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3255 Association between dopaminergic genetic variants, COMTrs4680 and DRD2rs1076560, and alcohol consumption and reward behaviors in non-dependent drinkers

ABSTRACT: OBJECTIVES/SPECIFIC AIMS: The objective of this exploratory study is to evaluate the relationship between the individual genetic variants in COMTrs4680 and DRDrs1076560 and relevant alcohol use behaviors (i.e. alcohol consumption and reward processing behaviors) in non-dependent drinkers within experimentally controlled IV-ASA CAIS sessions. The overall goal of this study is to begin gathering data on the influence of individual genetic variants on alcohol consumption and other drinking-related behaviors. This will aid in the creation of a polygenic model of risk for AUD which will provide more insight into how the mesolimbic pathway is affected by alcohol use. METHODS/STUDY POPULATION: Study population: The sample included male and female non-dependent drinkers (N=149). Genotypes for functional polymorphisms in COMT (rs4680) and DRD2 (rs1076560) genes were determined for all subjects from blood samples obtained during screening. Alcohol consumption was assessed using the 90-day Timeline Followback Interviews (TLFB). Study population demographics: Self-reported gender (53.5% identified as male); Self-reported race (61.2% identified as white); Age ranged from 21-46 years old, with 22 years being the mode. Experiment: Free access (open-bar) intravenous alcohol self-administration (IV-ASA) using the computer-assisted alcohol infusion system (CAIS) paradigm; Subjects had the choice of pressing a button ad libitum for IV alcohol infusions during the session, neurobehavioral questionnaires were collected throughout the 2.5-hr alcohol infusion session. Primary outcome measures included: Total Rewards, Peak breath alcohol concentration (BrAC) achieved, and Total Ethanol consumed. Statistical Analyses: Conducted using SPSS IBM Statistics Versions 1.0.0-2482; non-dependent drinkers were organized into two groups based on their genotypes, minor allele carriers and major allele homozygotes. Outcome measures were compared between genotype groups using analysis of variance or non-parametric Mann-Whitney U-test as appropriate. RESULTS/ANTICIPATED RESULTS: -We expect the genetic makeup of the sample to be reflective of larger genome samples that are publically available (e.g. e!Ensembl) - Initial analysis for COMTrs4680 did not reveal significant effects on IV-ASA measures. Specifically, the majo DISCUSSION/SIGNIFICANCE OF IMPACT: Alcohol Use Disorder (AUD) affects millions of men and women globally. The heterogeneity within AUD individuals has made it difficult to identify biological and/or psychological factors that could be targeted for the development of treatments. By using the human laboratory model of free access IV-ASA, this study evaluated the relationship between dopaminergic genetic variants, COMTrs4680 and DRDrs1076560, and alcohol consumption in non-dependent drinkers within a controlled experimental environment. This study will begin to evaluate genetic and behavioral data that can be used to create a polygenic model of risk for AUD, which will provide more insight as to how the mesolimbic reward pathway is affected by alcohol use and contributes to risk for AUD.

SUBMITTER: Ortega N

PROVIDER: S-EPMC6799251 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Project description:Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the "brain reward cascade," a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]).We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members.Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants.Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific "reward" phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.

Project description:Binge drinking refers to a pattern of alcohol intake that raises blood alcohol concentration to or above legal intoxication levels. It is common among young adults and is associated with health risks that scale up with alcohol intake. Acute intoxication depresses neural activity via complex signaling mechanisms by enhancing inhibition mediated by gamma-amino butyric acid (GABA), and by decreasing excitatory glutamatergic effects. Evidence primarily rooted in animal research indicates that the brain compensates for the acute depressant effects under the conditions of habitual heavy use. These neuroadaptive changes are reflected in neural hyperexcitability via downregulated inhibitory signaling, which becomes apparent as withdrawal symptoms. However, human evidence on the compensatory reduction in GABA signaling is scant. The neurochemical aspect of this mechanistic model was evaluated in the present study with proton magnetic resonance spectroscopy (1H-MRS) which is sensitive to GABA plus macromolecule signal (GABA + ). Furthermore, we examined sex differences in GABA + levels as a function of a recent history of binge drinking, given interactions between endogenous neurosteroids, GABA signaling, and alcohol. The study recruited young adult women and men (22.2 ± 2.8 years of age) who were classified as binge drinkers (BDs, N = 52) if they reported ≥ 5 binge episodes in the previous six months. Light drinkers (LDs, N = 49) reported drinking regularly, but not exceeding ≤ 2 binge episodes in the past six months. GABA-edited 1H-MR spectra were acquired from the occipital cortex at 3 T with the MEGA-PRESS sequence. GABA + signal was analyzed relative to water and total creatine (Cr) levels as a function of binge drinking history and sex. Controlling for within-voxel tissue composition, both GABA + indices showed decreased GABA + levels in BDs relative to LDs. The reduced GABA + concentration was associated with occasional high-intensity drinking in the BD group. This evidence is consistent with compensatory GABA downregulation that accompanies alcohol misuse, tipping the excitation/inhibition balance towards hyperexcitability. Analysis of the time course of GABA + neuroplasticity indicated that GABA + was lowest when measured one day after the last drinking occasion in BDs. While the BD vs LD differences were primarily driven by LD women, there was no interaction between Sex and a history of binge drinking. GABA + was higher in LD women compared to LD men. Aligned with the allostasis model, the mechanistic compensatory GABA downregulation observed in young emerging adults engaging in occasional binge drinking complements direct neural measures of hyperexcitability in BDs. Notably, these results suggest that neuroadaptation to alcohol is detectable at the levels of consumption that are within a normative range, and may contribute to adverse health outcomes.

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3255 Association between dopaminergic genetic variants, COMTrs4680 and DRD2rs1076560, and alcohol consumption and reward behaviors in non-dependent drinkers

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