1. ¹Department of Psychiatry, Alcohol Research Center, University of Connecticut School of Medicine, Farmington, CT, USA
2. ²Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA
3. ³Departments of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC, USA

Correspondence: Dr HR Kranzler, Department of Psychiatry, MC2103, Health Center, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030, USA. Tel: +1 860 679 4151; Fax: +1 860 679 1316; E-mail: kranzler@psychiatry.uchc.edu

Received 6 May 2004; Revised 10 December 2004; Accepted 15 December 2004; Published online 9 February 2005.

Abstract

GABA_A receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABA_A receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABA_A receptor -2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5- steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n=7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n=20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.