Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Acute Tolerance; Alcohol Use Disorders; Family History of Alcoholism; GABA Receptors; Intravenous Alcohol.

Copyright © 2015 by the Research Society on Alcoholism.

Figures

Figure 1. Session design

Subjective perceptions of alcohol were collected at the beginning and end of Block 0, Block 1, and Block 2, then averaged to give a single measurement for each block.

Figure 2. The Subjective Perceptions Assessment

The 7 questions were presented one at a time, in random order, at the beginning and end of each block. For questions 1–6, subjects rated their perceptions by moving a pointer along a visual analog scale anchored at 5 positions (coded from 0–100). For question 7, subjects estimated how many drinks it would take to create their current perceptions by moving a pointer on a scale ranging from 0 to 10 in half-drink increments. After the first assessment, the pointer was presented in the position selected for that question on the previous assessment. During the practice session, subjects were instructed to place the slider at 0 for number of Drinks, and at “Not at all” for Intoxicated and Enjoy. For Stimulated, Tired, Relaxed and Anxious, they were told to move the slider to reflect their current perceptions, independent of the effect of alcohol. Subjects were required to read each question aloud before moving the slider. Responses were automatically time-stamped and logged; subjects were able to answer all 7 questions in less than a minute.

Figure 3. Recent drinking history by subgroup

Mean and SEM for recent drinking history (drinks/drinking day in the last 30 days) grouped by gender, family history of alcoholism, GABRG1 genotype, and GABRA2 genotype. * indicates P=0.001.

Figure 4. Initial and Adaptive Response to Alcohol

Mean and SEM of (A.) initial and (B.) adaptive response to alcohol scores for each of the seven subjective measures are shown. Black bars represent the mean scores for all subjects during the alcohol infusion; striped bars represent the mean scores during the placebo (saline) infusion; estimated number of drinks was multiplied by 10 so that it could be shown on the same scale as the other measures. Negative values of the adaptive response to alcohol reflect acute (within-session) tolerance (return toward baseline), while positive values reflect acute sensitization.

Figure 5. Adaptive response to alcohol as moderated by genotype and recent drinking history

This graph illustrates the significant genotype by recent drinking history interaction. Mean and SEM for PC1 is shown for GABRA2 rs279858 genotypes, with subjects divided by a median split into either lower (black bars) or higher (striped bars) drinks per drinking day. Group N’s are indicated above the bars. All groups, on average, showed tolerance, but the relative degree varied.