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GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers.

ABSTRACT: The heritable risk for alcohol use disorder (AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of 2 AUD-risk-associated single nucleotide polymorphisms, GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting.In total, 93 self-identified European American social drinkers underwent 3 blinded laboratory sessions in which they received intravenous infusions of ethanol at 3 target blood alcohol levels (0.00 mg%, 40 mg%, and 100 mg%) using a "clamp" procedure. The self-reported Biphasic Alcohol Effects Scale (BAES) stimulation and sedation subscales were the primary outcome measures. We examined the effects of these 2 genetic variants on subjective response to alcohol.For the BAES stimulation subscale scores, adjusting for age, baseline scores, and time effects, individuals with 2 copies of the GABRA2 rs279858 C "risk" allele for AUD exhibited the greatest stimulant responses to high-dose alcohol compared to the other risk allele counts (dose-by-allele count interaction effect, p = 0.001, post hoc contrast for C-allele, p = 0.012). For the BAES sedation subscale scores, adjusting for the same covariates, we detected a dose-by-allele count interaction effect (p = 0.0044) such that subjects with 2 copies of the GRIK1 C "risk" allele reported the greatest sedative response to the higher alcohol dose.This study suggests that gene variants contributing to the risk for AUD may alter features of the alcohol dose-response relationship in specific ways. GABRA2 rs279858*C enhances stimulant responses to higher levels of alcohol, while the GRIK1 rs2832407*C-allele increases sedative responses. In summary, GRIK1 and GABRA2 variants have distinct effects on the dose-related subjective response to intravenous alcohol in humans.

SUBMITTER: Yang BZ

PROVIDER: S-EPMC5764175 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers.

Yang Bao-Zhu BZ Arias Albert J AJ Feinn Richard R Krystal John H JH Gelernter Joel J Petrakis Ismene L IL

Alcoholism, clinical and experimental research 20171113 12

<h4>Background</h4>The heritable risk for alcohol use disorder (AUD) is expressed partly through alterations in subjective alcohol response. In this study, we investigated the effects of 2 AUD-risk-associated single nucleotide polymorphisms, GABRA2 rs279858 and GRIK1 rs2832407, on the subjective response to alcohol administered intravenously to healthy social drinkers in a laboratory setting.<h4>Methods</h4>In total, 93 self-identified European American social drinkers underwent 3 blinded labora ...[more]

PMID: 29131352

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Project description:IntroductionAlcohol is among the most commonly used psychoactive drugs, yet it can produce markedly different subjective effects in different people. Certain effects, including both heightened stimulatory effects and lesser sedative effects, are thought to predict repeated or excessive use. However, we do not fully understand the nature of these individual differences or their relationships to alcohol consumption. This controlled laboratory study examined subjective and physiologic responses to a moderate dose of alcohol in social drinkers in relation to the subjects' decision to consume alcohol.MethodsHealthy adult volunteers (N = 95) participated in a 5-session double-blind alcohol choice study. On the first 4 sessions, they received alcohol (0.8 g/kg) and placebo in alternating order, and on the fifth session, they chose and consumed whichever of the 2 they preferred. During each session, participants completed the Profile of Mood States (POMS) and Biphasic Alcohol Effects Scale (BAES) questionnaires and had their vitals recorded every 30 minutes. We compared subjective and physiologic response to alcohol during the sampling sessions in participants who chose alcohol or placebo on session 5.ResultsOf the 95 participants, 55 chose alcohol (choosers) and 40 chose placebo (nonchoosers). In the full sample, alcohol produced its expected effects (e.g., increased friendliness, elation, and vigor (POMS), and stimulation and sedation (BAES)). The chooser and nonchooser groups did not differ in demographic characteristics, blood alcohol levels, or cardiovascular measures. However, the choosers experienced greater alcohol-induced increases in positive mood (POMS) and liked the drug more, whereas the nonchoosers experienced greater anger, anxiety (POMS), and sedation (BAES) after alcohol.ConclusionBoth greater positive mood effects and lesser sedative effects after alcohol predicted preference under controlled conditions, suggesting that both factors can predict future consumption of alcohol.

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:BackgroundAcute alcohol intoxication has wide-ranging neurobehavioral effects on psychomotor, attentional, inhibitory, and memory-related cognitive processes. These effects are mirrored in disruption of neural metabolism, functional activation, and functional network coherence. Metrics of intraregional neural dynamics such as regional signal variability (RSV) and brain entropy (BEN) may capture unique aspects of neural functional capacity in healthy and clinical populations; however, alcohol's influence on these metrics is unclear. The present study aimed to elucidate the influence of acute alcohol intoxication on RSV and to clarify these effects with subsequent BEN analyses.Methods26 healthy adults between 25 and 45 years of age (65.4% women) participated in 2 counterbalanced sessions. In one, participants consumed a beverage containing alcohol sufficient to produce a breath alcohol concentration of 0.08 g/dl. In the other, they consumed a placebo beverage. Approximately 35 minutes after beverage consumption, participants completed a 9-minute resting-state fMRI scan. Whole-brain, voxel-wise standard deviation was used to assess RSV, which was compared between sessions. Within clusters displaying alterations in RSV, sample entropy was calculated to assess BEN.ResultsCompared to the placebo, alcohol intake resulted in widespread reductions in RSV in the bilateral middle frontal, right inferior frontal, right superior frontal, bilateral posterior cingulate, bilateral middle temporal, right supramarginal gyri, and bilateral inferior parietal lobule. Within these clusters, significant reductions in BEN were found in the bilateral middle frontal and right superior frontal gyri. No effects were noted in subcortical or cerebellar areas.ConclusionsFindings indicate that alcohol intake produces diffuse reductions in RSV among structures associated with attentional processes. Within these structures, signal complexity was also reduced in a subset of frontal regions. Neurobehavioral effects of acute alcohol consumption may be partially driven by disruption of intraregional neural dynamics among regions involved in higher-order cognitive and attentional processes.

Project description:AimsTo test whether non-dependent drinkers show place preference for a location paired with alcohol, and to test if the amount of time spent in the alcohol-paired location is related to self-reported subjective alcohol effects experienced in that environment.DesignTwo groups of subjects completed six conditioning sessions: three with alcohol (0.8 g/kg) and three without alcohol. Individuals were assigned randomly to two groups, paired and unpaired, in a 2 : 1 ratio. The paired group (n = 78) received alcohol in one testing room and no-alcohol in another testing room (biased assignment). The unpaired group (n = 30) received alcohol and no-alcohol in each testing room.SettingHuman Behavioral Pharmacology Laboratory, University of Chicago, Chicago, IL, USA (single site).ParticipantsHealthy male and female social drinkers (n = 108) aged 21-40 years participated in the study (consisting of 10 separate laboratory visits) between March 2012 and August 2014 (an average of 36 separate subject visits per month).MeasurementsThe primary outcome measure was the pre- to post-conditioning change in the percentage of time spent in the least preferred room (obtained during drug-free exploration tests conducted at separate visits before and after the six conditioning sessions were completed). Secondary measures included self-reported subjective mood and drug effects obtained during the conditioning sessions.FindingsThe groups differed in the change in the percentage of time spent in the initially least preferred room, from pre- to post-conditioning; paired group = 11.0%, unpaired group = -1.4%, mean difference = 12.4%, 95% confidence interval = 1.9-23.0, P = 0.02. The change in the percentage of time spent in the least-preferred room was related to the self-reported sedative effects of alcohol during conditioning sessions among paired group participants only.ConclusionsNon-dependent consumers of alcohol appear to develop a behavioral preference for locations paired with alcohol consumption, more so for those who experience sedative effects from alcohol in those locations.

Dataset Information

GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers.

Publications

GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers.

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