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

INTRODUCTION: Cannabidiol (CBD) is a major cannabinoid extracted from Cannabis sativa with no abuse potential. Data from recent rodent studies suggest that amelioration of alcohol-motivated behaviors may be one of the numerous pharmacological effects of CBD. This study was designed to contribute to this research, assessing the effect of CBD on operant oral alcohol self-administration in selectively bred Sardinian alcohol-preferring (sP) rats, a validated animal model of excessive alcohol consumption. In addition, this study investigated the effect of CBD on operant self-administration of a highly palatable chocolate solution in Wistar rats. MATERIALS AND METHODS: Male sP rats were trained to lever respond for alcohol (15% v/v) under the fixed ratio 4 (FR4) schedule of reinforcement. Once lever responding had stabilized, rats were exposed to test sessions under the FR4 and progressive ratio (PR) schedules of reinforcement. Test sessions were preceded by acute treatment with CBD (0, 6.25, 12.5, and 25 mg/kg or 0, 25, 50, and 100 mg/kg, i.p.; each dose range was tested in an independent experiment). Male Wistar rats were trained to lever respond for a chocolate solution (5% w/v chocolate powder) under the FR10 schedule of reinforcement. Once lever responding had stabilized, rats were exposed to test sessions under the same schedule. Test sessions were preceded by acute treatment with CBD (0, 6.25, 12.5, and 25 mg/kg or 0, 25, 50, and 100 mg/kg, i.p., in two independent experiments). RESULTS: Under the FR schedule, treatment with doses of CBD ≥12.5 mg/kg markedly reduced lever responding for alcohol and amount of self-administered alcohol. Under the PR schedule, treatment with CBD produced a slight tendency toward a decrease in lever responding and breakpoint for alcohol. Finally, no dose of CBD affected lever responding for the chocolate solution and amount of self-administered chocolate solution. DISCUSSION: These results extend previous data on CBD ability to affect alcohol-motivated behaviors to an animal model of genetically-determined proclivity to high alcohol consumption. Because of the predictive validity of sP rats, these results may be of relevance in view of possible future studies testing CBD in patients affected by alcohol use disorder.

Recent studies demonstrated that saikosaponin (SS) A and other SSs extracted from

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 GABAThe present study investigated whether the "anti-alcohol" properties of COR659 extend to binge-like drinking in rodents.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.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.The present data demonstrate the ability of COR659 to suppress binge-like drinking in rodents and strengthen the hypothesis that GABA

Alcohol use disorder remains a major health problem. The mesocorticolimbic dopaminergic system, including the nucleus accumbens region and multiple neural circuits, is involved in its complex underlying mechanism. For instance, alcohol intake stimulates the central and peripheral renin-angiotensin system and increases angiotensin II levels, which predominantly affect angiotensin 1 receptors both in the periphery and in the brain. In this study, we aimed to investigate the effects of the intracerebroventricularly-administered angiotensin 1 receptor blocker telmisartan on the alcohol consumption of male Sardinian alcohol-preferring (sP) rats and on the alcohol-induced dopamine levels in the nucleus accumbens region in Wistar rats. Acute intracerebroventricular administration of telmisartan (100 nM) reduced the alcohol intake for 24 hours without affecting food and water consumption in sP rats. Acute intracerebroventricular injection of the opioid receptor antagonist naloxone (75 nM), tested as a reference compound, also reduced the alcohol consumption in sP rats; however, naloxone's effect lasted only for 30 minutes. In microdialysis experiments, telmisartan administered intracerebroventricularly did not change dopamine levels in the nucleus accumbens that had been induced by acute intraperitoneal alcohol administration in Wistar rats. According to these results, further studies are needed to elucidate the role of the renin-angiotensin system on alcohol use disorder pathophysiology.

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 (IESEEE) 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.

COR659 is a recently synthesized positive allosteric modulator (PAM) of the GABA

The hallmark of joint diseases, such as osteoarthritis (OA), is pain, originating from both inflammatory and neuropathic components, and compounds able to modulate the signal transduction pathways of the cannabinoid type-2 receptor (CB2R) can represent a helpful option in the treatment of OA. In this perspective, a set of 18 cannabinoid type-2 receptor (CB2R) ligands was developed based on an unprecedented structure. With the aim of improving the physicochemical properties of previously reported 4-hydroxy-2-quinolone-3-carboxamides, a structural optimization program led to the discovery of isosteric 7-hydroxy-5-oxopyrazolo[4,3

We report an in vitro phase I metabolism study on COR659 (1), a 2-acylaminothiophene derivative able to suppress alcohol and chocolate self-administration in rats, likely via positive allosteric modulation of the GABA

Aims Treatment with saikosaponin A (SSA)—an ingredient of the medicinal herb, Bupleurum falcatum—has been reported to suppress several addictive-like behaviors, including morphine, cocaine, alcohol and chocolate self-administration in male rats. The aim of this investigation was to investigate whether saikosaponins of B. falcatum other than SSA affect alcohol and chocolate self-administration in rats. Methods Ovariectomized female Sardinian alcohol-preferring (sP) and Wistar rats were trained to self-administer alcohol (15%, v/v) and a chocolate solution [5% (w/v) Nesquik® in water], respectively, under fixed ratio schedules of reinforcement. The following saikosaponins were compared to SSA: saikosaponin D (SSD; epimer of SSA), saikosaponin C (SSC), saikosaponin B2 (SSB2) and saikosaponin B4 (SSB4). All saikosaponins were tested acutely at the doses of 0, 0.25, 0.5 and 1 mg/kg (i.p.). Results Treatment with SSA and SSD resulted in highly similar, marked reductions in alcohol self-administration; SSC failed to alter lever-responding for alcohol, while SSB2 and SSB4 produced intermediate reductions. Only SSA and SSD reduced chocolate self-administration, with SSC, SSB2 and SSB4 being ineffective. Conclusions The wide spectrum of efficacy of saikosaponins in reducing alcohol and chocolate self-administration suggests that even relatively small structural differences are sufficient to produce remarkable changes in their in vivo pharmacological profile. Together, these results confirm that roots of B. falcatum may be an interesting source of compounds with anti-addictive potential.

Systemic administration of the orthosteric agonist, baclofen, and several positive allosteric modulators (PAMs) of the GABAB receptor has repeatedly been reported to decrease operant oral alcohol self-administration in rats. The aim of the present study was to evaluate the contribution of the mesolimbic dopamine system to the reducing effect of baclofen and GABAB PAMs on the reinforcing properties of alcohol. To this end, baclofen or the GABAB PAM CGP7930 were microinjected into the ventral tegmental area (VTA) of selectively bred, Sardinian alcohol-preferring (sP) rats trained to self-administer alcohol. Baclofen (0, 0.03, 0.1, and 0.3 μg) or CGP7930 (0, 5, 10, and 20 μg) were microinjected via indwelling unilateral guide cannula aiming at the left hemisphere of the VTA. Treatment with baclofen resulted in a dose-related suppression of the number of lever-responses for alcohol and the amount of self-administered alcohol. No dose of baclofen altered rat motor-performance, evaluated by the inverted screen test immediately before the self-administration session. Treatment with CGP7930 halved the number of lever-responses for alcohol and amount of self-administered alcohol, with no effect on rat motor-performance. Site-specificity was investigated testing the effect of microinjection of baclofen and CGP7930 into the left hemisphere of deep mesencephalic nucleus: compared to vehicle, neither 0.3 μg baclofen nor 20 μg CGP7930 altered lever-responding for alcohol and amount of self-administered alcohol. Collectively, the results of the present study suggest the involvement of GABAB receptors located in the VTA in the mediation of alcohol reinforcing properties in sP rats. This article is part of the “Special Issue Dedicated to Norman G. Bowery”.

The existence of sex differences was studied in a rat model of operant self-administration of a chocolate-flavored beverage (CFB), which possesses strong reinforcing properties and is avidly consumed by rats. Whether these differences occurred concomitantly to changes in extracellular dopamine in the dialysate obtained from the nucleus accumbens, was assessed by intracerebral microdialysis. Male, ovariectomized and intact female rats showed similar self-administration profiles, with minor differences in both acquisition and maintenance phases. Intact females self-administered larger amounts of CFB, when expressed per body weight, than males and ovariectomized females, in spite of similar values of lever-responding, latency to the first lever-response and consumption efficiency (a measure of rat’s licking effectiveness) in males, ovariectomized and intact females and no difference in breakpoint value and number of lever-responses emerged when males, ovariectomized and intact females were exposed to a progressive ratio schedule of reinforcement. Intracerebral microdialysis revealed a slight but significant increase in dopamine activity in the shell of the nucleus accumbens of male rats when compared to intact female rats during CFB self-administration. The above differences may be caused by the hormonal (mainly estradiol) fluctuations that occur during the estrus cycle in intact females. Accordingly, in intact females CFB self-administration and dopamine activity were found to fluctuate across the estrus cycle, with lower parameters of CFB self-administration and lower dopamine activity in the Proestrus and Estrus phases vs. the Metestrus and Diestrus phases of the cycle.

Background: Preparations from roots of Salvia miltiorrhiza, a herb widely used in traditional Chinese medicine, have been reported to induce a series of central effects, including sedation. In the wake of this ethnopharmacological information, the present study was designed to assess the anxiolytic potential of an extract of S. miltiorrhiza roots. Methods: To this end, rats were acutely treated with S. miltiorrhiza extract (0, 50, and 100 mg/kg; i.g.) and exposed to the Elevated Plus Maze (EPM) test. The effect of treatment with S. miltiorrhiza extract on Stress-Induced Hyperthermia (SIH; a physiological response to stressful events) was also evaluated. Results: Treatment with 100 mg/kg S. miltiorrhiza extract produced robust anxiolytic effects at the EPM test; specifically, it increased (a) percent of entries into open arms, (b) percent of time spent in open arms, (c) total number of head dips, (d) number of unprotected head dips, and (e) number of end-arm explorations in open arms, without any alteration in spontaneous locomotor activity. Treatment with 100 mg/kg S. miltiorrhiza extract also suppressed SIH response. The anxiolytic effects produced by 100 mg/kg S. miltiorrhiza extract were comparable to those exerted by acute treatment with 1.5 mg/kg (i.p.) of the reference compound, diazepam. Conclusion: These data demonstrate the ability of an extract of S. miltiorrhiza roots to produce anxiolysis in two different rodent models of “anxiety”. Keywords: Anxiety, Rats, Salvia miltiorrhiza

Sardinian alcohol-preferring (sP) and Sardinian alcohol-non preferring (sNP) rats have been selectively bred for opposite alcohol preference and consumption. Aiming to verify possible differences at the proteomics level between sP and sNP rats, we investigated the salivary proteome by a a liquid chromatography-mass spectrometry top-down-bottom-up integrated approach. For this purpose, submandibular saliva was collected from alcohol-naive sP and sNP rats under isoprenaline stimulation. A total of 200 peptides and proteins were detected and quantified in the two rat lines, 149 of which were characterized in their naturally occurring structure. The data are available via ProteomeXchange with identifier PXD006997. Surprisingly, sP rats exhibited marked quantitative and qualitative differences with respect to sNP rats, namely higher levels of proteoforms originating from submandibular gland protein C, and from submandibular rat protein 2, as well as those of several unidentified peptides and proteins. sP rats expressed some proteins not detectable in sNP rats such as the glutamine and glutamic acid-rich protein (GRP)-CB. The isoform GRP-B, detectable in both rat lines, was more abundant in sNP rats. The submandibular saliva of sNP rats was also characterized by very high levels of GRP-B proteolytic peptides and rat salivary protein 1. Whether these differences could contribute to the opposite alcohol preference and consumption of sP and sNP rats is currently unknown and requires further investigation.

This study investigated whether (i) the 5:1 combination of standardized extracts of

The orthosteric γ-aminobutyric acid

Recent findings have identified salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, as a potential regulator of alcohol-induced activation of the mesolimbic dopamine system and alcohol consumption. Providing that the role of amylin signalling in alcohol-related behaviours remains unknown, the present experiments investigate the effect of sCT on these behaviours and the mechanisms involved. We showed that repeated sCT administration decreased alcohol and food intake in outbred rats. Moreover, single administration of the potent amylin receptor antagonist, AC187, increased short-term alcohol intake in outbred alcohol-consuming rats, but did not affect food intake. Acute administration of sCT prevented relapse-like drinking in the “alcohol deprivation effect” model in outbred alcohol-experienced rats. Additionally, acute sCT administration reduced operant oral alcohol self-administration (under the fixed ratio 4 schedule of reinforcement) in selectively bred Sardinian alcohol-preferring rats, while it did not alter operant self-administration (under the progressive ratio schedule of reinforcement) of a highly palatable chocolate-flavoured beverage in outbred rats. Lastly, we identified differential amylin receptor expression in high compared to low alcohol-consuming rats, as reflected by decreased calcitonin receptor and increased receptor activity modifying protein 1 expression in the nucleus accumbens (NAc) of high consumers. Collectively, our data suggest that amylin signalling, especially in the NAc, may contribute to reduction of various alcohol-related behaviours.

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.

Positive allosteric modulators (PAMs) of the GABA

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.

Background There is strong evidence that alcoholism leads to dysbiosis in both humans and animals. However, it is unclear how changes in the intestinal microbiota (IM) relate to ethanol (EtOH)-induced disruption of gut-liver homeostasis. We investigated this issue using selectively bred Sardinian alcohol-preferring (sP) rats, a validated animal model of excessive EtOH consumption. Methods Independent groups of male adult sP rats were exposed to the standard, home-cage 2-bottle "EtOH (10% v/v) versus water" choice regimen with unlimited access for 24 h/d (Group Et) for 3 (T1), 6 (T2), and 12 (T3) consecutive months. Control groups (Group Ct) were composed of matched-age EtOH-naive sP rats. We obtained samples from each rat at the end of each experimental time, and we used blood and colon tissues for intestinal barrier integrity and/or liver pathology assessments and used stool samples for IM analysis with 16S ribosomal RNA gene sequencing. Results Rats in Group Et developed hepatic steatosis and elevated serum transaminases and endotoxin/lipopolysaccharide (LPS) levels but no other liver pathological changes (i.e., necrosis/inflammation) or systemic inflammation. While we did not find any apparent alteration of the intestinal colonic mucosa, we found that rats in Group Et exhibited significant changes in IM composition compared to the rats in Group Ct. These changes were sustained throughout T1, T2, and T3. In particular, Ruminococcus, Coprococcus, and Streptococcus were the differentially abundant microbial genera at T3. The KEGG Ortholog profile revealed that IM functional modules, such as biosynthesis, transport, and export of LPS, were also enriched in Group Et rats at T3. Conclusions We showed that chronic, voluntary EtOH consumption induced liver injury and endotoxemia together with dysbiotic changes in sP rats. This work sets the stage for improving our knowledge of the prevention and treatment of EtOH-related diseases.

A quantitative genetic approach, which involves correlation of transcriptional networks with the phenotype in a recombinant inbred (RI) population and in selectively bred lines of rats, and determination of coinciding quantitative trait loci for gene expression and the trait of interest, has been applied in the present study. In this analysis, a novel approach was used that combined DNA-Seq data, data from brain exon array analysis of HXB/BXH RI rat strains and six pairs of rat lines selectively bred for high and low alcohol preference, and RNA-Seq data (including rat brain transcriptome reconstruction) to quantify transcript expression levels, generate co-expression modules and identify biological functions that contribute to the predisposition of consuming varying amounts of alcohol. A gene co-expression module was identified in the RI rat strains that contained both annotated and unannotated transcripts expressed in the brain, and was associated with alcohol consumption in the RI panel. This module was found to be enriched with differentially expressed genes from the selected lines of rats. The candidate genes within the module and differentially expressed genes between high and low drinking selected lines were associated with glia (microglia and astrocytes) and could be categorized as being related to immune function, energy metabolism and calcium homeostasis, as well as glial-neuronal communication. The results of the present study show that there are multiple combinations of genetic factors that can produce the same phenotypic outcome. Although no single gene accounts for predisposition to a particular level of alcohol consumption in every animal model, coordinated differential expression of subsets of genes in the identified pathways produce similar phenotypic outcomes.The datasets supporting the results of the present study are available at http://phenogen.ucdenver.edu.

Sardinian alcohol-preferring (sP) rats displayed high sensitivity to time schedule and consumed intoxicating amounts of alcohol during the last portion of the dark phase of the light/dark cycle when exposed to daily drinking sessions of 1 h, with concurrent availability of multiple alcohol concentrations and unpredictability of time of alcohol access.The present study investigated whether sensitivity of sP rats to time schedule extended to operant procedures of alcohol self-administration.In experiment 1, three different alcohol solutions (10, 20, and 30%, v/v) were concurrently available under a fixed ratio 4 schedule of reinforcement and with unpredictable time schedule; water was available uncontingently. Experiments 2 and 3 assessed the sensitivity of the motivational properties of alcohol to time schedule; rats were exposed to (a) self-administration sessions under the progressive ratio (PR) schedule of reinforcement and (b) sessions of alcohol seeking under the extinction responding (ER) schedule.In experiment 1, number of lever responses and amount of self-administered alcohol were positively correlated with time of alcohol access during the dark phase. When the self-administration session occurred at the first and latest hours of the dark phase, the amount of self-administered alcohol averaged 0.95-1.0 and 1.55-1.65 g/kg, respectively. In experiments 2 and 3, values of breakpoint and ER for alcohol were approximately 50% higher when the sessions occurred at the last than first hour of the dark phase.The reinforcing and motivational properties of alcohol were sensitive to time schedule and stronger at the end of the dark phase.

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.

The progressive predominance of rewarding effects of addictive drugs over their aversive properties likely contributes to the transition from drug use to drug dependence. By inhibiting the activity of DA neurons in the VTA, GABA projections from the rostromedial tegmental nucleus (RMTg) are well suited to shift the balance between drug-induced reward and aversion. Since cannabinoids suppress RMTg inputs to DA cells and CB1 receptors affect alcohol intake in rodents, we hypothesized that the endocannabinoid system, by modulating this pathway, might contribute to alcohol preference. Here we found that RMTg afferents onto VTA DA neurons express CB1 receptors and display a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, that is, depolarization-induced suppression of inhibition (DSI). Next, we compared rodents with innate opposite alcohol preference, the Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. We found that DA cells from alcohol-naive sP rats displayed a decreased probability of GABA release and a larger DSI. This difference was due to the rate of 2-AG degradation. In vivo, we found a reduced RMTg-induced inhibition of putative DA neurons in sP rats that negatively correlated with an increased firing. Finally, alcohol failed to enhance RMTg spontaneous activity and to prolong RMTg-induced silencing of putative DA neurons in sP rats. Our results indicate functional modifications of RMTg projections to DA neurons that might impact the reward/aversion balance of alcohol attributes, which may contribute to the innate preference observed in sP rats and to their elevated alcohol intake.

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

ABSTRACT: Aim: This study investigated the protective effect of a standardized extract of Panax ginseng on multiple cisplatin-induced ‘sickness behaviors’ (model of cancer-induced cachexia) in rats. Materials & methods: Cisplatin was administered twice weekly (1–2 mg/kg, intraperitoneal) for 5 consecutive weeks. Panax ginseng extract (0, 25 and 50 mg/kg, intragastric) was administered daily over the 5-week period of cisplatin exposure. Malaise, bodyweight and temperature, pain sensitivity, and endurance running were recorded at baseline and at 5 weekly intervals. Results: Treatment with cisplatin produced severe signs of malaise, marked loss of bodyweight, hypothermia, hyperalgesia and reduction in running time. Treatment with Panax ginseng extract completely prevented all cisplatin-induced alterations. Conclusion: These data indicate that treatment with Panax ginseng extract exerted a protective effect in a rat model of cachexia and suggest that Panax ginseng extract may be a therapeutic promising tool for supportive care in oncology.

The objectives of this study were to determine innate differences in gene expression in 2 regions of the extended amygdala between 5 different pairs of lines of male rats selectively bred for high or low ethanol consumption: a) alcohol-preferring (P) vs. alcohol-non-preferring (NP) rats, b) high-alcohol-drinking (HAD) vs. low-alcohol-drinking (LAD) rats (replicate line-pairs 1 and 2), c) ALKO alcohol (AA) vs. nonalcohol (ANA) rats, and d) Sardinian alcohol-preferring (sP) vs. Sardinian alcohol-nonpreferring (sNP) rats, and then to determine if these differences are common across the line-pairs. Microarray analysis revealed up to 1,772 unique named genes in the nucleus accumbens shell (AcbSh) and 494 unique named genes in the central nucleus of the amygdala (CeA) that significantly differed [False Discovery Rate (FDR) = 0.10; fold-change at least 1.2] in expression between the individual line-pairs. Analysis using Gene Ontology (GO) and Ingenuity Pathways information indicated significant categories and networks in common for up to 3 or 4 line-pairs, but not for all 5 line-pairs. However, there were almost no individual genes in common within these categories and networks. ANOVAs of the combined data for the 5 line-pairs indicated 1,014 and 731 significant (p < 0.01) differences in expression of named genes in the AcbSh and CeA, respectively. There were 4–6 individual named genes that significantly differed across up to 3 line-pairs in both regions; only 1 gene (Gsta4 in the CeA) differed in as many as 4 line-pairs. Overall, the findings suggest that a) some biological categories or networks (e.g., cell-to-cell signaling, cellular stress response, cellular organization, etc.) may be in common for subsets of line-pairs within either the AcbSh or CeA, and b) regulation of different genes and/or combinations of multiple biological systems may be contributing to the disparate alcohol drinking behaviors of these line-pairs.

Craving for chocolate is a common phenomenon, which may evolve to an addictive-like behaviour and contribute to obesity. Nepicastat is a selective dopamine β-hydroxylase (DBH) inhibitor that suppresses cocaine-primed reinstatement of cocaine seeking in rats. We verified whether nepicastat was able to modify the reinforcing and motivational properties of a chocolate solution and to prevent the reinstatement of chocolate seeking in rats. Nepicastat (25, 50 and 100 mg/kg, intraperitoneal) produced a dose-related inhibition of operant self-administration of the chocolate solution in rats under fixed-ratio 10 (FR10) and progressive-ratio schedules of reinforcement, measures of the reinforcing and motivational properties of the chocolate solution, respectively. The effect of nepicastat on the reinstatement of chocolate seeking was studied in rats in which lever-responding had been extinguished by removing the chocolate solution for approximately 8 d. Nepicastat dose-dependently suppressed the reinstatement of lever-responding triggered by a ‘priming’ of the chocolate solution together with cues previously associated with the availability of the reward. In a separate group of food-restricted rats trained to lever-respond for regular food pellets, nepicastat reduced FR10 lever-responding with the same potency as for the chocolate solution. Spontaneous locomotor activity was not modified by nepicastat doses that reduced self-administration of the chocolate solution and regular food pellets and suppressed the reinstatement of chocolate seeking. The results indicate that nepicastat reduces motivation to food consumption sustained by appetite or palatability. Moreover, the results suggest that DBH inhibitors may be a new class of pharmacological agents potentially useful in the prevention of relapse to food seeking in human dieters.

COR659 [methyl2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate] is a new, positive allosteric modulator (PAM) of the GABATreatment with non-sedative doses of COR659 (2.5, 5, and 10 mg/kg; i.p.) suppressed lever-responding for alcohol (15% v/v) in Sardinian alcohol-preferring (sP) rats under the fixed ratio (FR) 4 (FR4) and progressive ratio (PR) schedules of reinforcement; COR659 was more potent and effective than the reference GABACOR659 might exert its behavioral effects via a composite mechanism: (i) positive allosteric modulation of the GABA

Recent lines of experimental evidence have indicated that saikosaponin A (SSA) - a bioactive ingredient of the medicinal plant, Bupleurum falcatum L. - suppressed alcohol, morphine, and cocaine self-administration in rats. The present paper was designed to assess whether the protective properties of SSA on addiction-related behaviors generalize to a hyperpalatable food such as a chocolate-flavored beverage (CFB). To this end, rats were initially trained to lever-respond for CFB [5% (w/v) Nesquik® powder in water] under fixed ratio (FR) 10 (FR10) schedule of reinforcement. Once lever-responding reached stable levels, rats were treated acutely with two different dose ranges of SSA (0, 0.25, 0.5, and 1mg/kg; 0, 1, 2.5, and 5mg/kg; i.p.) and exposed to the FR10 and progressive ratio (PR) schedules of reinforcement in four independent experiments. The effect of acutely administered SSA (0, 0.25, 0.5, and 1mg/kg; i.p.) on cue-induced reinstatement of seeking behavior for CFB was also assessed. Under the FR and PR schedules of reinforcement, treatment with SSA diminished lever-responding for CFB, amount of self-administered CFB, and breakpoint for CFB. All variables were virtually completely suppressed after treatment with 5mg/kg SSA. Treatment with SSA also suppressed reinstatement of CFB-seeking behavior. No dose of SSA altered rat motor-performance, evaluated exposing all rats to an inverted screen test immediately after the self-administration session. These results demonstrate that acute treatment with SSA potently suppressed several addictive-like behaviors motivated by highly hedonic nourishment. These data extend to a highly rewarding natural stimulus the anti-addictive properties of SSA recently disclosed in rats self-administering alcohol, morphine, and cocaine.

Modulation of metabotropic glutamate 2 (mGlu2) receptor function has huge potential for treating psychiatric and neurological diseases. Development of drugs acting on mGlu2 receptors depends on the development and use of translatable animal models of disease. We report here a stop codon mutation at cysteine 407 in Grm2 (cys407*) that is common in some Wistar rats. Therefore, researchers in this field need to be aware of strains with this mutation. Our genotypic survey found widespread prevalence of the mutation in commercial Wistar strains, particularly those known as Han Wistar. Such Han Wistar rats are ideal for research into the separate roles of mGlu2 and mGlu3 receptors in CNS function. Previous investigations, unknowingly using such mGlu2 receptor-lacking rats, provide insights into the role of mGlu2 receptors in behaviour. The Grm2 mutant rats, which dominate some selectively bred lines, display characteristics of altered emotionality, impulsivity and risk-related behaviours and increased voluntary alcohol intake compared with their mGlu2 receptor-competent counterparts. In addition, the data further emphasize the potential therapeutic role of mGlu2 receptors in psychiatric and neurological disease, and indicate novel methods of studying the role of mGlu2 and mGlu3 receptors. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Recent studies demonstrated that treatment with saikosaponin A (SSA) - an active ingredient of the medicinal herb, Bupleurum falcatum L. - selectively suppressed, likely via a GABAB receptor-mediated mechanism, intravenous self-administration of morphine and cocaine in rats [Yoon et al., 2012; 2013]. The present study was designed to investigate whether the capacity of SSA to suppress morphine and cocaine self-administration extends to oral alcohol self-administration. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were trained to lever-respond on a Fixed Ratio (FR) 4 (FR4) schedule of reinforcement for alcohol (15%, v/v) in daily 30-min sessions. Once responding had stabilized, rats were tested under the FR4 (measure of alcohol reinforcing properties) and Progressive Ratio (PR; measure of alcohol motivational properties) schedules of reinforcement. The possible involvement of the GABAB receptor system was investigated testing the effect of (a) pretreatment with the GABAB receptor antagonist, SCH50911, and (b) combined treatment with the positive allosteric modulator of the GABAB receptor, GS39783. Treatment with SSA (0, 0.25, 0.5, and 1mg/kg, i.p.) 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). Pretreatment with 2mg/kg SCH50911 (i.p.) resulted in a partial blockade of the reducing effect of 0.5mg/kg SSA on lever-responding for alcohol and amount of self-administered alcohol. Combination of per se ineffective doses of GS39783 (5mg/kg, i.g.) and SSA (0.1mg/kg, i.p.) reduced lever-responding for alcohol and amount of self-administered alcohol. These results (a) extend to alcohol self-administration the capacity of SSA to suppress morphine and cocaine self-administration in rats and (b) suggest that the GABAB receptor system is likely part of the neural substrate underlying the reducing effect of SSA on alcohol self-administration.

The incretin hormone, glucagon‐like peptide 1 (GLP‐1), regulates gastric emptying, glucose‐dependent stimulation of insulin secretion and glucagon release, and GLP‐1 analogs are therefore approved for treatment of type II diabetes. GLP‐1 receptors are expressed in reward‐related areas such as the ventral tegmental area and nucleus accumbens, and GLP‐1 was recently shown to regulate several alcohol‐mediated behaviors as well as amphetamine‐induced, cocaine‐induced and nicotine‐induced reward. The present series of experiments were undertaken to investigate the effect of the GLP‐1 receptor agonist, liraglutide, on several alcohol‐related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well‐documented effects of alcohol on the mesolimbic dopamine system, namely alcohol‐induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self‐administration of alcohol in selectively bred Sardinian alcohol‐preferring rats. Collectively, these data suggest that GLP‐1 receptor agonists could be tested for treatment of alcohol dependence in humans.

The objective of this study was to determine if there are common innate differences in gene expression or gene pathways in the ventral tegmental area (VTA) among 5 different pairs of rat lines selectively bred for high (HEC) or low (LEC) ethanol consumption: (a) alcohol-preferring (P) vs. alcohol-non-preferring (NP) rats; (b) high-alcohol-drinking (HAD) vs. low-alcohol-drinking (LAD) rats (replicate line pairs 1 and 2); (c) ALKO alcohol (AA) vs. nonalcohol (ANA) rats; and (d) Sardinian alcohol-preferring (sP) vs. alcohol-nonpreferring (sNP) rats. Microarray analysis revealed between 370 and 1340 unique named genes that significantly differed in expression between the individual line-pairs. Analysis using Gene Ontology (GO) and Ingenuity Pathways information indicated significant categories and networks in common for up to 3 line-pairs, but not for all 5 line-pairs; moreover, there were few genes in common in these categories and networks. ANOVA of the combined data for the 5 line-pairs indicated 1,295 significant (p < 0.01) differences in expression of named genes. Although no individual named gene was significant across all 5 line-pairs, there were 22 genes that overlapped in the same direction in 3 or 4 of the line-pairs. Overall, the findings suggest that (a) some biological categories or networks may be in common for subsets of line-pairs; and (b) regulation of different genes and/or combinations of multiple biological systems (e.g., transcription, synaptic function, intracellular signaling and protection against oxidative stress) within the VTA (possibly involving dopamine and glutamate) may be contributing to the disparate alcohol drinking behaviors of these line-pairs.

New 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as cannabinoid (CB) receptor ligands. Compound 11 (CB(1)K(i) = 2.3 nM, CB(1) SI = 163.6) showed CB(1) receptor affinity and selectivity superior to Rimonabant and AM251. Acute administration of 2mg/kg 11 reduced sucrose, but not regular food, intake in rats. On the other hand, compound 23 (CB(2)K(i) = 0.51 nM, CB(2) SI = 30.0) showed significant affinity and selectivity for the CB(2) receptor. The results presented here show that the 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamide may serve as an effective scaffold for the design of either CB(1) or CB(2) receptor ligands.

Previous lines of experimental evidence have suggested that Phaseolus vulgaris extracts reduce food intake, body weight, lipid accumulation, hedonic properties of food, carbohydrate absorption and metabolism, and glycaemia in rats. The present study was designed to assess the effect of multiple cycles of repeated treatments with a standardised P. vulgaris dry extract on daily food intake and body weight in genetically obese Zucker fa/fa rats (Expt 1). Additionally, the study tested the effect of acute treatment with P. vulgaris dry extract on postprandial glycaemia in Zucker fa/fa rats (Expt 2). In Expt 1, P. vulgaris dry extract was administered daily, at doses of 50 and 500 mg/kg, in three 5 d treatment periods followed by three 20 d off-treatment periods. Administration of P. vulgaris dry extract resulted in dose-dependent decreases in daily food intake and body weight in each treatment phase. Reductions in food intake were of comparable magnitude in each treatment phase. In Expt 2, food-deprived rats were acutely treated with 50 and 500 mg P. vulgaris dry extract per kg immediately before access to a fixed amount of a starch-enriched chow. Treatment with P. vulgaris dry extract resulted in a dose-dependent suppression of glycaemia. These results extend previous data on the anorectic and hypoglycaemic effects of the P. vulgaris dry extract to a validated animal model of obesity. Together with data published previously in the literature, these results strengthen the hypothesis that potentially effective, novel pharmacotherapies for obesity and related disorders may originate from extracts and derivatives of P. vulgaris.

Extracts of kidney beans ( Phaseolus vulgaris ) are known to reduce food intake and glycemia in rodents and humans. This study evaluated the effect of a novel extract of P. vulgaris on food (regular food pellets, starch-enriched diet, and chocolate-flavored beverage) intake, body weight, and glycemia in rats. The effect of the combination of the colecistokinin (CCK) receptor antagonist, lorglumide, and P. vulgaris dry extract on food intake was also investigated. Administration of doses of P. vulgaris dry extract devoid of any behavioral toxicity dose-dependently decreased food intake (irrespective of the diet), body weight gain, and glycemia. Pretreatment with lorglumide blocked the reducing effect of P. vulgaris dry extract on food intake. The capacity of this P. vulgaris dry extract to reduce food intake, body weight, and glycemia in rats may be due to (a) inhibition of alpha-amylase, (b) stimulation of CCK release from the intestinal brush border cells, and/or (c) interference with the central mechanism(s) regulating appetite, food intake, and food palatability.

Background: Activation of the GABAB receptor—either by means of direct agonists (like baclofen) or positive allosteric modulators (like GS39783)—has been observed to suppress alcohol drinking and reinforcement in rats and mice. The present study was conducted to assess and compare the effect of baclofen and GS39783 on the motivational properties of alcohol. Methods: Selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to respond on a lever (on an fixed ratio 4 schedule of reinforcement) to orally self-administer alcohol (15%, v/v) or sucrose (3%, w/v) in daily 30-minute sessions. Once lever-responding reached stable levels, rats were exposed to sessions with a progressive ratio schedule of reinforcement. The effect of nonsedative doses of baclofen (0, 1, and 3 mg/kg, i.p.) and GS39783 (0, 25, 50, and 100 mg/kg, i.g.) on breakpoint for alcohol and sucrose (defined as the lowest response requirement not achieved by each rat and used as index of the motivational strength of alcohol and sucrose) was determined. Results: Baclofen administration resulted in a dose-dependent decrease in breakpoint for alcohol; this effect was not specific, as baclofen also reduced—to a comparable extent—breakpoint for sucrose. Conversely, GS39783 administration resulted in a dose-dependent and completely specific reduction in breakpoint for alcohol. Conclusions: The present results (i) confirm previous data on baclofen’s capacity to suppress, although nonspecifically, alcohol’s motivational properties, and (ii) extend to alcohol’s motivational properties the capacity of GS39783 to inhibit alcohol drinking and reinforcement in rats.

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 (3 mg/kg) were administered via a permanent intraperitoneal catheter, 30 min 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.

The endogenous brain constituent, γ-hydroxybutyric acid (GHB), as well as its prodrug, γ-butyrolactone (GBL), have recently gained interest in the drug addiction field due to their abuse potential and fatalities caused by overdose. It is known that GHB has two sites of actions: the γ-aminobutyric acidB(GABAB) receptor and a specific-GHB binding site. The present study was designed to extend to GBL the investigations on the contribution of the GABABreceptor and the specific-GHB binding site to its in vivo effects. To this aim, DBA mice were pretreated either with GABAB-receptor antagonists, (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) and (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), or a putative antagonist of the specific-GHB binding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382), prior to the administration of doses of GBL that induced hypothermia, motor-incoordination (measured as motor-impairment at the Rota-Rod task), and sedation/hypnosis. The capability of SCH 50911 and NCS-382 to protect against GBL-induced lethality was also investigated. Pretreatment with either GABAB-receptor antagonist completely prevented GBL-induced hypothermia, motor-incoordination, and sedation /hypnosis. SCH 50911 also provided complete protection against GBL-associated lethality. Vice versa, NCS-382 failed to exert any antagonistic or protective effect. These results suggest that the in vivo GBL effects tested in the present study are mediated by activation of the GABABreceptor. Keywords:: γ-butyrolactone (GBL), γ-hydroxybutyric acid (GHB), γ-aminobutyric acidB(GABAB)-receptor antagonist (CGP 35348, SCH 50911), antagonist of the specific-GHB binding site, NCS-382

The positive allosteric modulator of the GABA(B) receptor, GS39,783, 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 GS39,783 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 GS39,783 (0, 25, 50, and 100 mg/kg, i.g.) on responding for alcohol and sucrose was determined.Pretreatment with GS39,783 resulted in a significant, dose-dependent reduction in responding for alcohol; at the dose of 100 mg/kg GS39,783, the number of lever responses for alcohol was reduced by approximately 50% in comparison to vehicle-treated rats. The effect of GS39,783 on alcohol self-administration was specific, as responding for sucrose was completely unaffected by pretreatment with GS39,783.These data demonstrate the capability of GS39,783 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 GABA(B) receptor in the control of alcohol drinking and reinforcement.

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

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.

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

Recent research found that exposure of selectively bred, Sardinian alcohol-preferring (sP) rats to multiple alcohol concentrations (10%, 20%, and 30%, v/v), under the 4-bottle “alcohol vs. water” choice regimen, in daily 1-h drinking sessions with an unpredictable time schedule, promoted high intakes of alcohol (≥2 g/kg) when the drinking session occurred over the final hours of the dark phase of the light/dark cycle. The present study was aimed at investigating whether these high intakes of alcohol (a) were associated with alterations in rats’ emotional state (Experiment 1) and (b) were pharmacologically manipulable (Experiment 2). In both experiments, over a period of 12 days, sP rats were initially exposed daily to a1-h drinking session performed during the 12-h duration of the dark phase; time of alcohol exposure was changed each day and was unpredictable to rats. The day after this 12-day drinking phase, rats were (a) exposed to the Social Interaction (SI) test at the 1st or 12th hour of the dark phase with no alcohol available (Experiment 1) or (b) treated acutely with the positive allosteric modulator of the GABAB receptor, GS39783 (0, 25, 50, and 100 mg/kg, intragastrically [i.g.]), and exposed to a drinking session at the 12th hour of the dark phase (Experiment 2). In Experiment 1, rats exposed to the SI test during the 12th hour spent approximately 35% less time in “social” behaviors than rats exposed to the SI test during the 1st hour. No difference in “social” behaviors was observed between alcohol-naive sP rats exposed to the SI test at the 1st and 12th hour. In Experiment 2, all doses of GS39783 selectively reduced alcohol intake. These results suggest that (a) expectation of alcohol availability likely exacerbated the anxiety-like state of sP rats and (b) the GABAB receptor is part of the neural substrate underlying these exceptionally high intakes of alcohol in sP rats.

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

The present paper focuses on the different lines of evidence indicating that cannabinoid CB(1) receptor antagonists, including the prototype rimonabant, reduce food intake and body weight in laboratory animals. Recent clinical surveys demonstrated that rimonabant significantly reduced body weight also in overweight/obese humans. Treatment with rimonabant was associated with a beneficial effect on different metabolic parameters and cardiovascular risk factors linked to overweight. The data reviewed in this paper suggest that cannabinoid CB(1) receptor antagonists may constitute a novel class of drugs potentially effective in the treatment of obesity-related disorders.

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

The aim of this study was to assess whether a pet therapy program had a favorable effect on psychopathological status and perception of quality of life in cognitively unimpaired institutionalized elderly. Seven elderly rest homes in Veneto Region of Northern Italy participated in the project, which was conducted on 144 cognitively intact elderly residents (97 females and 47 males). The participants were randomly divided into three groups: 48 subjects were given a canary, 43 subjects were given a plant, and 53 subjects were given nothing. The observation period (t0-t1) lasted for 3 months. At time t0 and t1 participants were administered the mini mental state examination (MMSE) to assess their cognitive status, the LEIPAD II-Short Version (LEIPAD-SV), to gauge subjective perception of quality of life in the elderly, and the brief symptom inventory (BSI), for self-evaluation of the presence of psychopathological symptoms. At the end of the 3-month trial, tests were re-administered, without removing the experimental condition. Even if the group that received a plant seemed to benefit from the experience, they did not achieve the same positive results on BSI and quality of life subscales exhibited by the group that received a pet. This study reinforces the hypothesis that pet therapy may have a beneficial effect on the psychological well being of institutionalized elderly, in particular on aspects related to depressive symptoms and perception of quality of life.