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Given the high coexistence of anxiety symptoms in people with alcohol use disorder (AUD), we aimed to determine the influence of anxiety symptoms on outcomes in patients with AUD treated with the GABAB receptor agonist baclofen. A meta-analysis of 13 comparisons (published 2010-2020) including baseline and outcome data on alcohol consumption and anxiety after 12 weeks was undertaken. There were significantly higher rates of abstinent days in patients treated with baclofen compared to placebo (p = 0.004; high certainty evidence); specifically in those with higher baseline anxiety levels (p < 0.00001; high certainty evidence) compared to those with lower baseline anxiety levels (p = 0.20; moderate certainty evidence). The change in anxiety ratings over 12 weeks did not differ between those treated with baclofen or placebo (p = 0.84; moderate certainty evidence). This may be due to different anxiety constructs being measured by scales not validated in this patient group, or that anxiety is not a biobehavioral mechanism by which baclofen may reduce alcohol drinking. Given the prevalence of anxiety symptoms in AUD all these factors warrant further research.

We are particularly pleased that Alcohol and Alcoholism has dedicated this special collection to ‘Sex and Gender differences in Alcohol Use Disorder’. To date, a series of preclinical and clinical studies have tried to shed light on the similarities and differences in the field of alcohol research between men and women (Agabio et al., 2016a and 2017; Salvatore et al., 2017; McHugh et al., 2018; Ait-Daoud et al., 2019; Becker and Chartoff, 2019). However, our understanding of the complexities on this topic remains limited.

Preclinical Research Δ9 -Tetrahydrocannabinol (THC) is a hydrophobic compound that has a potent antinociceptive effect in animals after intrathecal (IT) or intracerebroventricular (ICV) administration. The lack of a suitable solvent precludes its IT administration in humans. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) increases the water solubility of hydrophobic drugs and is approved for IT administration in humans. To investigate whether HPβCD might be a suitable carrier for ICV administration of THC in rats, two formulations containing THC complexed with HPβCD (30 and 135 μg of THC per animal) and vehicle were administered to Wistar rats. The antinociceptive effect (using the tail flick test), locomotor activity, and body temperature were evaluated. ICV injection of 135 μg of THC/HPβCD complex increased tail flick latency, reduced locomotor activity, and had a dual effect on body temperature. The 30 μg THC/HPβCD formulation only produced a hyperthermic effect. All animals appeared healthy, with no difference between the groups. These results were similar to those obtained in other preclinical studies in which THC was administered centrally using solvents that are unsuitable for IT administration in humans because of their toxicity. Our findings suggest that HPβCD may be a useful carrier for IT administration of THC in humans. Drug Dev Res 78 : 411-419, 2017. © 2017 Wiley Periodicals, Inc.

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30-80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an "off-label" prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

A limited number of medications are approved to treat Alcohol Use Disorder (AUD). Furthermore, the magnitude of their therapeutic effect is relatively modest, suggesting the potential for subtypes of patients who respond to a specific medication. The use of these medications is also limited in clinical practice by a series of contraindications such as medical comorbidities and/or concurrent use of other medications. In recent years, animal and human studies have been conducted to evaluate the efficacy of baclofen, a GABAB receptor agonist approved for clinical use as a muscle relaxant, in the treatment of AUD. However, these studies have yielded contrasting results. Despite this discrepancy, baclofen is often used off-label to treat AUD, especially in some European countries and Australia. Recently, several factors have been considered to try to shed light on the potential reasons and mechanisms underlying the inconsistent results obtained until now. The presence of a psychiatric comorbidity may be amongst the abovementioned factors playing a role in explaining different responses to baclofen treatment in terms of alcohol drinking outcomes. Therefore, the aim here was to conduct a narrative review of the scientific literature related to the use of baclofen in AUD, both in patients with and without concomitant psychiatric disorders. All clinical studies (randomized and controlled, open-label, retrospective, human laboratory studies, and case reports) were analyzed and discussed, bearing in mind other potential factors that may have influenced baclofen response, including dose administered, severity of AUD, use of other psychosocial therapies, and the presence of physical disorders. This review indicates that the most frequent psychiatric comorbidities in patients affected by AUD undergoing baclofen treatment are anxiety and mood disorders. Unfortunately, no definitive conclusions can be drawn due to the lack of specific analyses on whether baclofen efficacy is different in AUD patients with comorbid psychiatric disorders vs. those without. Therefore, it will be critical that psychiatric comorbidities are considered in the planning of future studies and in the analysis of the data, with the ultimate goal of understanding whether subtypes of AUD patients may respond best to baclofen.

The chronic use of alcohol can lead to the onset of an alcohol use disorder (AUD). About 50% of subjects with an AUD may develop alcohol withdrawal syndrome (AWS) when they reduce or discontinue their alcohol consumption and, in 3-5% of them, convulsions and delirium tremens (DTs), representing life-threatening complications, may occur. Unfortunately, few physicians are adequately trained in identifying and treating AWS. The Italian Society on Alcohol has, therefore, implemented a task force of specialists to draw up recommendations for the treatment of AWS with the following main results: (1) while mild AWS may not require treatment, moderate and severe AWS need to be pharmacologically treated; (2) out-patient treatment is appropriate in patients with mild or moderate AWS, while patients with severe AWS need to be treated as in-patients; (3) benzodiazepines, BDZs are the "gold standard" for the treatment of AWS and DTs; (4) alpha-2-agonists, beta-blockers, and neuroleptics may be used in association when BDZs do not completely resolve specific persisting symptoms of AWS; (5) in the case of a refractory form of DTs, the use of anaesthetic drugs (propofol and phenobarbital) in an intensive care unit is appropriate; (6) alternatively to BDZs, sodium oxybate, clomethiazole, and tiapride approved in some European Countries for the treatment of AWS may be employed for the treatment of moderate AWS; (7) anti-convulsants are not sufficient to suppress AWS, and they may be used only in association with BDZs for the treatment of refractory forms of convulsions in the course of AWS.

The poor implementation of alcohol use disorder treatment programs has been well documented in many countries. Among the barriers have been identified in health professionals and patients, lack of awareness about existing medications and perceived lack of efficacy seem to deter physicians from offering pharmacotherapy to their patients. Indeed, existing registered medications are only modestly effective. Therefore, there is an urgent need to develop more effective treatments in this area, ideally targeting new mechanisms of action. The efficacy of GABAB agonists has been explored for some time, as they are believed to reduce alcohol craving, possibly through alcohol mimicking effects. In particular, two drugs, both decades-long marketed for other purposes, have been tested: baclofen and sodium oxybate. Sodium oxybate is approved for the treatment of alcohol use disorder in several countries, and efforts or currently been made to obtain an approval at the European level. This medication has showed medium to large treatment effects in patients with severe alcohol dependence [1] . Baclofen has recently been labeled for the treatment of alcohol use disorder in France, the only country so far having officially approved baclofen in this indication. Off-label Baclofen prescription for alcohol use disorder substantially increased a decade ago, leading to a regulatory recognition named a “temporary recommendation for use” in 2014, and eventually a full approval in 2018, despite the lack of consistent evidence of efficacy [2] . At the international level, a number of experts meeting in Cagliari succeeded in publishing a consensual statement regarding baclofen for the treatment of alcohol use disorder [3] . The aim of this session is to provide a scientific and historical background on the development of GABA-B agonists in alcohol use disorders, state of the art regarding baclofen efficacy and safety, and to elucidate the singularity of the French experience with baclofen that eventually permitted it's official approval.

Alcohol Use Disorder (AUD) is a common mental disorder with severe medical, psychological and social consequences [1] . AUD leads up to 3- and 4-fold increases in the risk of mortality in men and women, respectively [2] . Nevertheless, less than 10% of people with AUD seek and receive treatment for their disorder and less than 4% receive any pharmacological intervention [3] . The identification of new medications is crucial to increase the number of people with AUD who receive effective treatment. Baclofen, a GABAB receptor agonist approved for clinical use as a muscle relaxant, has emerged as a promising drug for AUD [4] . Preclinical studies have provided consistent evidence that baclofen administration dose-dependently reduces alcohol consumption in validated animal models of AUD [5] . On the other hand, clinical studies have yielded less consistent results [6] . Some randomized controlled trials (RCTs) found that AUD patients treated with baclofen significantly reduced alcohol consumption compared to patients treated with placebo, whereas other RCTs found no differences between AUD patients treated with baclofen or placebo [6] . In addition, recent meta-analyses report there is insufficient evidence of effectiveness to support the use of baclofen to treat AUD [7] , [8] , [9] , [10] . Several methodological differences among these RCTs may have contributed to these contrasting results, including (i) the daily dose of baclofen (ranging from 30 to 300 mg), (ii) prescribing regimes (fixed doses or titration until the desired clinical effect was achieved), and (iii) presence/absence of comorbid medical (e.g. liver disease) or psychiatric diseases (e.g. anxiety disorders) [6] , [11] . Nevertheless, baclofen is used off-label to treat AUD in several countries, and in France baclofen was officially approved for AUD treatment in October 2018 [6] . In May 2018, during the GABAB Receptor Conference, held in Cagliari, Italy, a group of international experts in the clinical use of baclofen for AUD met and combined their expertise to provide concise and well-balanced information regarding this controversial topic. This group included 26 researchers and physicians who had contributed to the majority of RCTs (both positive and negative) on baclofen and AUD as well as studies focused on the side effects of baclofen in patients with AUD. A modified Delphi method was used. Each statement was discussed, modified, and rated until consensus was reached by the entire group. The final draft included 18 statements and was recently published as “the Cagliari Statement” in Lancet Psychiatry [12] . This Consensus paper is intended as a helpful tool for clinicians deciding whether or not prescribe baclofen off-label to their patients with AUD and to researchers planning investigations with baclofen. The Cagliari Statement may be particularly useful clinicians in France, where baclofen has been officially approved for AUD treatment [6] .

Accumulating lines of experimental and clinical evidence suggest that the prototypic, orthosteric GABA type B (GABAB) receptor agonist, baclofen, may possess therapeutic potential for treatment of alcohol use disorder (AUD). At preclinical level, acute or repeated treatment with nonsedative doses of baclofen has repeatedly been reported to suppress several alcohol-motivated behaviors, including alcohol drinking, in rats and mice. At clinical level, administration of doses of baclofen ranging from low to extremely high doses has been found to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal signs and symptoms in patients affected by AUD, confirming that baclofen may represent a promising option for treatment of AUD. A more recent avenue of research is represented by generalization of baclofen effects to the positive allosteric modulators of the GABAB receptor: preclinical data collected to date suggest that these compounds reproduce, with a much higher therapeutic index, several suppressing effects of baclofen on alcohol-motivated behaviors.

Tekst ten podsumowuje dane eksperymentalne i kliniczne wskazujące na potencjał terapeutyczny agonisty receptora GABAB, baklofenu w leczeniu zaburzeń związanych z używaniem alkoholu (AUD) oraz zaburzeń związanych z używaniem substancji psychoaktywnych (SUD). W wielu badaniach przedklinicznych wykazano zdolność baklofenu do zmniejszania picia alkoholu (w tym picia ciągami i nawrotów spożycia alkoholu), instrumentalnego doustnego samopodawania alkoholu, samopodawania dożylnego kokainy, nikotyny, amfetaminy, metamfetaminy, morfiny i heroiny u gryzoni. Niektóre randomizowane, kontrolowane badania kliniczne (RCT) oraz opisy przypadków potwierdzają skuteczność baklofenu w zakresie hamowania spożycia alkoholu, odczuwania głodu alkoholu oraz symptomatologii zespołu abstynencyjnego u pacjentów uzależnionych od alkoholu. Dane z badań z randomizacją i badań otwartych oceniających skuteczność baklofenu w SUD są mniej jednoznaczne. Ostatnio pojawiło się zainteresowanie podawaniem wysokich dawek baklofenu u pacjentów z AUD i SUD. Badania przedkliniczne pozwoliły ustalić, że "antyuzależniające" właściwości baklofenu są również cechą pozytywnych allosterycznych modulatorów receptora GABAB (PAM GABAB). W świetle ich bardziej korzystnego profilu działań niepożądanych (w stosunku do baklofenu), PAM GABAB mogą stanowić istotny krok naprzód w farmakoterapii AUD i SUD opartej o ligandy receptora GABAB.

Summary Recent preclinical and clinical studies have suggested that baclofen, the prototypic γ-aminobutyric acid B (GABAB) receptor agonist, is a promising pharmacological compound for use in the treatment of alcohol dependence. In particular, baclofen has been found to suppress symptoms of alcohol withdrawal syndrome with an efficacy comparable with that of the ‘gold standard’ diazepam. Moreover, baclofen has proven effective in the prevention of relapse due to its ability to reduce alcohol intake and craving in alcoholic patients. Baclofen proved to be manageable, producing no significant side effects and displaying no addictive properties. The efficacy of the drug in the management of both alcohol withdrawal syndrome and relapse prevention should entail a vastly simplified pharmacotherapy of alcohol dependence.

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

The present paper describes the results of recent preclinical and clinical studies conducted in this laboratory in order to characterize the anti-alcohol properties of the GABA(B) receptor agonist, baclofen. At a preclinical level, the repeated administration of non-sedative doses of baclofen dose-dependently suppressed the acquisition and maintenance of alcohol drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats tested under the homecage, 2-bottle "alcohol vs water" choice regimen. Acute injection of baclofen completely blocked the temporary increase in voluntary alcohol intake occurring after a period of alcohol abstinence (the so-called alcohol deprivation effect, which models alcohol relapses in human alcoholics). Acute treatment with baclofen also dose-dependently suppressed extinction responding for alcohol (an index of motivation to consume alcohol) in sP rats trained to lever-press for oral alcohol self-administration. Taken together, these results suggest the involvement of the GABA(B) receptor in the neural substrate mediating alcohol intake and alcohol motivational properties in an animal model of excessive alcohol consumption. Further, acutely administered baclofen dose-dependently reduced the severity of alcohol withdrawal signs in Wistar rats made physically dependent upon alcohol. Preliminary clinical surveys suggest that the anti-alcohol properties of baclofen observed in rats may generalize to human alcoholics. Indeed, a double-blind survey demonstrated that repeated daily treatment with baclofen was associated, when compared to placebo, with a higher percentage of subjects totally abstinent from alcohol and a higher number of days of total abstinence. Treatment with baclofen also suppressed the number of daily drinks and decreased the obsessive and compulsive components of alcohol craving. Finally, a single non-sedative dose of baclofen resulted in the rapid disappearance of alcohol withdrawal symptomatology, including delirium tremens, in alcohol-dependent patients. In both clinical studies, baclofen was well tolerated with minimal side effects. These results suggest that baclofen may represent a potentially effective medication in the treatment of alcohol-dependent patients.

Alcohol withdrawal syndrome is a distressing and at times life-threatening condition in alcohol-dependent patients (1). Usually, symptoms develop within 6 –24 hours after the last drink (2). Early symptoms include raised blood pressure and pulse rate, tremor, hyperreflexia, and anxiety with increased irritability. Clinical management is aimed at symptom relief, prevention of seizures and delirium, and a smooth transition to a treatment program to maintain long-term abstinence from alcohol (3). Benzodiazepines are presently the drug of choice (4). We recently found that baclofen, a -aminobutyric acid (GABA)B receptor agonist used to control spasticity (5), reduced voluntary alcohol intake in alcohol-preferring rats (6), as well as alcohol craving and intake, up to complete alcohol abstinence, in alcohol-dependent patients (7). Furthermore, baclofen suppressed the intensity of alcohol withdrawal syndrome in rats who were physically dependent on alcohol (6). We therefore studied the effects of oral administration of baclofen in patients with severe alcohol withdrawal syndrome.

Cancer patients submitted to gastrointestinal surgery are at risk of thiamine deficiency (TD) and Wernicke's encephalopathy (WE). Although permanent neurological damage and death could be prevented by a timely replacement therapy, they often remain undiagnosed and untreated. We hypothesized that WE remains unrecognized because most cases may manifest several months after hospital discharge.WE frequency was investigated in a sample of cancer patients who underwent gastrointestinal surgery, by using the diagnostic criteria proposed to improve diagnosis among alcoholics. Patients were evaluated at discharge through the examination of medical records and 6 months after by telephonic interview.Forty-five patients were selected. Signs of WE resulted in 4.4% at discharge. At 6 months, 21 patients were interviewed. Among them, 90.4% had signs of WE. The number of affected patients was significantly higher 6 months after discharge than at discharge (90.4 vs 9.5%, p 0.0001).Further studies with larger samples are needed to establish the prevalence of TD and related WE in cancer patients after gastrointestinal surgery. This study suggests that the problem is understated. Even in absence of symptoms of TD, the use of prophylactic thiamine supplementation should be taken in consideration, as consequences of misdiagnosis can be severe.

The present paper summarizes the preclinical and clinical studies conducted to define the “anti-alcohol” pharmacological profile of the prototypic GABAB receptor agonist, baclofen, and its therapeutic potential for treatment of alcohol use disorder (AUD). Numerous studies have reported baclofen-induced suppression of alcohol drinking (including relapse- and binge-like drinking) and alcohol reinforcing, motivational, stimulating, and rewarding properties in rodents and monkeys. The majority of clinical surveys conducted to date – including case reports, retrospective chart reviews, and randomized placebo-controlled studies – suggest the ability of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. The recent identification of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, represents a novel, and likely more favorable, option for pharmacological manipulations of the GABAB receptor. Accordingly, data collected to date suggest that positive allosteric modulators of the GABAB receptor reproduce several “anti-alcohol” effects of baclofen and display a higher therapeutic index (with larger separation – in terms of doses – between “anti-alcohol” effects and sedation).

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.

The possible presence of a functional interaction in the constipating effect of opioids and cannabinoids has been assessed. We have measured the ability of the opioid receptor antagonist, naloxone, to antagonize the inhibitory effect of the cannabinoid receptor agonist, WIN 55,212-2, and also, the ability of the cannabinoid CB1-receptor antagonist, SR 141716A, to antagonize the inhibitory effect of morphine, on transit of an orally administered, non-absorbable marker (carmine) in the mouse small intestine. Naloxone failed to alter the reducing effect of WIN 55,212-2 on the propulsive activity; conversely, pretreatment with SR 141716A did not prevent morphine-induced inhibition of marker transit. These results suggest that the constipating effect of opioids and cannabinoids occur through independent and unrelated mechanisms. We assessed also the possible existence of an interaction between CB1 and dopamine D2 receptor systems. The effect of the D2-receptor antagonist, S(-)-sulpiride, on the inhibiting effect of WIN 55,212-2 and of SR 141716A on the inhibiting effect of the D2 agonist, bromocriptine, on intestinal propulsion were assessed. Combination of 50 mg kg−1S(-)-sulpiride and 0.5 mg kg−1 WIN 55,212-2, but not higher doses, resulted in the blockade of WIN 55,212-2 effect; similarly, combination of 0.1 mg kg−1 SR 141716A abolished bromocriptine-induced decrease in intestinal motility. These results suggest the existence of a functional interaction between the CB1 and D2 receptors in mouse intestinal motility.

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.

Experiment 1 in the present study investigated the time course and dose range of gamma-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 the 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.

The present study was designed to further investigate the pharmacological profile of the discriminative stimulus effects of gamma-hydroxybutyric acid (GHB). Drugs acting at the gamma-aminobutyric acid (GABA)B receptor (baclofen and CGP 35348), GABA(A)/benzodiazepine receptor complex (diazepam), N-methyl-D-aspartate (NMDA) receptor complex (dizocilpine), and cannabinoid receptor (WIN 55,212-2) were tested for substitution or blockade of the GHB interoceptive cue in rats trained to discriminate either 300 or 700 mg/kg of GHB i.g. from water in a T-maze, food-reinforced drug discrimination paradigm. Baclofen completely substituted for both training doses of GHB; however, its potency in substituting for GHB increased as the training dose of GHB was increased. CGP 35348 partially and completely blocked the cue elicited by 300 and 700 mg/kg of GHB, respectively. In contrast, diazepam partially substituted for 300 mg/kg of GHB, while failing to produce a GHB-appropriate response in the rat group trained to the higher GHB dose. Neither dizocilpine nor WIN 55,212-2 substituted for GHB. Collectively, these data suggest that: a) GHB produces a compound stimulus; and b) GABA(B)- and GABA(A)-mediated cues are prominent components of the mixed stimulus of GHB. However, the quality (i.e., the proportion of the component cues) of the stimulus varies as the training dose of GHB is increased; indeed, the contribution of the GABA(A)- and GABA(B)-mediated cues were smaller and greater, respectively, at 700 and 300 mg/kg of GHB training doses.

The present study was aimed at determining whether the concurrent availability of highly palatable fluids (i.e., a chocolate-flavored drink and a sucrose solution) would alter voluntary ethanol drinking in selectively bred, alcohol-preferring sP and -nonpreferring sNP rats. Ethanol intake occurred under the three-bottle, free choice regimen between 10% ( v v ) ethanol solution, tap water, and the palatable fluids for 24 h per day. When rats were given ethanol and water, but no alternative fluids, mean ethanol intake in sP rats ranged between 6 and 7 g/kg per day and mean preference ratio was steadily higher than 80%, whereas mean ethanol intake and preference ratio in sNP rats were constantly lower than 0.3 g/kg and 5%, respectively. In the presence of either the chocolate-flavored drink or sucrose solution, both prepared as isocaloric to the ethanol solution, absolute ethanol intake in sP rats declined by 60–70%; similarly, the preference ratio was reduced by 80–90%. Ethanol intake in sNP rats was unaffected by the simultaneous presentation of either palatable fluids. The results of the present study closely replicate those previously reported in genetically selected, ethanol-preferring HAD rats; however, they differ from those of ethanol-preferring P rats, which were reported to maintain high levels of ethanol intake and preference in the presence of highly palatable fluids. These results are discussed in terms of a) an alternative reinforcement partially substituting for the reinforcing properties of ethanol in sP rats, resulting in a less urgent need of ethanol, and b) genetic animal models of alcoholism diverging in some neurochemical and behavioral traits (e.g., response to the presentation of palatable fluids), which might parallel the different types of alcoholism observed in humans.

Aims: Alcopops are ready-mixed drinks containing approximately the same amount of alcohol as beer, usually sweet, and flavoured, particularly appealing to young people. The present study was aimed to investigate whether young adolescents aged 12-14 years, corresponding to the average age of the first drink, are capable of identifying the presence of alcohol in these beverages. Methods: Administration of a questionnaire comprising 8 questions investigating knowledge and consumption of different alcoholic and non-alcoholic beverages to a sample of 13-year old Italian students. Results: More than 20% of a sample of 224 students reported that they were unaware of the alcoholic content of alcopops at the age of the first drink. The number of students unable to distinguish alcopops from non-alcoholic beverages was significantly higher than students who were not able to distinguish beer from alcohol-free beverages. Conclusions: At the age of the first drink, the identification of alcopops as alcoholic beverages is more difficult than that of other beverages containing the same amount of alcohol. Information aimed at increasing the ability of adolescents to distinguish between alcoholic and non-alcoholic beverages should be provided to young adolescent students before they start drinking.

Background: It has been reported that baclofen, a drug used in the treatment of spasticity, reduces the severity of withdrawal symptoms and substance use disorders (SUDs) for some psychoactive drugs. Aims and Methods: To evaluate the effectiveness and safety of baclofen in the treatment of withdrawal syndrome and/or SUDs, providing (1) an outline of its pharmacological features; (2) a summary of studies that have suggested its possible effectiveness in the treatment of SUDs, and (3) a review of randomized, controlled trials (RCTs) on baclofen and SUDs. Results: Baclofen tolerability is generally considered to be good. Eleven RCTs investigated its effectiveness in the treatment of SUDs. Of these, 5 RCTs found that baclofen is effective, 5 RCTs found that it is ineffective and the results of 1 RCT were not appreciable because it did not achieve the preplanned level of participation. Conclusions: The number of RCTs on baclofen and SUDs is still low, and their results are divergent. Further RCTs should be undertaken, particularly with higher doses of baclofen. Its administration may be suggested in patients who fail to respond to other approved drugs or who are affected by liver disease that prevents their administration, or in patients affected by SUDs for which no approved drugs are available. Treatment should be conducted under strict medical supervision.

The present study was designed to assess the temporal pattern of ethanol intake over a 24 h period in selectively bred, Sardinian alcohol-preferring (sP) rats. Ethanol intake occurred under the two-bottle, free choice regimen. sP rats consumed ethanol in three distinct peaks, rather regularly distributed over the 12 h dark phase of the light-dark cycle and positively correlated with food intake episodes. The temporal distribution of ethanol intake and estimated blood alcohol levels are consistent with the hypothesis that sP rats voluntarily drink ethanol for its pharmacological effects.

The present study was designed to assess the anxiety profile of the selectively bred alcohol-preferring sP and alcohol-nonpreferring sNP rats. Rats were offered either water (ethanol-naive rats) or a free choice of 10% (v/v) ethanol and water (ethanol-experienced rats) for 14 consecutive days prior to the test. Spontaneous exploration of an elevated plus maze was used as a behavioral measure of anxiety. Ethanol-naive sP rats spent less time in and made fewer entries into the open arms of the maze than ethanol-naive sNP rats. These results suggest a higher innate degree of anxiety in sP than in sNP rats. Moreover, time spent in and number of entries into the open arms of the maze were higher in ethanol-experienced than in ethanol-naive sP rats. This finding suggests that ethanol consumed voluntarily produces anxiolytic effects in sP rats. The results of the present study are discussed in terms of (a) anxiety as a genetic trait related to ethanol-preference in sP rats and (b) self-medication of anxiety as a possible factor promoting voluntary ethanol consumption in sP rats.

Gamma-hydroxybutyric acid (GHB) has been shown to reduce ethanol consumption and suppress ethanol withdrawal syndrome both in laboratory animals and humans. The present study was designed to assess the similarity between the discriminative stimulus effects, or subjective feelings, of GHB and ethanol using a T-maze, food-reinforced drug discrimination procedure. Three groups of rats were trained to discriminate ethanol (1.0 or 2.0 g/kg; p.o.) or GHB (300 mg/kg; p.o.) from water. In the 1.0 g/kg ethanol-trained rats, substitution for ethanol was an inverted U-shape function of GHB dose, with only 300 mg/kg GHB resulting in complete substitution for ethanol. No dose of GHB elicited selection of ethanol-appropriate arm higher than 10% in the 2.0 g/kg ethanol-trained group. In the 300 mg/kg GHB-trained rats, complete substitution for GHB occurred only at the dose of 1.0 g/kg ethanol. Doses of ethanol lower or higher than 1.0 g/kg did not substitute for GHB. The results of the present study indicate that symmetrical generalization between ethanol and GHB occurred within narrow dose ranges. They are discussed in terms of common neurotransmitter systems involved in the mediation of GHB and ethanol effects.

The present paper summarizes experimental and clinical data suggesting the therapeutic potential of the prototypic GABAB receptor agonist, baclofen, for the treatment of alcohol-use disorders (AUDs). Numerous studies have reported baclofen-induced suppression of alcohol drinking, relapse-like drinking, and alcohol reinforcing, rewarding, stimulating, and motivational properties in rats and mice. The majority of clinical surveys conducted to date have demonstrated the capacity of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. More recently, the discovery of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, provided a new tool for pharmacological manipulations of the GABAB receptor. Accumulating lines of preclinical evidence suggest that positive allosteric modulators of the GABAB receptor (GABAB PAMs), such as GS39783, display a high therapeutic index and retain baclofen's capacity to suppress alcohol consumption and alcohol reinforcing and motivational properties. The present paper also summarizes the most relevant patents on GABAB receptor agonists and GABAB PAMs as possible pharmacotherapies for AUDs.

The effect of the dihydropyridine Ca2+ channel antagonist, isradipine, on ethanol discrimination was assessed in rats trained to discriminate 1.5 g/kg ethanol from water in a T-maze, food-reinforced drug discrimination procedure. Pretreatment with isradipine (0, 1.0, 3.0 and 5.0 mg/kg i.p.) resulted in a dose-dependent blockade of ethanol discrimination. The results of the present study suggest that L-type Ca2+ channels are involved in the mediation of ethanol discriminative stimulus effects.

γ-Hydroxybutyric acid (GHB) is a naturally occurring constituent of the mammalian brain, where it likely functions as neurotransmitter or neuromodulator. When exogenously administered, GHB exerts a variety of psychopharmacological effects, including euphoria, anxiolysis, sedation, and anesthesia. Most of these effects appear to be mediated by activation of the GABAB receptor, although a GHB-specific binding site has also been described. Applications of GHB in the treatment of narcolepsy and alcoholism have been proposed. Recreational use of GHB, often leading to cases of intoxication, dependence and withdrawal, has dramatically spread over the past 20 years.

The present study examined the involvement of GABA(A) and GABA(B) receptors in the discriminative stimulus effects of gamma-hydroxybutyric acid (GHB). Rats were trained to discriminate either 300 or 700 mg/kg GHB IG from water using a T-maze, food-reinforced drug-discrimination procedure. The direct GABA(B) agonist, baclofen, substituted completely for both training doses of GHB; its potency to substitute for GHB increased moderately as the training dose of GHB was increased. The positive GABA(A) modulator, diazepam, substituted partially for 300 mg/kg GHB, but failed to elicit GHB-appropriate responding in rats trained with the higher GHB dose. Finally, the GABA(B) antagonist, CGP 35348, completely blocked the discriminative stimulus effects of the high training dose of GHB, but only partially antagonized the effects of the low training dose. These results suggest that (a) GHB produces a compound stimulus, and (b) both GABA(B)- and GABA(A)-mediated cues are prominent components of this compound stimulus; the contribution of each component, however, appears to vary as the training dose of GHB is increased.

The present study demonstrates that the gamma-hydroxybutyric acid receptor antagonist, NCS-382, markedly reduces blood ethanol levels (BELs) in rats when ethanol is administered via the intragastric route, whereas it is completely ineffective when ethanol is injected IP. The reducing effect of NCS-382 on BELs is likely due to a lessened absorption of ethanol from the gastrointestinal tract.

Aims: To evaluate the number of subjects with possible alcohol use disorders (SPAUD) among primary care patients in Cagliari, Sardinia, Italy, by means of the self-administration of Alcohol use disorder identification test (AUDIT) and CAGE questionnaires. Methods: 939 patients waiting in 10 surgeries of primary care physicians were asked to take part in the study. A sample of 309 women and 197 men (total 506), aged between 18 and 65 years, agreed to participate and completed both questionnaires. SPAUD were defined as those achieving cut-off scores of 5 for AUDIT and/or 1 for CAGE. Results: Seventy-nine (15.61%) patients were SPAUD, achieving a positive score in at least one questionnaire. Fifty-six (11.07%) and forty-six (9.09%) patients yielded positive results with AUDIT and CAGE, respectively. Twenty-three (4.55%) patients were positive at both AUDIT and CAGE. Significantly higher proportions of men than women were recorded among SPAUD.Conclusions:The results of the present survey indicate a high number of SPAUD in a sample of primary care settings in Cagliari, closely similar to the occurrence of alcohol use disorders estimated in several other community-based primary care clinics in Western Countries.

This chapter describes the clincial experience related to the use of Baclofen as a pharmacological treatment of alcohol withdrawal syndrome.

Purpose Benzodiazepines are the drugs of choice in the treatment of alcohol withdrawal syndrome (AWS). Recent data have shown that baclofen may reduce AWS symptoms. At present, no comparative studies between baclofen and any benzodiazepine used in AWS treatment are available. Accordingly, the present study was designed to compare efficacy, tolerability and safety of baclofen versus diazepam in the treatment of AWS. Subjects and methods Thirty-seven patients with AWS were enrolled in the study and randomly divided into 2 groups. Baclofen (30 mg/day for 10 consecutive days) was orally administered to 18 patients (15 males, 3 females; median age: 46.5 years). Diazepam (0.5-0.75 mg/kg/day for 6 consecutive days, tapering the dose by 25% daily from day 7 to day 10) was orally administered to 19 patients (17 men, 2 women; median age: 42.0 years). The Clinical Institute Withdrawal Assessment (CIWA-Ar) was used to evaluate physical symptoms of AWS. Results Both baclofen and diazepam significantly decreased CIWA-Ar score, without significant differences between the 2 treatments. When CIWA-Ar subscales for sweating, tremors, anxiety and agitation were evaluated singly, treatment with baclofen and diazepam resulted in a significant decrease in sweating, tremors and anxiety score, without significant differences between the 2 drug treatments. Both treatments decreased the agitation score, although diazepam was slightly more rapid than baclofen. Conclusion The efficacy of baclofen in treatment of uncomplicated AWS is comparable to that of the "gold standard" diazepam. These results suggest that baclofen may be considered as a new drug for treatment of uncomplicated AWS.

The effect of acutely administered gamma-hydroxybutyric acid (GHB) and GHB receptor antagonist, NCS-382, on the propulsive activity in the mouse small intestine was assessed by measuring the transit of an orally administered, non absorbable marker. Both GHB (0, 25, 50, 100, 200 and 300 mg/kg; i.p.) and NCS-382 (0, 25, 50 and 75 mg/kg; i.p.) induced a dose-dependent inhibition (up to 50–60%) of the marker transit. Pretreatment with the GABA B receptor antagonist, SCH 50911 (100 mg/kg; i.p.), resulted in the blockade of the inhibiting effect of both GHB and NCS-382. These results suggest that the constipating effect of GHB and NCS-382 are secondary to stimulation of the GABA B receptor.

Alcohol deprivation effect (ADE), defined as a temporary increase in voluntary alcohol intake following a period of alcohol abstinence, was evaluated in selectively bred Sardinian alcohol-preferring (sP) rats. Alcohol was initially offered in free choice with water for 35 consecutive days (predeprivation phase). Subsequently, one group of rats was deprived of alcohol for 1, 3, 7, 15, 30, 90 or 180 consecutive days, while the second group had continuous access to alcohol (deprivation phase). Once alcohol was re-presented, alcohol intake in alcohol-deprived rats was recorded 1 and 24 h after alcohol re-presentation and compared to that monitored in alcohol-nondeprived rats over the same time periods (postdeprivation phase). Alcohol deprivation for 3 to 30 days resulted in a significant increase in voluntary alcohol intake only in the first hour of re-access. These results demonstrate the development of ADE in sP rats. However, the rapid return of alcohol intake to control levels is discussed as evidence in favor of a set-point mechanism capable of regulating alcohol-drinking behavior in sP rats.

Treatment with gamma-hydroxybutyric acid has been reported to effectively decrease alcohol craving and consumption as well as alcohol withdrawal symptoms in alcoholics. We describe the results of animal studies demonstrating the ability of gamma-hydroxybutyric acid to reduce (1) the severity of ethanol withdrawal signs in rats rendered physically dependent on ethanol and (2) voluntary ethanol intake in selectively bred Sardinian alcohol-preferring rats. Furthermore, we review experimental data suggesting that gamma-hydroxybutyric acid and ethanol have several pharmacological effects in common. Relevant similarities are: (1) stimulation of firing rate of dopaminergic neurons and dopamine release in specific rat brain areas; (2) development of cross-tolerance to the motor-impairing effects after repeated administration in rats; 3) abuse potential, as indicated by self-administration of pharmacologically relevant doses of gamma-hydroxybutyric acid in rats and mice; (4) induction of anxiolytic effects in rats; and (5) induction of similar discriminative stimulus effects, as evidenced by symmetrical generalization in a drug discrimination study in rats. These lines of evidence are discussed in relation to gamma-hydroxybutyric acid exerting its antialcohol effects by a substitution mechanism.

Background: It has been proposed that ethanol intake and consumption of sweet tasting solutions are positively correlated in rodents. Experiment 1 of the present study investigated whether selectively bred ethanol-preferring (sP) and -nonpreferring (sNP) rats differed, consistently with the above hypothesis, as to saccharin intake and preference. Experiment 2 evaluated whether saccharin addition to the ethanol solution, likely resulting in a highly palatable fluid, would result in an increase in voluntary ethanol intake in sP rats. Methods: The saccharin solution was offered, in free choice with water, at a fixed concentration of 1 giliter for 6 consecutive days in Experiment 1A or at ascending concentrations (0.002 to 16.4 g/liter, doubling the concentration every day) in Experiment 1B. In Experiment 2, 1 g/liter, doubling the concentration every day) in Experiment 1B. In Experiment 2, 1 g/liter saccharin was added to the standard 10% ethanol solution and offered to sP rats in free choice with water for 7 consecutive days. Results: In both Experiments 1A and 1B, sP and sNP rats showed avidity for the saccharin solution with marginal line difference in saccharin intake and preference. In Experiment 2, daily ethanol intake remained stable at baseline levels (6–7 g/kg), irrespective of the saccharin addition to the ethanol solution. Conclusions: The results of Experiments 1A and 1B suggest that saccharin drinking behavior in sNP rats deviates from the hypothesis that saccharin and ethanol intakes may co-vary; thus, at least in sNP rats, saccharin and ethanol intakes do not appear to be influenced by the same genetic factors. The results of Experiment 2 provide further support to the existence of a central set-point mechanism that regulates daily ethanol intake in sP rats, likely based on the pharmacological effects of ethanol.

Alcohol administration (1 g/kg, i.p.) increased the levels of the neurosteroids 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) in the cerebral cortex and hippocampus both in alcohol-naive Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats (two rat lines selectively bred for alcohol preference and non-preference, respectively). However, the increase reached several fold higher levels in sP than in sNP rats (6-24 vs. 2-11 fold the basal levels, respectively). Since the two neurosteroids are the most potent endogenous positive modulators of GABA(A) receptors and elicit anxiolytic and rewarding effects, while voluntary alcohol consumption produces anxiolytic and rewarding effects in sP but not in sNP rats, the results suggest that the neurosteroids may play a role in the anxiolytic and rewarding effects of alcohol in sP rats.

Experiment 1 of the present study investigated the ability of a standardized extract of Salvia miltiorrhiza in reducing voluntary ethanol intake in ethanol-preferring rats of the sP line. Ethanol intake occurred under the two-bottle free-choice regimen between 10% (v/v) ethanol and water in daily 4-h scheduled access periods; water was present 24 h/day. Intragastric administration of 200 mg/kg Salvia miltiorrhiza extract resulted in approximately 40% reduction in ethanol intake and preference throughout the 4-day treatment. This effect of Salvia miltiorrhiza extract was likely due to its ability of altering ethanol absorption from the gastrointestinal tract. Indeed, Experiments 2 and 3 of this study demonstrated that 200 mg/kg Salvia miltiorrhiza extract reduced blood ethanol levels (BELs) up to 60% in comparison to control rats, when ethanol was given IG, whereas it failed to modify BELs when ethanol was injected IP. The reducing effect of Salvia miltiorrhiza extract on ethanol absorption may have therefore resulted in an attenuated perception of the psychoactive effects of ethanol sought by ethanol-drinking rats. Consistently, the results of Experiment 4 of the present study demonstrated that a combination of 200 mg/kg Salvia miltiorrhiza extract IG and 1 or 2 g/kg ethanol IG resulted in a partial blockade of the discriminative stimulus effects of ethanol in sP rats trained to discriminate these doses of ethanol from water in a drug discrimination procedure. Collectively, the results are discussed as being suggestive that drugs curbing ethanol absorption from the gastrointestinal tract may constitute a novel strategy for controlling excessive alcohol consumption in human alcoholics.

Stimulation of motor activity induced by ethanol has been proposed to reflect the positive reinforcing properties of the drug. The present study was designed to assess whether voluntary ethanol intake would stimulate locomotor activity in Sardinian alcohol-preferring (sP) rats, selectively bred for high ethanol preference and consumption. Rats were habituated to a) consume either water alone (water-consuming rats) or ethanol (10%, v/v) as free choice together with water (ethanol-consuming rats) according to a 15-min limited access protocol for 10 consecutive days prior to the test, and b) explore an open field for 10 min immediately after the drinking session in a trial on 3 consecutive days before the test. On the test day, voluntary ethanol consumption in ethanol-consuming rats averaged 1.2 g/kg. Values for activity measures (time spent moving, number of square crossings and number of rearings) were significantly higher in ethanol- than in water-consuming rats at both 5- and 10-min intervals. These results suggest that the euphorigenic effects of ethanol, supposedly represented by the stimulation of locomotor activity, are part of the reinforcing properties of ethanol in sP rats.

COLOMBO, G., R. AGABIO, G. DIAZ, M. FA, C. LOBINA, R. REALI AND G. L. GESSA. γ-Hydroxybutyric acid intake in ethanol-preferring sP and -nonpreferring sNP rats. Physiol Behav 64(2) 197–202, 1998. γ-hydroxybutyric acid (GHB) and ethanol share several pharmacological similarities, suggesting that GHB may exert ethanol-like effects in the central nervous system. The present study was designed to test whether selectively bred ethanol-preferring rats would, unlike ethanol-nonpreferring ones, self-administer GHB, consistent with their higher preference for ethanol. Male ethanol-naive Sardinian alcohol-preferring (sP) and Sardinian alcohol-nonpreferring (sNP) rats were used. In Experiment 1, GHB solution (1% (w/v) in water) was initially offered as the sole fluid available for 14 consecutive days and then presented under the two-bottle, free-choice regimen, one bottle containing water and the other the GHB solution, for an additional 14 consecutive days. During the free-choice phase, high preference for GHB and intake of pharmacologically relevant daily doses of GHB developed in both rat lines, presumably because the 14-day no-choice period would unmask the reinforcing properties of GHB and lead to acquisition of GHB preference also in the supposedly less susceptible sNP rats. In Experiment 2, the forced GHB drinking phase was reduced to 3 days. Under the subsequent free-choice regimen, daily GHB preference and intake were initially low in both sP and sNP rats; however, after approximately 10 days, GHB preference and intake in sP rats rose progressively and then stabilized to significantly higher levels than in sNP rats throughout the entire free-choice phase. It is likely that episodic binges of GHB intake occurring during the first 10 days resulted in experiencing the reinforcing properties of GHB by sP but not sNP rats. The results of the present study suggest that a) sP rats are genetically more sensitive to the reinforcing effects of both ethanol and GHB than sNP rats; and b) disclosure of the higher sensitivity of sP rats to the reinforcing effects of GHB is a function of the length of the induction procedure. The results are also discussed in terms of differences in GHB receptors contributing to the predisposition to ethanol preference and avoidance, respectively.

The effect of cannabinoid receptor activation and blockade on the propulsive activity in the mouse small intestine was assessed in the present study by measuring the transit of an orally administered, non-absorbable marker. The cannabinoid receptor agonist WIN 55,212-2 ( R (+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl]pyrrolo[1,2,3-de-1,4benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) inhibited, while the selective cannabinoid CB 1 receptor antagonist SR 141716A ( N -piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide) stimulated the marker transit. Furthermore, a per se non-effective dose of SR 141716A reversed WIN 55,212-2-induced reduction of the transit. The results of the present study suggest a role for cannabinoid CB 1 receptors in the control of propulsive activity in the mouse small intestine.

The present study was designed to evaluate ethanol drinking behaviour in Sardinian alcohol-preferring (sP) and Sardinian alcohol-non-preferring (sNP) rats in the presence of different ethanol concentrations. Ethanol intake was tested under the two-bottle, free-choice regimen and continuous access schedule. Ethanol-naive sP and sNP rats were initially given ethanol solution at the standard, constant concentration of 10% (v/v) for 8 consecutive days (Phase 1). As expected, daily ethanol intake in sP rats rose from 4 to approximately 6 g/kg; in contrast sNP rats consumed10 g/kg/day ethanol. Subsequently, an ascending series of ethanol concentrations, ranging from 3 to 60% (v/v), was presented to sP and sNP rats over a 28-day period (Phase 2). At concentrations varying from 7 to 30%, sP rats consumed constant amounts of absolute ethanol per kg of body weight (approximately 6.0 g/kg/day). Daily ethanol intake in sNP rats remained constantly lower than 1.0 g/kg, irrespective of the ethanol concentration. Data from Phase 2 demonstrate the ability of sP rats to precisely adjust daily ethanol intake and support the hypothesis that voluntary ethanol drinking in sP rats is sustained by specific pharmacological effects of ethanol.