Reducing effect of the positive allosteric modulators of the GABA B receptor, CGP7930 and GS39783, on alcohol intake in alcohol-preferring rats

Abstract

The γ-aminobutyric acid B (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.