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

Department of Psychiatry, Alcohol Research Center, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 07/2005; 30(6):1193-203. DOI: 10.1038/sj.npp.1300688
Source: PubMed


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 alpha-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-alpha 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.

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    • "Genes encoding ionotropic gammaaminobutyric acid (GABA A ) receptors are associated with alcohol use disorders (Borghese and Harris, 2012; Covault et al., 2008; Edenberg et al., 2004). Single nucleotide polymorphisms (SNPs) in GABRG1 and GABRA2 have also been associated with various subjective responses to alcohol (Arias et al., 2014; Kareken et al., 2010; Pierucci-Lagha et al., 2005; Ray and Hutchison, 2009; Uhart et al., 2012) and to cues associated with alcohol intoxication (Kareken et al., 2010). Roh and colleagues (2011) used IV alcohol to hold BrAC steady at 50 mg/dl for 165 minutes in 110 moderate–heavy social drinkers and found that adaptive subjective responses to alcohol were affected by a combination of GABRA2 and ALDH2 SNP status. "
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    ABSTRACT: Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol. Copyright © 2015 by the Research Society on Alcoholism.
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    • "Specifically, individuals carrying one or two copies of the more common GABRA2 allele (which is not associated with AD) showed greater subjective responses to alcohol than did individuals carrying two copies of the allele associated with AD. These results are, to some extent, in agreement with previous studies (Haughey et al. 2008; Pierucci-Lagha et al. 2005). Another study (Kareken et al. 2010) examined the association between GABRA2 SNPs and the brain's reward system. "
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    ABSTRACT: One approach to identifying the causes of alcoholism, particularly without crossing ethical boundaries in human subjects, is to look at the person's genome (and particularly at the variations that naturally arise in the DNA) to identify those variations that seem to be found more commonly in people with the disease. Some of these analyses have focused on the genes that encode subunits of the receptor for the brain chemical (i.e., neurotransmitter) γ-aminobutyric acid (GABA). Different epidemiological genetic studies have provided evidence that variations in certain GABAA receptor (GABAA-R) subunits, particularly subunits α2 and γ1, are correlated with alcohol dependence. Manipulations of these genes and their expression in mice and rats also are offering clues as to the role of specific GABAA-Rs in the molecular mechanisms underlying alcoholism and suggest possibilities for new therapeutic approaches.
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    • "These findings suggest a more direct relationship between ethanol and α2-subunit containing GABAA receptors and may be resolved by considering the role of intermediate neurotransmitters. For example, inhibition of neurosteroid synthesis (which is activated by ethanol) attenuates differences between risk and protective haplotypes [23], suggesting that ethanol may indirectly facilitate transmission at α2-subunit containing receptors by increasing levels of neurosteroids. "
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    ABSTRACT: Human genetic studies have suggested that polymorphisms of the GABRA2 gene encoding the GABA(A) α2-subunit are associated with ethanol dependence. Variations in this gene also convey sensitivity to the subjective effects of ethanol, indicating a role in mediating ethanol-related behaviours. We therefore investigated the consequences of deleting the α2-subunit on the ataxic and rewarding properties of ethanol in mice. Ataxic and sedative effects of ethanol were explored in GABA(A) α2-subunit wildtype (WT) and knockout (KO) mice using a Rotarod apparatus, wire hang and the duration of loss of righting reflex. Following training, KO mice showed shorter latencies to fall than WT littermates under ethanol (2 g/kg i.p.) in both Rotarod and wire hang tests. After administration of ethanol (3.5 g/kg i.p.), KO mice took longer to regain the righting reflex than WT mice. To ensure the acute effects are not due to the gabra2 deletion affecting pharmacokinetics, blood ethanol concentrations were measured at 20 minute intervals after acute administration (2 g/kg i.p.), and did not differ between genotypes. To investigate ethanol's rewarding properties, WT and KO mice were trained to lever press to receive increasing concentrations of ethanol on an FR4 schedule of reinforcement. Both WT and KO mice self-administered ethanol at similar rates, with no differences in the numbers of reinforcers earned. These data indicate a protective role for α2-subunits, against the acute sedative and ataxic effects of ethanol. However, no change was observed in ethanol self administration, suggesting the rewarding effects of ethanol remain unchanged.
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