and reciprocally potentiating inhibitory action on alcohol-induced activation of mesolimbic dopamine transmission. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: The present study was aimed at assessing the in vivo effectiveness of the positive allosteric modulator of the γ-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 γ-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 γ-hydroxybutyric acid. These results confirm that CGP7930 may constitute an interesting tool for pharmacological studies in the GABAB receptor field. [Copyright &y& Elsevier]

Different effects of moderate to high doses of γ-hydroxybutyric acid, including sedation/hypnosis, have been found to be blocked by γ-aminobutyric acidB (GABAB) receptor antagonists. The present study investigated whether the protective effect of GABAB receptor antagonists extends also to γ-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 γ-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 γ-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 γ-hydroxybutyric acid, and (b) GABAB receptor antagonists may constitute potentially effective therapeutic interventions for γ-hydroxybutyric acid intoxication. [Copyright &y& Elsevier]

Administration of the cannabinoid CB1 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. [Copyright &y& Elsevier]

The cannabinoid CB1 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. [Copyright &y& Elsevier]

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 γ-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 GABAB receptor in the neural circuitry mediating the stimulating effect of morphine and cannabinoids on alcohol consumption in sP rats. [Copyright &y& Elsevier]

The present paper describes the completion of the bidirectional selective breeding of γ-hydroxybutyric acid (GHB)-sensitive (GHB-S) and GHB-resistant (GHB-R) rats, which display opposite sensitivity to the sedative/hypnotic effect of 1 g/kg GHB. Completion of the selective breeding process was achieved by the F10, when 100% of rats of each line fulfilled the selection criterion. GHB-S and GHB-R rats may constitute a valuable tool for investigations on GHB physiology and pharmacology. [Copyright &y& Elsevier]

Rationale: Recent studies demonstrated that treatment with the γ-aminobutyric acid (GABA)[sub B] receptor agonist baclofen reduced alcohol intake in selectively bred Sardinian alcohol-preferring (sP) rats tested under the home-cage, two-bottle choice regimen. Objectives: The present study investigated the effect of baclofen on the appetitive, rather than consummatory, aspects of alcohol ingestion in sP rats. Methods: Rats were trained to lever-press for oral alcohol (10%, v/v) or sucrose (3%, w/ v) under a fixed-ratio schedule of 4. Once self-administration behavior was established, alcohol intake averaged approximately 0.7 g/kg over the 30-min session. Subsequently, the effect of the acute administration of baclofen (0, 1, 2 and 3 mg/kg, i.p.) on the extinction responding for alcohol and sucrose (defined as the maximal number of lever responses reached in the absence of reinforcement and used as index of motivation to consume alcohol and sucrose) was evaluated. Results: All doses of baclofen produced a marked suppression of extinction responding for alcohol. Conversely, only the 3-mg/kg baclofen dose significantly affected extinction responding for sucrose. A separate open-field test indicated that baclofen (0, 1, 2 and 3 mg/kg, i.p.) did not affect spontaneous motor activity in sP rats. Conclusions: These results suggest that baclofen may specifically reduce the motivational properties of alcohol; further, these results are in agreement with the recently reported anti-craving potential of baclofen in alcoholics. [ABSTRACT FROM AUTHOR]

Alcohol deprivation effect (ADE), i.e. the transient increase in alcohol intake that takes place in laboratory animals after a period of alcohol deprivation, has been proposed to model alcohol relapses in alcoholics. The present study investigated the effect of the GABAB receptor agonist, baclofen, on the development of ADE in selectively bred Sardinian alcohol-preferring (sP) rats. Acute administration of non-sedative doses of baclofen (0, 1, 1.7 and 3 mg/kg, i.p.) resulted in the complete suppression of the extra-amount of alcohol consumed during the first hour of re-access to alcohol after 7 days of deprivation. These results implicate the GABAB receptor in the neural substrate mediating ADE and suggest that baclofen may possess anti-relapse properties. [Copyright &y& Elsevier]

— Aims: The present study investigated the effect of the γ-aminobutyric acid (GABA)B receptor agonists, baclofen and CGP 44532, on the acquisition of alcohol drinking behaviour in selectively bred Sardinian alcohol-preferring (sP) rats. Methods: Baclofen [0, 1 and 3 mg/kg, intraperitoneally (i.p.)] and CGP 44532 (0, 0.1, 0.3 and 1 mg/kg, i.p.) were administered immediately before alcohol presentation to alcohol-naive sP rats. Alcohol was offered under the two-bottle free-choice regimen with unlimited access for 24 h/day. Drug treatment was repeated once daily for 10 consecutive days. Results: Baclofen and CGP 44532, dose-dependently and with comparable efficacy, suppressed alcohol intake; compensatory increases in water intake left total fluid intakes virtually unchanged. Conclusions: These results demonstrate that baclofen and CGP 44532 prevent the acquisition of alcohol drinking behaviour in sP rats, and suggest the involvement of the GABAB receptor in the mechanisms underlying the disclosure and experience of the reinforcing properties of alcohol in this rat line. [ABSTRACT FROM PUBLISHER]

The aliphatic alcohol 1,4-butanediol in converted into γ-hydroxybutyric acid (GHB) via two enzymatic steps: first, it is oxidised by alcohol dehydrogenase in γ-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 GABAB 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 GABAB 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 GABAB receptors. Accordingly 1,4-butanediol, unlike GHB, failed to displace [3H]GHB and [3H]baclofen in brain membranes. [Copyright &y& Elsevier]

Previous experiments demonstrated that the selectively bred Sardinian alcohol-preferring (sP) rats possess a genetically based proclivity to consume pharmacologically relevant doses of gamma-hydroxybutyric acid (GHB). The present study was aimed at comparing the reinforcing properties of GHB and ethanol, measuring the propensity of sP rats to consume GHB and ethanol when both drugs were concomitantly available. Initially, two groups of sP rats (ethanol-naive and ethanol-experienced, respectively) were forced to consume GHB in order to help them discover the reinforcing properties, which could then prevail over the unpleasant taste of the GHB solution. Subsequently GHB (at concentrations increasing from 1 to 6% w/v) was offered in free choice with water and all rats consumed pharmacologically relevant amounts of GHB. Finally, under the free-choice regimen between GHB (presented to each rat at its preferred concentration), ethanol and water, daily ethanol intake averaged ∼6 g/kg (i.e. the amount of ethanol usually consumed by sP rats), whereas GHB intake declined by ∼75%. In the few rats showing a high intake of GHB, ethanol intake was not altered. No difference in GHB drinking behaviour was ever recorded between ethanol-naive and ethanol-experienced rats. The results of the present study demonstrate that freely available GHB is not capable of altering ethanol preference and consumption in sP rats and suggest that the postulated reciprocal substitutability of the two drugs does not completely include the reinforcing properties, at least in sP rats and when oral self-administration of GHB is considered. The results also provide a model of the low abuse liability of GHB observed in human alcoholics. [ABSTRACT FROM PUBLISHER]

Rationale: Recent studies have shown that the cannabinoid CB[sub 1] receptor antagonist, SR 141716, is capable of reducing voluntary ethanol intake in rodents, suggesting the involvement of the CB[sub 1] receptor in the neural circuitry mediating the positive reinforcing properties of ethanol. Objectives: The present study extended to the agonists the investigation on the pharmacological manipulation of ethanol intake by cannabinoid agents. Methods: Selectively bred, Sardinian alcohol-preferring (sP) rats were offered ethanol and water under the two-bottle free choice procedure with unlimited access for 24 h/day. Results: The acute administration of WIN 55,212-2 (0.5–2 mg/kg; IP) and CP 55,940 (3-30 µg/kg; IP) induced a significant, dose-dependent increase in ethanol intake. Conversely, water consumption and intake of regular food and a highly palatable sucrose solution were not affected by treatment with WIN 55,212-2 and CP 55,940. The stimulatory effect of WIN 55,212-2 and CP 55,940 on ethanol intake was completely prevented by administration of SR 141716 (0.3 mg/kg; IP) and the opioid receptor antagonist, naloxone (0.1 mg/kg; IP). Conclusions: Administration of WIN 55,212-2 and CP 55,940 promoted voluntary ethanol intake in sP rats. This effect was mediated by stimulation of the cannabinoid CB[sub 1] receptor and required the activation of the endogenous opioid system. The results of the present study add further support to the hypothesis that the cannabinoid CB[sub 1] receptor is part of the neural substrate regulating ethanol intake. These results are also discussed in terms of WIN 55,212-2 and CP 55,940 administration possibly fixing to a higher level the hedonic set-point mechanism regulating ethanol drinking behavior in sP rats. [ABSTRACT FROM AUTHOR]

Background and Objectives Clinical research has proposed that initial sensitivity to ethanol may be negatively correlated with levels of subsequent ethanol intake; consistently, alcohol-preferring P rats were found to be less sensitive to the ataxic and sedative/hypnotic effects of ethanol than -nonpreferring NP rats. The present study investigated the initial sensitivity to the ataxic and sedative/hypnotic effects of ethanol and to the sedative/hypnotic effects of pentobarbital and diazepam in selectively bred Sardinian alcohol-preferring sP and -nonpreferring sNP rats. Methods: In experiment 1, time to lose (onset) and regain (sleep time) the righting reflex after the acute intraperitoneal (ip) administration of 3.0 and 3.5 g/kg ethanol were measured in sP and sNP rats. In experiment 2, sP and sNP rats were required to perform a motor coordination task on a Rota-Rod after the acute intragastric administration of 2.0, 2.5, and 3.0 g/kg ethanol. Experiment 3 assessed onset and sleep time in sP and sNP rats after the acute injection of pentobarbital (40 mg/kg; ip) and diazepam (15 and 20 mg/kg; ip). Results: In experiment 1, sP rats took shorter times to lose the righting reflex and regained this reflex over longer periods of time and at lower blood ethanol levels than sNP rats. In experiment 2, ethanol affected motor coordination to a greater extent in sP than sNP rats. In contrast, results from experiment 3 showed that sP and sNP rats were not differentially sensitive to the sedative/hypnotic effects of pentobarbital and diazepam. Conclusions: The results of experiments 1 and 2 suggest that sP rats possess a genetically determined, greater sensitivity to the motor impairing and sedative/hypnotic effects of ethanol than sNP rats. Although caution should be adopted before hypothesizing any comparison to humans, these results may feature sP rats as an experimental model of those subsets of human alcoholics with initial high sensitivity to ethanol challenges. Finally, the results of experiment 3 suggest a minimal involvement of the benzodiazepine and barbiturate recognition sites in the differential sensitivity to ethanol of sP and sNP rats. [ABSTRACT FROM AUTHOR]

Gamma-hydroxybutyric acid (GHB) is an endogenous constituent of the mammalian brain, where it likely functions as a neurotransmitter or a neuromodulator. Its exogenous administration exerts a number of pharmacological effects, including reduction of intensity of alcohol withdrawal syndrome and alcohol consumption in both laboratory animals and human alcoholics. The clinical studies conducted to date, although often testing samples of limited size, feature GHB as an effective, well-tolerated and safe drug for the treatment of alcohol dependence. Behavioural data in rats suggest that GHB may produce alcohol-like effects. This similarity may explain why GHB produces positively reinforcing properties, being subsequently self-administered by rodents and sometimes abused by humans (although episodes of self-directed intake of GHB appear to be a limited phenomenon in alcoholics); in addition it provides support to the hypothesis that GHB constitutes for alcoholism a replacement therapy similar to methadone in heroin addiction. [ABSTRACT FROM AUTHOR]

Background: The similarities between the pharmacological effects of the γ-aminobutyric acid receptor agonist, baclofen, and the alcohol-substituting agent, γ-hydroxybutyric acid, led us to investigate whether baclofen was capable of reducing (a) ethanol withdrawal syndrome in ethanol-dependent rats and (b) voluntary ethanol intake in ethanol-preferring rats. Methods: In experiment 1, Wistar rats were rendered physically dependent on ethanol by the repeated administration of intoxicating doses of ethanol for 6 consecutive days. Baclofen was acutely administered intraperitoneally at doses of 10, 20, and 40 mg/kg. In experiment 2, baclofen (0, 2.5, 5, and 10 mg/kg, intraperitoneally) was administered once a day for 14 consecutive days to ethanol-preferring sP rats that had continuous access to ethanol (10%, v/v) and water under the two-bottle free choice regimen. Results: In experiment 1, baclofen dose-dependently decreased the intensity of ethanol withdrawal signs; furthermore, 20 mg/kg of baclofen protected from audiogenic seizures in ethanol-withdrawn rats. In experiment 2, baclofen selectively and dose-dependently reduced voluntary ethanol intake; a compensatory increase in water intake left total fluid intake virtually unchanged. Conclusions: These results are in close agreement with those of a preliminary clinical study and suggest that baclofen may constitute a novel therapeutic agent for alcoholism. [ABSTRACT FROM AUTHOR]