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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.

SUBMITTER: Kosobud AE

PROVIDER: S-EPMC4490958 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Kosobud Ann E K AE Wetherill Leah L Plawecki Martin H MH Kareken David A DA Liang Tiebing T Nurnberger John L JL Windisch Kyle K Xuei Xiaoling X Edenberg Howard J HJ Foroud Tatiana M TM O'Connor Sean J SJ

Alcoholism, clinical and experimental research 20150619 7

<h4>Background</h4>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.<h4>Methods</h4>One hundred and thirty-two ...[more]

PMID: 26087834

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Project description: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 ?-aminobutyric acid A (GABA(A)) receptor ?2 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.

Project description:BACKGROUND:Alcohol use disorders are associated with single-nucleotide polymorphisms in GABRA2, the gene encoding the GABAA receptor ?2-subunit in humans. Deficient GABAergic functioning is linked to impulse control disorders, intermittent explosive disorder, and to drug abuse and dependence, yet it remains unclear whether ?2-containing GABAA receptor sensitivity to endogenous ligands is involved in excessive alcohol drinking. METHODS:Male wild-type (Wt) C57BL/6J and point-mutated mice rendered insensitive to GABAergic modulation by benzodiazepines (BZD; H101R), allopregnanolone (ALLO) or tetrahydrodeoxycorticosterone (THDOC; Q241M), or high concentrations of ethanol (EtOH) (S270H/L277A) at ?2-containing GABAA receptors were assessed for their binge-like, moderate, or escalated chronic drinking using drinking in the dark, continuous access (CA) and intermittent access (IA) to alcohol protocols, respectively. Social approach by mutant and Wt mice in forced alcohol abstinence was compared to approach by EtOH-naïve controls. Social deficits in forced abstinence were treated with allopregnanolone (0, 3.0, 10.0 mg/kg, intraperitoneal [i.p.]) or midazolam (0, 0.56, 1.0 mg/kg, i.p.). RESULTS:Mice with BZD-insensitive ?2-containing GABAA receptors (H101R) escalated their binge-like drinking. Mutants harboring the Q241M point substitution in Gabra2 showed blunted chronic intake in the CA and IA protocols. S270H/L277A mutants consumed excessive amounts of alcohol but, unlike wild-types, they did not show forced abstinence-induced social deficits. CONCLUSIONS:These findings suggest a role for: (i) H101 in species-typical binge-like drinking, (ii) Q241 in escalated chronic drinking, and (iii) S270 and/or L277 in the development of forced abstinence-associated social deficits. Clinical findings report reduced BZD-binding sites in the cortex of dependent patients; the present findings suggest a specific role for BZD-sensitive ?2-containing receptors. In addition, amino acid residue 241 in Gabra2 is necessary for positive modulation and activation of GABAA receptors by ALLO and THDOC; we postulate that neurosteroid action on ?2-containing receptor may be necessary for escalated chronic EtOH intake.

Project description:BackgroundSelf-reported consumption is pervasive in alcohol research, though retrospective recall bias is a concern. Fine-grained methods are designed to limit retrospection; yet, discrepancies can arise when comparing responses on fine-grained surveys with responses to retrospective surveys across weeks or months. Many fine-grained studies use both repeated daily surveys (RDS) and end-of-day (EOD) summaries, but little research has examined whether these survey types are consistent. The purpose of this study was to quantify the magnitude and directionality of discrepancy between EOD summaries and RDS and identify alcohol-related predictors of discrepancy.MethodsAs a part of a larger study, college student alcohol and cannabis users (N = 341; 53% women; Mage = 19.79 years) were recruited to complete 56 days of data collection, including 5 daily assessments of their substance use and related constructs, one of which included an EOD summary of the previous day. Generalized linear mixed-effects models were used to examine between- and within-person predictors of a 5-category, discrepancy outcome: no discrepancy, low discrepancy where RDS < EOD, low discrepancy where EOD < RDS, high discrepancy where RDS < EOD, and high discrepancy where EOD < RDS.ResultsDiscrepancies between EOD and RDS were observed in both directions. Alcohol problems predicted more alcohol consumption reported on the EOD survey than across RDS. Within-person alcohol quantity and hourly rate of consumption were most strongly related to less alcohol consumption reported on the EOD survey. Between- and within-person peak subjective intoxication and within-person liquor consumption were associated with discrepancies in both directions.ConclusionsSurveys requiring more retrospection may overestimate alcohol consumption in problematic drinkers and underestimate consumption on days where more alcohol is consumed than typical. Evidence also suggests that greater day-to-day instability in alcohol behavior is linked to less consistent reporting overall. More research is needed to discern factors contributing to inconsistent reporting on fine-grained surveys to maximize the validity of reports.

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

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

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