Role of GABRA2 in Moderating Subjective Responses to Alcohol

Abstract

Background Human twin studies have shown that certain responses to alcohol, including subjective perceptions, are genetically influenced. Previous studies have provided evidence that a low level of response to alcohol predicts future alcohol use disorders in humans. Recent genetic studies suggest an association between alcohol dependence and genetic variation in the γ-aminobutyric acid A (GABAA) receptor α2 subunit gene (GABRA2). Based on a haplotypic association of alcohol dependence with GABRA2, we investigated whether GABRA2 alleles are associated with the subjective responses to clamped alcohol concentration. Methods One hundred and ten healthy social drinkers (53 men) underwent the alcohol clamp. Fifteen minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 50 ± 5 mg/dl for 165 minutes. Subjective physiologic responses to alcohol and stimulant and sedative effects of alcohol were measured repeatedly during the alcohol clamp. Because aldehyde dehydrogenase 2 (ALDH2) has been shown to have a great impact on the subjective responses to alcohol, we divided subjects by ALDH2 genotype for further analyses. To examine the role of genetic variation in GABRA2, 7 single nucleotide polymorphisms (SNPs) that were informative in association studies were included as factors in the analysis. Results Among these 7 SNPs, 3 SNPs (rs279869, rs279858, and rs279837) located in the middle of the GABRA2 gene showed significant associations with subjective effects of alcohol. Subjects with 1 or 2 copies of the more common allele showed greater subjective responses to alcohol than did individuals homozygous for the alcohol dependence–associated allele regardless of ALDH2 genotype. Conclusions These findings confirm and extend the observation that the GABRA2 alleles affect the subjective responses to alcohol, and suggest that the genetic variations in GABRA2 might play a role in the risk of alcohol use disorders by moderating the subjective effects of alcohol.

Dutasteride reduces alcohol’s sedative effects in men in a human laboratory setting and reduces drinking in the natural environment

“…The results of the earlier study also contrast with other more recent reports that GABRA2 alleles, which are overrepresented in alcohol dependence subjects, were associated with a greater “high” following alcohol administration (Kareken et al 2010; Arias et al 2014). The lack of a GABRA2 genotype×alcohol interaction on BAES stimulation and sedation subscales reported herein is consistent with the lack of GABRA2 genotype moderation of alcohol effects on the BAES reported by three other groups examining moderately large samples (Haughey et al 2007; Roh et al 2011; Uhart et al 2013). …”

Genetic Influences on the Development of Alcoholism

“…Two subsequent studies in the COGA dataset have shown that the original evidence for association with AUD derived only from individuals with comorbid illicit drug dependence [48] and in adolescents, GABRA2 is associated with childhood conduct disorder symptoms, known to be a predictor of later-onset AUD [49]. Furthermore, GABRA2 variation appears to influence the subjective response to alcohol [50] and an fMRI study using a monetary incentive delay task has shown that GABRA2 variation is probably associated with impulsivity through variation of insula activity responses [51]. …”

Alcohol use disorders and current pharmacological therapies: the role of GABAA receptors

“…In human brain imaging studies, a persistent down-regulation of central GABA A Rs in early abstinence was demonstrated [52][53][54] . One hundred and ten healthy social drinkers (53 men) in a drinking study showed that the GABRA2 gene is associated with subjective (pleasant or unpleasant sensations) effects of alcohol, suggesting that GABRA2 may play a role in the risk of developing alcohol use disorders by moderating the subjective effects of alcohol [55] . However, the neurobiological basis by which genetic variation and in which brain region translates into alcohol dependence is largely unknown.…”