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Christina S. Barr, VMD, PhD; Melanie Schwandt, PhD; Stephen G. Lindell, BS; Scott A. Chen, PhD; David Goldman, MD; Stephen J. Suomi, PhD; J. Dee Higley, PhD; Markus Heilig, MD, PhD

Arch Gen Psychiatry. 2007;64(3):369-376.

Context  Innate differences in opioid neurotransmission are hypothesized to influence abuse liability of alcohol. In humans, a variant of the µ-opioid receptor gene (OPRM1A118G) increases receptor affinity, alcohol-induced euphoria, and risk for alcohol use disorders.

Objective  To determine whether a variant in the µ-opioid receptor gene (OPRM1C77G) that increases affinity of the receptor is associated with alcohol response and consumption in macaques.

Design  Young adult rhesus macaques (Macaca mulatta) were intravenously administered 2.0 to 2.1 g of ethanol per kilogram of body weight and assessed for alcohol response. Animals were later given simultaneous access to an aspartame-sweetened 8.4% (vol/vol) ethanol solution and a vehicle for 1 hour per day, 5 days a week, for a period of 6 weeks. Animals (N = 82) were genotyped for the OPRM1C77G polymorphism; the effects of the genotype on alcohol response and consumption were determined by analysis of variance, with sex included as a nominal independent variable.

Main Outcome Measures  Alcohol response (ataxia, stimulation, and sedation), average alcohol consumption, the percentage of days during which an animal consumed alcohol at a level sufficient to produce intoxication (0.67 g of alcohol per kilogram of body weight), and alcohol preference (calculated as 100 x {alcoholic solution/[alcoholic solution + nonalcoholic solution]}).

Results  Increased alcohol-induced stimulation was observed among male macaques carrying the OPRM1C77G allele. OPRM1C77G allele carriers consumed more ethanol and exhibited increased ethanol preference. Male carriers of the OPRM1C77G allele exhibited higher alcohol preference and consumption, and drank to intoxication more frequently than did C/C males.

Conclusions  These findings demonstrate that the rhesus macaques' equivalent of the OPRM1A118G variant is associated with increased alcohol response, consumption, and preference. Our results reveal effects of the OPRM1C77G genotype to be male-restricted or more marked among male macaques. This is of interest, given the fact that early-onset type II alcoholism is more common among men and that, among addicted individuals, men are more responsive to µ-opioid receptor blockade.

Author Affiliations: Laboratory of Clinical and Translational Studies (Drs Barr, Schwandt, Chen, Higley, and Heilig, and Mr Lindell) and Laboratory of Neurogenetics (Drs Barr and Goldman), National Institute on Alcohol Abuse and Alcoholism, and Laboratory of Comparative Ethology, National Institute of Child Health & Human Development (Dr Suomi), National Institutes of Health, Bethesda, Md.

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