Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring p rats.

Neuroactive steroids modulate ethanol intake in several self-administration models with variable effects. The purpose of this work was to examine the effects of the long-acting synthetic GABAergic neurosteroid ganaxolone and the endogenous neurosteroid pregnenolone, a precursor of all GABAergic neuroactive steroids, on the maintenance of ethanol self-administration in an animal model of elevated drinking-the alcohol-preferring (P) rats. P rats were trained to self-administer ethanol (15% v/v) versus water on a concurrent schedule of reinforcement, and the effects of ganaxolone (0 to 30 mg/kg, subcutaneous [SC]) and pregnenolone (0 to 75 mg/kg, intraperitoneal [IP]) were evaluated on the maintenance of ethanol self-administration. After completion of self-administration testing, doses of the neuroactive steroids that altered ethanol self-administration were assessed on spontaneous locomotor activity. Finally, the effect of pregnenolone administration on cerebral cortical levels of the GABAergic neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone, 3α,5α-THP) was determined in both ethanol-experienced and ethanol-inexperienced P rats because pregnenolone is a precursor of these steroids. Ganaxolone produced a dose-dependent biphasic effect on ethanol reinforcement, as the lowest dose (1 mg/kg) increased and the highest dose (30 mg/kg) decreased ethanol-reinforced responding. However, the highest ganaxolone dose also produced a nonspecific reduction in locomotor activity. Pregnenolone treatment significantly reduced ethanol self-administration (50 and 75 mg/kg), without altering locomotor activity. Pregnenolone (50 mg/kg) produced a significant increase in cerebral cortical allopregnanolone levels. This increase was observed in the self-administration trained animals, but not in ethanol-naïve P rats. These results indicate that pregnenolone dose-dependently reduces operant ethanol self-administration in P rats without locomotor impairment, suggesting that it may have potential as a novel therapeutic for reducing chronic alcohol drinking in individuals that abuse alcohol.