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Saikosaponin A (SSA) is an active ingredient of the Asian medicinal herb, Bupleurum falcatum L. When administered via the intraperitoneal (i.p.) route, SSA suppressed multiple addictive-like behaviours, including operant alcohol self-administration, in rodents. It is unknown whether these effects are retained after intragastric (i.g.) administration, a desirable prerequisite for a compound with therapeutic potential. To fill this gap, i.g. SSA (0, 50, and 100 mg/kg) was tested in Sardinian alcohol-preferring (sP) rats trained to lever-respond for oral alcohol. SSA reduced lever-responding and amount of self-administered alcohol. However, when compared to i.p. SSA, i.g. SSA resulted to be markedly less potent and effective, suggestive of reduced bioavailability after i.g. treatment. Finally, and in agreement with previous data on the suppressing effect of i.p. SSA on behaviours motivated by highly palatable foods, i.g. SSA (0, 50, and 100 mg/kg) reduced oral sucrose self-administration in a separate set of sP rats. [ABSTRACT FROM AUTHOR]

Background: Recent work has demonstrated that acute administration of the novel positive allosteric modulator of the GABAB receptor, COR659, reduces several alcohol-related behaviors in rodents. Objective: To assess whether COR659 continues to lessen alcohol intake after repeated administration, a fundamental feature of drugs with therapeutic potential. Methods: Male C57BL/6J mice (n = 40) were exposed to daily 2-hour drinking sessions (20% (v/v) alcohol) under the 1-bottle "drinking in the dark" protocol and male Sardinian alcohol-preferring rats (n = 40) were exposed to daily 1-hour drinking sessions under the 2-bottle "alcohol (10%, v/v) vs water" choice regimen. COR659 (0, 10, 20, and 40 mg/kg in the mouse experiment; 0, 5, 10, and 20 mg/kg in the rat experiment) was administered intraperitoneally before 7 consecutive drinking sessions. Results: Alcohol intake in vehicle-treated mice and rats averaged 2.5–3.0 and 1.5–1.6 g/kg/session, respectively, indicative of high basal levels. In both experiments, treatment with COR659 resulted in an initial, dose-related suppression of alcohol intake (up to 70–80% compared to vehicle treatment; P <.0005 and P <.0001 in mouse and rat experiments, respectively). The magnitude of the reducing effect of COR659 on alcohol drinking diminished progressively, until vanishing over the subsequent 2–4 drinking sessions. Conclusion: COR659 effectively reduced alcohol intake in two different rodent models of excessive alcohol drinking. However, tolerance to the anti-alcohol effects of COR659 developed rapidly. If theoretically transposed to humans, these data would represent a possible limitation to the clinical use of COR659. [ABSTRACT FROM AUTHOR]

Recent studies demonstrated that saikosaponin (SS) A and other SSs extracted from Bupleurum falcatum L. (Apiaceae) roots abolished different behaviours motivated by drugs of abuse and palatable foods in rats. The present study was designed to investigate the effect of an SS-enriched extract fraction of B. falcatum roots on operant, oral self-administration of alcohol and chocolate in rats. To this end, female Sardinian alcohol-preferring and Wistar rats were trained to lever-respond for alcohol (15% v/v) and chocolate (5% w/v powdered Nesquik in water), respectively. Acute treatment with B. falcatum extract (0, 0.75, 1.5, and 3 mg/kg, i.p.) reduced, in a dose-related manner, both alcohol and chocolate self-administration. These data confirm the notion that B. falcatum extracts may be a valuable source of pharmacological agents with anti-addictive and anorectic potential. The use of experimental procedures with predictive validity for the human disease adds strength to the translational potential of these results. [ABSTRACT FROM AUTHOR]

Rationale: Binge drinking (BD) is a widespread drinkingpattern that may contribute to promote the development of alcohol use disorder (AUD). The comprehension of its neurobiological basis and the identification of molecules that may prevent BD are critical. Preclinical studies demonstrated that positive allosteric modulators (PAMs) of the GABAB receptor effectively reduced, and occasionally suppressed, the reinforcing and motivational properties of alcohol in rodents, suggesting their potential use as pharmacotherapy for AUD, including BD. Recently, we demonstrated that COR659, a novel GABAB PAM, effectively reduced (i) alcohol drinking under the 2-bottle choice regimen, (ii) alcohol self-administration under both fixed and progressive ratio schedules of reinforcement, and (iii) cue-induced reinstatement of alcohol-seeking behavior in Sardinian alcohol-preferring (sP) rats. Objectives: The present study investigated whether the "anti-alcohol" properties of COR659 extend to binge-like drinking in rodents. Methods: COR659 was tested on the "drinking in the dark" (DID) paradigm in C57BL/6J mice and the 4-bottle "alcohol [10%, 20%, 30% (v/v)] versus water" choice regimen with limited and unpredictable access to alcohol in sP rats. Results: Acute administration of non-sedative doses of COR659 (10, 20, and 40 mg/kg; i.p.) effectively and selectively suppressed the intake of intoxicating amounts of alcohol (> 2 g/kg) consumed by C57BL/6J mice and sP rats exposed to these binge-like drinking experimental procedures. Conclusions: The present data demonstrate the ability of COR659 to suppress binge-like drinking in rodents and strengthen the hypothesis that GABAB PAMs may represent a potentially effective pharmacotherapy for alcohol misuse. [ABSTRACT FROM AUTHOR]

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]

Preclinical work suggests that GET 73 (N-[4-(trifluoromethyl)benzyl]-4-methoxybutyramide), a novel metabotropic glutamate receptor subtype 5 negative allosteric modulator, may represent a novel pharmacological treatment for alcohol use disorder. Two independent experiments evaluated the effect of acutely administered GET 73 (0, 30, and 100 mg/kg, intragastrically) on alcohol-induced hypolocomotion ( n=72) and sedation/hypnosis ( n=36) in rats. In healthy male volunteers ( n=14), an open-label, randomised, crossover study was conducted to compare adverse events and pharmacokinetic parameters, in two experiments in which 300 mg GET 73 was administered, with and without alcohol, once and thrice. In rats, when administered with alcohol-vehicle, 100 mg/kg, but not 30 mg/kg, GET 73 reduced spontaneous locomotor activity. When administered with alcohol, no dose of GET 73 altered either alcohol-induced hypolocomotion or sedation/hypnosis. In humans, both single and thrice 300 mg GET 73 administration were well tolerated, in the presence and absence of alcohol, with no differences in adverse events. There were no significant differences in relative bioavailability between administering 300 mg GET 73 in the presence or absence of alcohol. [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]

Several lines of preclinical evidence indicate the ability of the prototypic cannabinoid CB1 receptor antagonist, rimonabant, to suppress various alcohol-related behaviors, including alcohol drinking and seeking behavior and alcohol self-administration in rats and mice. Together, these data—synthetically reviewed in the present paper—suggest (a) the involvement of the cannabinoid CB1 receptor in the neural substrate controlling alcohol intake, alcohol reinforcement, and the motivational properties of alcohol and (b) that rimonabant may constitute a new and potentially effective medication for the treatment of alcohol dependence. [ABSTRACT FROM AUTHOR]

The positive allosteric modulator of the GABAB receptor, GS39783, has recently been found to suppress acquisition and maintenance of alcohol drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats exposed to the standard, homecage two-bottle “alcohol vs water” choice regimen. The present study was designed to extend the characterization of the “anti-alcohol” effects of GS39783 to oral self-administration of alcohol under an operant procedure. Two separate groups of male sP rats were trained to lever-press (on an FR4 schedule) to orally self-administer alcohol (15%, v/ v) or sucrose (0.3%, w/ v) in daily 30-min sessions. Once lever-pressing behavior reached stable levels, the effect of GS39783 (0, 25, 50, and 100 mg/kg, i.g.) on responding for alcohol and sucrose was determined. Pretreatment with GS39783 resulted in a significant, dose-dependent reduction in responding for alcohol; at the dose of 100 mg/kg GS39783, the number of lever responses for alcohol was reduced by approximately 50% in comparison to vehicle-treated rats. The effect of GS39783 on alcohol self-administration was specific, as responding for sucrose was completely unaffected by pretreatment with GS39783. These data demonstrate the capability of GS39783 to attenuate the reinforcing properties of alcohol in alcohol-preferring rats. These data constitute a further piece of experimental evidence in support of the hypothesized role for the GABAB receptor in the control of alcohol drinking and reinforcement. [ABSTRACT FROM AUTHOR]

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]

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]

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]

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The organizer/chair was Ting-Kai Li and the co-chair was Rainer Spanagel. The presentations were (1) Genetic differences in alcohol drinking and reinforcement: The sP and sNP Rats, by Giancarlo Colombo; (2) Ventral tegmental area-Neuroanatomical substrate for alcohol reinforcement, by William J. McBride; (3) Metabolic mapping of alcohol reinforcement, by Linda J. Porrino; (4) Role of opioid receptors in the ethanol-induced place preference in rats exposed to conditioned fear stress, by Tsutomu Suzuki; and (5) Repeated deprivations enhance the reinforcing properties of ethanol in alcohol preferring (P) rats, by Zachary A. Rodd-Henricks. [ABSTRACT FROM AUTHOR]

Experiment 1 in the present study investigated the time course and dose range of γ-hydroxybutyric acid (GHB) to reduce voluntary ethanol intake in selectively bred Sardinian ethanol-preferring (sP) rats. Ethanol (10%, v/v) and tap water were offered under the two-bottle free choice regimen with unlimited access. GHB (200, 300, AND 400 mg/kg, i.p.) was administered 15-20 min prior to the start of the dark phase of the light-dark cycle. Ethanol and water intakes were recorded at different time intervals during the dark phase. GHB significantly reduced ethanol intake at doses of 300 and 400 mg/kg; statistical significance occurred only at 15-min and 30-min observation times. The GHB dose of 300 mg/kg was devoid of any sedative effect, as demonstrated in Experiment 2 by the lack of any impairment of spontaneous locomotor activity. Finally, this dose of GHB was also found to exert a robust anxiolytic effect in sP rats tested on the elevated plus maze (Experiment 3). Collectively, the results of the present study demonstrate that a non-sedative and anxiolytic dose of GHB effectively reduced voluntary ethanol intake in sP rats. The rapid onset of the reducing effect of GHB on ethanol intake as well as its anxiolytic effect, are discussed in terms of adding further support to the hypothesis that GHB may control alcohol craving and consumption in humans by substituting for ethanol's reinforcing effects. [ABSTRACT FROM PUBLISHER]

Presents a preface to a 2005 issue of the journal "Alcohol & Alcoholism," vol. 40.

Alcohol use disorder remains a major health problem. Mesocorticolimbic dopaminergic system including nucleus accumbens region and multiple neural circuits are involved in its complex underlying mechanism. For instance, alcohol intake stimulates central and peripheral renin-angiotensin system and increases angiotensin II levels, which predominantly affect angiotensin 1 receptors both in periphery and brain. In this study, we aimed to investigate the effects of 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 intracerebroventricularly administration of telmisartan (100 nM) reduced the alcohol intake for 24 hours without affecting food and water consumption in sP rats. Acute intracerebroventricularly 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 min. In microdialysis experiments, telmisartan administered intracerebroventricularly did not change dopamine levels in nucleus accumbens induced by acute intraperitoneal alcohol administration in Wistar rats. According to these results, further studies are needed to elucidate the role of renin-angiotensin system on alcohol use disorder pathophysiology. [ABSTRACT FROM AUTHOR]

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 GABAB 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Environmental enrichment is known to greatly impact several rodent behaviors • Alcohol-preferring rats were kept under impoverished, standard, and enriched environment • Environmental enrichment slowed acquisition of operant alcohol self-administration • Environmental enrichment reduced the reinforcing and motivational properties of alcohol • The hedonic properties of environmental enrichment likely replaced those of alcohol 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. [ABSTRACT FROM AUTHOR]

Abstract: The GABAB receptor agonist, baclofen, suppressed alcohol deprivation effect (a proposed experimental model of alcohol relapse) in Sardinian alcohol-preferring rats. The present study was designed to extend the characterization of the “anti-relapse” properties of baclofen to the reinstatement of alcohol-seeking behavior (another proposed model of alcohol relapse). Rats of the sP line were first trained to lever press for alcohol under a fixed ratio 4 schedule of reinforcement. Subsequently, rats were exposed to two within-session 70-min extinction/reinstatement tests with saline or baclofen administered in a counterbalanced, within-subject design. After a 60-min extinction phase, an alcohol-associated stimulus complex was presented (reinstatement phase). Saline or baclofen (3mg/kg) were administered via a permanent intraperitoneal catheter, 30min before the reinstatement phase. During the reinstatement phase, baclofen administration: (a) reduced by approximately 60% responses on the previously active lever, (b) increased latency to the first response and (c) decreased the response rate. These results indicate that baclofen reduced cue-induced reinstatement of alcohol-seeking behavior in sP rats. [Copyright &y& Elsevier]

Abstract: The function of the γ-aminobutyric acidB (GABAB) receptor, measured as baclofen-stimulated [35S]GTPγS binding, was evaluated in some brain regions of Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) rats. EC50 value of baclofen-stimulated [35S]GTPγS 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. [Copyright &y& Elsevier]

Salvia miltiorrhiza extracts have been reported to suppress acquisition and maintenance of alcohol drinking behavior in Sardinian alcohol-preferring (sP) rats. The present study investigated whether IDN 5082, a standardized extract of Salvia miltiorrhiza, was capable of preventing, in sP rats, the development of the so-called alcohol deprivation effect (ADE), i.e. the transient increase in alcohol intake that occurs in laboratory animals after a period of alcohol deprivation. Interestingly, ADE has been proposed to model alcohol relapses in human alcoholics. The acute, intragastric administration of 25, 50, and 100 mg/kg IDN 5082 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 suggest that IDN 5082 may possess anti-relapse properties. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]