Title: Effect of Opioid Receptor Modulation on Alcohol Self-Administration and Neural Response to Alcohol Cues in Heavy Drinkers: Role of OPRM1 Gene Variation

Previous studies have shown that the opioid receptor modulator nalmefene can reduce heavy drinking among alcoholics. Genetic variation at the micro-opioid receptor gene locus, OPRM1, specifically the A118G polymorphism, is associated with differential subjective responses to alcohol. Further, the A118G polymorphism has been shown to moderate the effect of opioid receptor modulators on alcohol consumption. However, the role of A118G on nalmefene s effectivenes, and the neural substrates underlying nalmefene s therapeutic effect remain to be explored in humans. Objective: To evaluate the effect of nalmefene on alcohol self-infusion and neural response to alcohol cues in healthy male and female heavy drinkers, and to examine the role of the OPRM1 A118G polymorphism on this effect. Study population: Participants will be 21-60 year-old male and female heavy drinkers in good health, as determined by medical history, physical exam, and ECG and lab tests. Participants with current Axis-I mood, anxiety or substance use diagnoses, except alcohol dependence, will be excluded. Participants will be divided into 2 genotypic groups: Group 1 (AA) will include participants homozygous for the major 118A allele (118AA genotype), and group 2 (GX) will include participants carrying 1 or 2 copies of the variant 118G allele (118AG or 118GG genotype). Design: Participants will undergo 3 study sessions. In the first session, participants will complete an intravenous alcohol self-administration (IV-ASA) where they will have an open bar phase to determine their baseline level of alcohol consumption in the laboratory, as well as to obtain data on tolerability and subjective measures of alcohol effects. In the second and third sessions, participants will receive a single dose of either nalmefene or placebo, in counter-balanced order, before completing functional magnetic resonance imaging (fMRI) scans and IV-ASA procedures. The fMRI scans will include a task where participants will see cues that indicate the possibility of earning alcohol rewards to examine the neural substrates involved in processing alcohol cues, and a task designed to measure neural responses during anticipation and processing of aversive events. The difference in alcohol self-infusions between the two sessions will be compared between the two genotypic groups. Outcome measures: The primary outcome measures are: (1) nalmefene-induced changes in IV alcohol self-administration; (2) nalmefene-induced BOLD signal changes in neural regions associated with alcohol reward processing, including ventral striatum, amygdala, and insula.;Secondary outcome measures include: (1) Nalmefene-induced BOLD signal changes in neural processing of aversive stimuli during fMRI; (2) Genotypic modulation (at the OPRM1 118 location) of nalmefene s effects on primary outcome measures (BOLD signal change during alcohol reward processing and IV alcohol self-administration).