Reducing effect of the positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, on alcohol intake in alcohol-preferring rats
ABSTRACT The gamma-aminobutyric acidB (GABA(B)) receptor full agonists, baclofen and CGP44532, have been found to suppress different aspects of alcohol drinking behavior, including acquisition and maintenance, in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to assess whether this capability extends to the recently synthesized, positive allosteric modulators of the GABA(B) receptor, 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783). In the "acquisition" experiments, CGP7930 (0, 25, 50 and 100 mg/kg; i.g.) and GS39783 (0, 6.25, 12.5 and 25 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-naive sP rats. In the "maintenance" experiments, (0, 50 and 100 mg/kg; i.g.) and GS39783 (0, 50 and 100 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-experienced sP rats. Alcohol intake was evaluated under the standard, homecage 2-bottle "alcohol (10%, v/v) vs water" regimen with unlimited access for 24 h/day. Both CGP7930 and GS39783 dose-dependently suppressed the acquisition of alcohol drinking behavior. In the "maintenance" experiments, CGP7930 and GS39783 reduced daily alcohol intake by 30-40% only at the highest dose when compared to vehicle-treated rats; this effect tended to vanish on continuing treatment. The results of the present study suggest that positive allosteric modulation of the GABA(B) receptor produced an effect on alcohol drinking behavior similar to that produced by GABA(B) receptor full agonists. These data also suggest that positive allosteric modulation of the GABA(B) receptor may constitute a potential strategy for developing new drugs for treating alcohol dependence.
SourceAvailable from: Anna Sadakierska-Chudy[Show abstract] [Hide abstract]
ABSTRACT: γ-Aminobutyric acid B (GABAB) receptors and their ligands are postulated as potential therapeutic targets for the treatment of several brain disorders, including drug dependence. Over the past fifteen years positive allosteric modulators (PAMs) have emerged that enhance the effects of GABA at GABAB receptors and which may have therapeutic effects similar to those of agonists but with superior side-effect profiles. This review summarizes current preclinical evidence supporting a role of GABAB receptor PAMs in drug addiction in several paradigms with relevance to reward processes and drug abuse liability. Extensive behavioral research in recent years has indicated that PAMs of GABAB receptors may have a therapeutic efficacy in cocaine, nicotine, amphetamine and alcohol dependence. The magnitude of the effects observed are similar to that of the clinically approved drug baclofen, an agonist at GABAB receptors. Moreover, given that anxiolytic effects are also reported with such ligands they may also benefit in mitigating the withdrawal from drugs of abuse. In summary, a wealth of data now supports the benefits of GABAB receptor PAMs and clinical validation is now warranted.Neuropharmacology 06/2014; DOI:10.1016/j.neuropharm.2014.06.016 · 4.82 Impact Factor
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ABSTRACT: 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).Frontiers in Neuroscience 06/2014; 8:140. DOI:10.3389/fnins.2014.00140
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ABSTRACT: Treatment with positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs) inhibits several alcohol-motivated behaviors in rodents, including operant, oral alcohol self-administration. The present study assessed the effects of (a) repeated administration of the GABAB PAMs, GS39783, and rac-BHFF and (b) a combination of an ineffective dose of either GS39783, or rac-BHFF, and an ineffective dose of the prototypic GABAB receptor agonist, baclofen, on operant, oral alcohol self-administration. Studies were conducted using selectively bred Sardinian alcohol-preferring (sP) rats exposed to a standard procedure of fixed ratio (FR) 4 (FR4) schedule of reinforcement for 15 % (v/v) alcohol. Repeated treatment with GS39783 (50 mg/kg, i.g.) or rac-BHFF (50 mg/kg, i.g.) produced an initial 40 % reduction in number of lever responses for alcohol and amount of self-administered alcohol that was maintained unaltered throughout the 10-day period of the GS39783 treatment and increased throughout the 5-day period of the rac-BHFF treatment. Combination of per se ineffective doses of GS39783 (5 mg/kg, i.g.), or rac-BHFF (5 mg/kg, i.g.), and baclofen (1 mg/kg, i.p.) reduced, by 35-45 %, both number of lever responses for alcohol and amount of self-administered alcohol. GS39783 and rac-BHFF (a) reduced alcohol reinforcing properties when given repeatedly, with no development of tolerance, and (b) potentiated baclofen effect. Both sets of data possess translational interest, as they suggest potential effectiveness of GABAB PAMs under chronic treatment and selective potentiation of baclofen effect.Psychopharmacology 11/2014; DOI:10.1007/s00213-014-3815-8 · 3.99 Impact Factor