Treatment with and withdrawal from finasteride alter ethanol intake patterns in male C57BL/6J mice: potential role of endogenous neurosteroids?
Exogenous administration of the gamma-aminobutyric acid (GABA)-ergic neurosteroid allopregnanolone (ALLO) can increase ethanol intake in rats and mice. To determine the contribution of endogenous neurosteroids (i.e., ALLO and related pregnane steroids) in the regulation of established ethanol consumption patterns in male C57BL/6J (B6) mice, the 5alpha-reductase (5alpha-R) enzyme inhibitor, finasteride (FIN), was chronically administered and then subsequently withdrawn. Mice were provided daily 2-h limited access to a 10% vol/vol ethanol solution (10E) and water in lickometer chambers during the dark phase. Following the establishment of stable 10E intake patterns, mice were injected intraperitoneally with either vehicle (20% wt/vol 2-hydroxypropyl-beta-cyclodextrin; n=8) or FIN (50 mg/kg; n=16) for 7 days. Effects of withdrawal from FIN treatment were subsequently assessed for an additional 7 days. Ethanol intakes were significantly decreased with acute FIN treatment (days 1-3) and during early withdrawal (days 1-3). Acute FIN treatment was also associated with an extended latency to first bout, reduced first bout size, and greatly attenuated sipper contact count during the initial 20-min interval of 10E access. These findings collectively indicated that acute FIN treatment markedly attenuated the initiation of 10E consumption during the limited access sessions. The influence of FIN on 10E intake patterns was largely dissipated with chronic treatment, suggesting that compensatory changes in neurosteroid modulation of inhibitory tone may have occurred. Thus, acute FIN treatment modulated ethanol intake patterns in a manner opposite to that previously demonstrated for a physiologically relevant, exogenous ALLO dose, consistent with the ability of a alpha-R inhibitor to block ALLO biosynthesis. Manipulation of endogenous neurosteroid activity via biosynthetic enzyme inhibition or antagonism of steroid binding to the GABA type A receptor may prove to be a beneficial pharmacotherapeutic strategy in the intervention of alcohol abuse and alcoholism.
Ford
Matthew M
MM
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239-3098, USA. fordma@ohsu.edu
Nickel
Jeffrey D
JD
Finn
Deborah A
DA
D000428:Alcohol Drinking / Q000188:drug therapy; D000818:Animals; D004326:Drinking / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood; D018120:Finasteride / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011280:Pregnanolone / Q000037:antagonists & inhibitors / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D012646:Self Administration; D013256:Steroids / Q000502:physiology*
D004791:Enzyme Inhibitors; D011963:Receptors, GABA-A; D013256:Steroids; D000431:Ethanol; D018120:Finasteride; D011280:Pregnanolone