Association of a Functional Polymorphism in the μ-Opioid Receptor Gene With Alcohol Response and Consumption in Male Rhesus Macaques

Abstract

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 mu-opioid receptor blockade.

Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates

“…Because of the involvement of the reward systems in the development of attachment, it has been proposed that social attachment could be considered an addictive disorder (36), and ''insecure early attachment'' is believed to be a risk factor for substance abuse and addiction (37,38). Of interest, we have shown there to be increased levels of alcohol preference in rhesus monkeys carrying the OPRM1 77G allele (15,18), and OPRM1 variation has been linked to various addictive disorders in human populations (25). Our findings may, therefore, lend support to ethological arguments in favor of attachment theory and its association with psychopathology, not necessarily in terms of causality, but by pointing to common underlying genetic or neurobiological substrates.…”

“…Although its consequences at the molecular level remain to be fully elucidated (14,16,17,31,32), recent in vivo data support the notion that the OPRM1 118G is indeed a gain-of-function variant, because it is associated with increased pain threshold, increased sensitivity to euphorogenic effects of addictive drugs, increased cortisol response after challenge with the opioid antagonist naltrexone, and higher rates of therapeutic response to the opioid antagonist naltrexone in alcoholism (19,20,(33)(34)(35). Findings in rhesus macaques suggest that rhOPRM1 77G has a gain-of-function role as well (15,18), indicating the human and rhesus OPRM1 variants are functionally similar. Based on the present data, we cannot exclude the possibility that another variant in LD with OPRM1 77G contributes to the functional effects observed here.…”

“…Several studies have demonstrated that cases exist in which genetic variants that are functionally similar to those that exist in humans are present in macaques (15,18,27,29). This affords us the opportunity to examine how genetic variation may influence complex behavioral traits in subjects living in a controlled environment (30).…”

“…Although the exact mechanism remains unclear (16,17), in vivo data support a gain-of-function role for these variants, as shown, for example, by increased alcohol-induced stimulation, an effect mediated through release of endogenous opioids (18)(19)(20). The aim of the present study was to examine whether the rhOPRM1 77G allele would influence attachment behavior in rhesus macaque infants.…”

Negative affect is associated with alcohol, but not cigarette use in heavy drinking smokers

“…First, ADs did not differ from HDs in their positive response to alcohol (i.e., stimulation). This null result may be partially explained by the fact that both studies were balanced on OPRM1 genotype, which has been linked with greater stimulation response to alcohol (Barr et al, 2007;Ray and Hutchison, 2004;Ray et al, 2010c). While, statistically controlling for OPRM1 did not alter the significance of the results presented, prospective genotyping may have biased our findings away from detecting group level differences on stimulation response.…”