Suppression of alcohol preference by naltrexone in the rhesus macaque: a critical role of genetic variation at the micro-opioid receptor gene locus

Abstract

Background: The role of a nonsynonymous A118G polymorphism of the human micro-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 aspartame-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.

Figure 1

Selective suppression of alcohol preference by naltrexone (0.1 mg/kg) in rhesus macaques carrying the 77G allele of the μ-opioid receptor gene. Genotype strongly interacted with treatment (p=0.002). Post-hoc analysis showed that following saline treatment, 77G carriers had significantly higher preference than 77A homozygous subjects (***p=0.001), and that naltrexone treatment markedly reduced alcohol preference compared to saline within the 77G carrier group (**p=0.002). In contrast, no naltrexone effect was found in the 77A homozygous group. Subjects were socially housed in their regular enclosures, and allowed access to drinking stations during 1h sessions 5 days a week. During drinking sessions, they were offered choice between an 8.4% v/v alcohol containing, aspartame sweetened solution, and the aspartame sweetened vehicle without alcohol. Individual baseline preference was assessed during an initial week, during which all subjects received saline injections. All subjects subsequently received naltrexone or saline, in counterbalanced order, during the second and third week of testing. Baseline preference was controlled for in the analysis. For detailed statistics, see Results.