Nicotinic Receptor Genetic Variation and Alcohol Reward

Summary

Participation Requirements

Description

Objectives: Alcohol use disorder (AUD) is a chronic disease that has a tremendously negative impact on individuals and their families and a substantial burden on society. Research on quantitative endophenotypes such as alcohol response, and their genetic and environmental determinants, is critical t...

Objectives: Alcohol use disorder (AUD) is a chronic disease that has a tremendously negative impact on individuals and their families and a substantial burden on society. Research on quantitative endophenotypes such as alcohol response, and their genetic and environmental determinants, is critical to understanding the risk for AUD. There has been a great interest in examining variation in target genes that may play a mechanistic role in the expression of these endophenotypes, such the missense single-nucleotide polymorphism (SNP) in the gene encoding the 5 subunit of the nicotinic acetylcholine receptor (CHRNA5) - rs16969968. Studies have shown that CHRNA5 A-allele carriers are at greater risk for nicotine addiction and smoking-related consequences. However, little work has been done to examine the effect of this SNP on alcohol use, dependence, or alcohol response. Given the high prevalence of nicotinic receptors on dopamine (DA) neurons in brain reward regions, and the high co-use and abuse of alcohol and nicotine, these receptors may play a critical role in modulating incentive salience and reward responses to alcohol. Thus, the goal of this project is to examine the influence of CHRNA5 variation and smoking status (smokers and non-smokers) on alcohol-related phenotypes, including intravenous alcohol self-administration (IV-ASA) behavior and neuroimaging responses to cues signaling alcohol rewards. Study Population: This study will include 128 male and female, non-dependent drinkers, 21-60 years of age. Participants will be stratified into equally-sized groups based on their smoking status (smokers and non-smokers) and rs16969968 genotype: 1). A-allele carriers (AA or AG genotype), and 2). G-allele homozygotes (GG genotype). The study will be open to all racial and ethnic groups, as long as the individual meets the genotype criteria. Participants will be in good health as determined by medical history, physical exam, ECG, and lab tests. Design: Following screening, participants will undergo three study visits. The first visit will include an IV alcohol self-administration (IV-ASA) session using the Computer-Assisted Infusion System (CAIS), which employs a physiologically-based pharmacokinetic (PBPK) model-based algorithm that allows participants free access to standardized alcohol infusions. During this session, breath alcohol concentrations (BrAC) and subjective responses will be measured as markers of the rewarding effects of alcohol. In another visit, participants will undergo a second IV-ASA session where they will have free-access to alcohol infusions along with the ability to control the rate of each individual self-administered infusion. This will provide an operant measure of sensitivity to rate of change of BrAC as an additional marker of the rewarding effect of alcohol. Finally, participants will undergo a magnetic resonance imaging (MRI) session where they will be scanned while performing the Alcohol-Food Incentive Delay (AFID) task, which assesses neural processing while responding to cues signaling alcohol reward. Additional fMRI task-based scans and a resting-state scan will also be obtained. Outcome Measures: The following measures will be examined as a function of smoking status (smokers and non-smokers) and CHRNA5 genotype. The influence of sex, age, and recent drinking history will be examined as covariates. Primary outcome measures include: (1a) BrAC exposure (peak BrAC, number of infusions, time to binge-level BrAC) during the free-access IV-ASA; (1b) BOLD response during the AFID task in neural regions associated with alcohol reward processing, including ventral striatum, amygdala, and insula. Secondary outcome measures include: (2a) resting state functional connectivity (rsFC) between the regions associated with the salience network, including dorsal anterior cingulate cortex, ventral striatum, and extended amygdala; (2b) preferred rate of self-infusion during the second IV-ASA session.

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