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

Background: Drugs like nalmefene interfere with opioid receptors. This might reduce drinking. The gene OPRM1 determines opioid receptor functions. Researchers want to see if nalmefene affects people s responses to alcohol cues. They also want to compare how nalmefene affects people with different forms of OPRM1. Objectives: To test nalmefene s effects on alcohol self-infusion and responses to alcohol cues. To test the role of different forms of OPRM1 on these effects. Eligibility: Healthy heavy drinkers ages 21 60: Women: over 15 drinks weekly Men: over 20 drinks weekly Design: Participants will be screened with: Medical history Physical exam Heart, blood, and urine tests Questionnaires Participants will have three 10-hour visits and one 2-hour follow-up visit. They will take a taxi. Visits are about 1 week apart. Before visits, participants cannot drink alcohol for 1 day or take medicine for 3 days. All study visits: Questionnaires Heart monitor Two-hour alcohol session: A needle guides a thin plastic tube into a vein in each arm. One tube receives alcohol. The other draws blood. Participants give themselves alcohol by pressing a button on a computer. Relaxing at the center until breath alcohol falls below 0.02 percent, or for 3 hours. Visits 2 and 3: Swallowing nalmefene or placebo. One-hour brain MRI: Participants lie on a table with a coil on their head. They press buttons in response to computer cues. Follow-up visit: participants will discuss their drinking habits.