Comparison of the Effect of the GABA_B Receptor Agonist, Baclofen, and the Positive Allosteric Modulator of the GABA_B Receptor, GS39783, on Alcohol Self‐Administration in 3 Different Lines of Alcohol‐Preferring Rats

Abstract

Background Administration of the GABAB receptor agonist, baclofen, and positive allosteric modulator (PAM), GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, including operant oral alcohol self-administration, in rats. The present study was designed to compare the effect of baclofen and GS39783 on alcohol self-administration in three lines of selectively bred, alcohol-preferring rats: Indiana alcohol-preferring (P), Sardinian alcohol-preferring (sP), and Alko Alcohol (AA). Methods Rats of each line were initially trained to respond on a lever, on a fixed ratio (FR) 4 (FR4) schedule of reinforcement, to orally self-administer alcohol (15%, v/v) in daily 30-min sessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testing baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) and GS39783 (0, 25, 50, and 100 mg/kg; i.g.) on FR4 and progressive ratio (PR) schedules of reinforcement. Finally, to assess the specificity of baclofen and GS39783 action, rats were slightly food-deprived and trained to lever-respond for food pellets. Results The rank of order of the reinforcing and motivational properties of alcohol was: P>sP>AA rats. Under both FR and PR schedules of reinforcement, the rank of order of potency and efficacy of baclofen and GS39783 in suppressing alcohol self-administration was: P>sP>AA rats. Only the highest dose of baclofen reduced lever-responding for food pellets; this effect was common to all three rat lines. Conversely, no dose of GS39783 altered lever-responding for food in any rat line. Conclusions These results suggest that: (a) the strength of the reinforcing and motivational properties of alcohol differ among P, sP, and AA rats; (b) the reinforcing and motivational properties of alcohol in P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (c) the heterogeneity in sensitivity to baclofen and GS39783 of alcohol self-administration in P, sP, and AA rats may resemble the differential effectiveness of pharmacotherapies among the different typologies of human alcoholics; (d) the GABAB receptor is part of the neural substrate mediating the reinforcing and motivational properties of alcohol.

Efficacy and Tolerability of Baclofen in Substance Use Disorders: A Systematic Review

“…Different typologies of patients display a varying response to medication [165,166]. Interestingly, a preclinical study found that different lines of alcohol-preferring rats vary in their sensitivity to treatment with baclofen [98]. It has been proposed that one of the main reasons for the divergent results collected by RCTs on AUDs may be the different typologies of patients recruited in these studies [119].…”

“…Specifically, treatment with baclofen has been reported to suppress the following: (1) alcohol drinking in rats exposed to the standard, home cage 2-bottle ‘alcohol versus water' choice regimen (a validated animal model of excessive alcohol consumption in humans) [29,85,86,87,88]; (2) relapse-like drinking in previously abstinent rats [89,90]; (3) alcohol reinforcing and motivational properties in rats, mice and nonhuman primates trained to perform a given amount of ‘work' (usually responding on a lever) to gain access to the alcohol solution [91,92,93,94,95,96,97,98,99]; (4) reinstatement of alcohol-seeking behavior triggered in rats by the noncontingent presentation of a complex of cues previously associated with alcohol availability [100]; (5) alcohol-induced conditioned place preference (CPP; index of alcohol rewarding properties) in mice [101], and (6) alcohol-induced stimulation of locomotor activity in rats and mice (index of alcohol euphorigenic properties) [102,103,104,105]. …”

Discriminative Stimulus Effects of the GABAB Receptor-Positive Modulator rac-BHFF: Comparison with GABAB Receptor Agonists and Drugs of Abuse

“…In addition, they reduce self-administration of alcohol (Orru et al, 2005(Orru et al, , 2012Liang et al, 2006;Maccioni et al, 2007Maccioni et al, , 2008Maccioni et al, , 2009Maccioni et al, , 2010aMaccioni et al, , b, 2012Agabio et al, 2012), cocaine , and nicotine (Mombereau et al, 2007;Paterson et al, 2008;Vlachou et al, 2011). GABA B receptorpositive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction, because they may have a better side-effect profile than GABA B receptor agonists, based on the notion that selective enhancement of activated receptors has effects that differ from indiscriminate activation of all receptors.…”

Individualised Treatment of Alcohol Dependent Patients with Baclofen: A Clinical Observation

“…The activation of these receptors with the GABA B receptor agonist baclofen inhibits dopaminergic neurons indirectly and directly [7]. The importance of the GABA B receptor in the reinforcing and motivational properties of alcohol was confirmed [8].…”