GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

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Abstract
GABAA receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABAA receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABAA receptor α-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-α 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.