A pharmacogenetic model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys

Abstract

Background: Variation at the human mu-opioid receptor has been associated with alcohol abuse. The A118G (N40D) polymorphism in humans is functionally mimicked by the C77G (P26R) polymorphism in rhesus monkeys; both show similar in vitro influences on ligand binding and in vivo correlations with physiological measures as well as behavioral measures including predilection towards alcohol consumption. Naltrexone, an antagonist at the receptor, has been used to treat alcoholism in humans and has been reported to show differences in effectiveness depending on genotype.

Methods: Here we describe a study in which we a priori selected rhesus monkeys based on genotype at the OPRM1 C77G single nucleotide polymorphism, trained them to self-administer alcohol, and assessed naltrexone responsiveness.

Results: Alcohol intake in rhesus monkeys varied with genotype across a range of alcohol concentrations (0.5-4%, w/v) such that animals with the G/G genotype drank consistently more alcohol than those animals with the C/C genotype. Additionally, naltrexone attenuated alcohol drinking in a dose- and genotype-dependent manner. Animals harboring the G/G genotype were more sensitive to the effects of naltrexone and showed greater reductions in alcohol consumption at lower naltrexone doses compared to animals with a C/G or C/C genotype.

Conclusions: This preliminary study demonstrates a pharmacogenomic response to naltrexone in rhesus monkeys that parallels that seen in humans. This finding provides a basis for developing a pharmacogenetic animal model for naltrexone effect that can expand further our understanding of the causes and treatments of alcohol use disorders.

Figure 1

Alcohol self-administration in rhesus monkeys. A) Intake (mean g/kg±SD) of alcohol across the last three days of availability at each concentration in individual subjects. B) Mean intakes (±SEM) for the last three sessions at each concentration for the group of six monkeys. *: significant difference compared to 0.5% and 1% (w/v) alcohol solution (F[4,12]=92.5, p<0.0001; Tukey’s HSD test, p<0.05). C) Mean intakes (± range) for the last three sessions at each concentration for each genotype (N = 2 monkeys/genotype). *: significant increase compared to OPRM1 C/C (F[8,12]=2.9, p<0.05; Tukey’s HSD test, p<0.05).

Figure 2

Reduction in self-administration of a A) 2% (w/v) alcohol solution following pretreatment with naltrexone in rhesus monkeys. *: significant reduction compared to OPRM1 C/C (F[2,3]=10.4, p<0.05; Tukey’s HSD test, p<0.05). Reduction in self-administration of a B) 4% (w/v) alcohol solution following pretreatment with naltrexone in rhesus monkeys. *: significant differences between all genotypes (F[2,3]=15.6, p<0.05; Tukey’s HSD test, p<0.05). Data are mean intakes (± range) expressed as a percentage of intake after vehicle administration for each genotype (N = 2 monkeys/genotype).