Interactive effects of OPRM1 and DAT1 genetic variation on subjective responses to alcohol.

AIMS Subjective response to alcohol represents a marker of alcoholism risk. The A118G single-nucleotide polymorphism (SNP) of the mu opioid receptor (OPRM1) gene has been associated with subjective response to alcohol. Recently, the dopamine transporter (DAT1) variable number of tandem repeat (VNTR; SLC6A3) has been found to interact with the OPRM1 A118G SNP in predicting neural and behavioral responses to naltrexone and to alcohol. This exploratory study examines the OPRM1 × DAT1 interaction on subjective responses to alcohol. METHODS Non-treatment-seeking problem drinkers (n = 295) were assessed in the laboratory for alcohol dependence. Following prospective genotyping for the OPRM1 gene, 43 alcohol-dependent individuals were randomized to two intravenous infusion sessions, one of alcohol (target BrAC = 0.06 g/dl) and one of saline. Measures of subjective responses to alcohol were administered in both infusion sessions. RESULTS Analyses revealed significant Alcohol × OPRM1 × DAT1 interactions for alcohol-induced stimulation, vigor and positive mood as well as significant Alcohol × OPRM1 × DAT1 × Time interactions for stimulation and positive mood. These effects were such that, compared with other genotype groups, OPRM1 G-allele carriers + DAT1 A10 homozygotes reported steeper increases in stimulation and positive mood across rising BrAC, when compared with placebo. All Alcohol × OPRM1 × DAT1 interactions remained significant when analyses were restricted to a subsample of Caucasian participants (n = 34); however, 4-way interactions did not reach statistical significance in this subsample. CONCLUSIONS This study suggests that the contribution of OPRM1 genotype to alcohol-induced stimulation, vigor and positive mood is moderated by DAT1 genotype. These findings are consistent with the purported interaction between opioidergic and dopaminergic systems in determining the reinforcing properties of alcohol.