Alcohol has major effects on GABA A receptors, which are composed of 5 subunits. Several studies have shown an association between alcoholism and genetic alterations in the GABA A receptor system. The frequency of a specific genetic variation in the GABA A alpha-2 subunit is increased in alcoholics and this variation confers less of a subjective response to alcohol in social drinkers.There is evidence that this variation reduces the response to neurosteroids since inhibition of neurosteroid syntheses reduces the subjective response to alcohol in individuals without but not with this variation.Alcoholics with this variation respond less well to treatment with twelve-step facilitation.These findings suggest that genetic variations in the GABA system that reduce the response to alcohol increase the risk of developing alcohol dependence.
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The GABA-A receptor alpha-2 subunit is involved in the subjective effects of alcohol.
Genetic Variation in the GABAA Receptor Alpha-2 Subunit Alters the Subjective Effects of Alcohol and Subjective Effects of Alcohol are Inhibited by Finasteride
27 healthy social drinkers mean age 30, drank 3 drinks of alcohol starting 30 min before self ratings were obtained when blood alcohol was about 60 mg/100 ml. Finasteride which blocks synthesis of some neuroactive steroids or placebo was administered 100 mg 26 hrs and 100 mg 2 hrs before alcohol drinking. There is an increase in the G allele frequency of theGABAAreceptor alpha-2 subunit (SNP, 2073557 – rs 279858) in alcoholics compared to controls. Social drinkers who carried the G allele had decreased subjective stimulation from alcohol. Inhibition of neurosteroid synthesis reduced subjective effects of alcohol in social drinkers without a G allele. This indicates that a genetic variant associated with alcoholism confers a reduced subjective response to alcohol in social drinkers and that neurosteroids are involved in producing some of the subjective effects of alcohol.(Constructed from data in Pierucci – Lagha, A. et al. Neuropsychopharmacology, 30: 1193, 2005) ©2010 NBEP
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The GABA-A alpha 2 subunit predicts drinking and interacts with treatment.
Genetic Variation in the GABAA Receptor Alpha-2 (GABRA2) Subunit Predicts Drinking in Alcohol Dependence and Interacts with Treatment
547 subjects with a G allele of the GABRA2 and 265 without a G allele (SNP - rs279858) had a 12 week treatment with either CBT, MET or TSF (from project MATCH research group). Over the treatment period and follow up subjects with a G allele had a greater likelihood of drinking (p < .0001) and a significant interaction with treatment type (p < .0001), compared to those without a G allele, the interaction effect was most evident for TSF. Similar results were found for heavy drinking. Genetic vulnerability not only predicts drinking but it also interacts with the effectiveness of treatment. (Constructed from data in Bauer, L.O. et al. Alcohol Clin Exp Res, 31: 1780, 2007) ©2010 NBEP
