Suppression of Alcohol Preference by Naltrexone in the Rhesus Macaque: A Critical Role of Genetic Variation at the mu-Opioid Receptor Gene Locus

Background: The role of a nonsynonymous A118G polymorphism of the human mu-opioid receptor gene (OPRM1) for alcohol reward and therapeutic efficacy of naltrexone remains controversial. A functionally equivalent OPRM1 C77G polymorphism in rhesus macaques allows this to be addressed under controlled experimental conditions. Methods: Twenty-one rhesus macaques (13 female rhesus macaques, 8 male rhesus macaques) were genotyped for OPRM1 C77G and studied during 1-hour sessions for preference between an a Spartame-sweetened alcohol solution (8.4%vol/vol) and a nonalcoholic control fluid in a baseline session followed by naltrexone (1 mg/kg) and vehicle treatment in a counterbalanced within-subject design. Results: Mixed-model analysis of variance controlling for baseline and sex showed a highly significant (p = .003) interaction between genotype and treatment. Post hoc analysis showed that vehicle-treated 77G carriers had markedly higher alcohol preference than 77C homozygous subjects (p = .001). Following naltrexone administration, 77G carriers decreased their preference (p = .002) and no longer differed from 77C homozygous subjects. In contrast, the latter group was unaffected by treatment and, in fact, showed a trend-level increase of preference following naltrexone. Conclusions: These results support a critical pharmacogenetic role of OPRM1 variation for therapeutic efficacy of naltrexone.