Pregnenolone and Ganaxolone Reduce Operant Ethanol Self-Administration in Alcohol-Preferring P Rats
Article first published online: 14 OCT 2010
Copyright © 2010 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 34, Issue 12, pages 2044–2052, December 2010
How to Cite
Besheer, J., Lindsay, T. G., O’Buckley, T. K., Hodge, C. W. and Morrow, A. L. (2010), Pregnenolone and Ganaxolone Reduce Operant Ethanol Self-Administration in Alcohol-Preferring P Rats. Alcoholism: Clinical and Experimental Research, 34: 2044–2052. doi: 10.1111/j.1530-0277.2010.01300.x
- Issue published online: 18 NOV 2010
- Article first published online: 14 OCT 2010
- Received for publication February 18, 2010; accepted May 25, 2010.
- Ethanol Self-Administration;
- Neuroactive Steroids;
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.