Nicotinic Receptor Genetic Variation and Alcohol Reward

Alcohol Drinking

Functional Magnetic Resonance Imaging (fMRI), Alcohol Use, Polymorphism, Genetic, Magnetic Resonance Imaging (MRI), Smoking

Background: People with the brain disease AUD (alcohol use disorder) have a serious problem with drinking. Researchers want to study how different people react to alcohol, and how genes affect this. They will focus on a nicotine receptor gene that may increase a person s AUD risk. Objectives: To see if people with variations of a nicotine receptor gene take alcohol differently and have different brain responses to alcohol cues. Eligibility: Healthy adults ages 21 - 60. This study includes smokers and non-smokers. Design: Participation will be based on evaluation under the NIAAA natural history protocol (14-AA-0181) or a screening visit under this protocol. Participants will have two 9-hour visits. They must have no alcohol or non-prescription drugs before all visits and no food or drink before the first visit. At every visit, participants will: * Get a light meal * Have breath and urine tests * Get taxi rides there and back At visits 1, participants will: * Have a thin plastic tube inserted in an arm and connected to a pump for alcohol infusion. * Have sensors on their chest to monitor heart rate. * Sit in a chair for 2.5 hours and get alcohol by pushing a button. Their breath alcohol level will be monitored. * Answer questions about mood and effects of alcohol * Give blood samples * Relax at the clinic while their breath alcohol level drops At visit 2, participants will: * Answer questions and do computer tests * Have an alcoholic drink and a snack * Have a magnetic resonance imaging (MRI) scan. They will lie in a machine that takes pictures of the brain. They will do computer tasks. * Have another drink and snack * Relax until their alcohol level drops Participants will have a follow-up call after each visit.

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 4 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 based on evaluation under the NIAAA natural history protocol (14-AA-0181) or a screening visit under this protocol. Design: Participants will undergo two study procedure visits. One 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. Another visit, 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; resting state functional connectivity (rsFC) between the regions associated with the salience network, including dorsal anterior cingulate cortex, insula, ventral striatum, and extended amygdala.

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United States