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

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 a-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-a 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 ¼ 7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n ¼ 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.

Sex differences in the effect of finasteride on acute ethanol withdrawal severity in C57BL/6J and DBA/2J mice

“…That is, in men already taking finasteride for the treatment of benign prostatic hyperplasia and androgenetic alopecia, finasteride may not exacerbate withdrawal symptoms following alcohol consumption. The present findings, in conjunction with recent work indicating that finasteride decreased the subject effects of alcohol in humans (Pierucci-Lagha et al, 2005) and EtOH selfadministration in C57BL/6J mice (Ford et al, 2005), may be particularly important for a cohort of men who have also been diagnosed with alcoholism. Further studies are necessary to examine the effect of finasteride on withdrawal-related symptoms in humans.…”

The role of GABAA receptors in the development of alcoholism

“…The G allele of a synonymous exonic GABRA2 SNP rs279858, a tag allele for this same less frequent alcoholism risk haplotype, was associated with a higher daily probability of drinking and heavy drinking during the 12-week treatment and 12-month post-treatment period in alcoholics from the Project MATCH study (Bauer et al, 2007). This GABRA2 rs279858 G allele was also associated with decreased pleasurable effects for alcohol in social drinkers (Pierucci-Lagha et al, 2005). Furthermore, the subjective experiences of the social drinkers who had the rs279858 protective AA genotype could be manipulated by pre-treatment with finasteride, a metabolism blocker of the endogenous neurosteroids ALLO and THDOC,that diminished their subjective experiences of alcohol (Pierucci-Lagha et al, 2005).…”

“…This GABRA2 rs279858 G allele was also associated with decreased pleasurable effects for alcohol in social drinkers (Pierucci-Lagha et al, 2005). Furthermore, the subjective experiences of the social drinkers who had the rs279858 protective AA genotype could be manipulated by pre-treatment with finasteride, a metabolism blocker of the endogenous neurosteroids ALLO and THDOC,that diminished their subjective experiences of alcohol (Pierucci-Lagha et al, 2005). There was no effect of neurosteroid blockade on individuals with the rs279858 G risk allele, possibly because of a floor effect.…”

“…In healthy humans, ethanol induces changes in ALLO concentration that correlates with alcohol liking and desire for more alcohol (Pierucci-Lagha et al, 2006). Pre-treatment with finasteride (5α-reductase inhibitor) that reduces the synthesis of ALLO and THDOC, diminishes the subjective response to a moderate dose of alcohol in social drinkers (Pierucci-Lagha et al, 2005). Several studies in rodents have shown that ethanol-induced neuroactive steroids contribute to the acute behavioral effects of ethanol such as sedative-hypnotic (Van Doren et al, 2000;Khisti et al, 2003), anti-depressant (Hirani et al, 2002) and anxiolytic (Hirani et al, 2005).…”

Effects ofGABRA2Variation on Physiological, Psychomotor and Subjective Responses in the Alcohol Challenge Twin Study

“…One single-nucleotide polymorphism (SNP) within GABRA2 (rs279858) has been reported to affect subjective response to alcohol (Pierucci-Lagha et al, 2005). This report, being based on only 27 subjects, needs replication and extension.…”