A Polymorphism of the ??-Opioid Receptor Gene (OPRM1) and Sensitivity to the Effects of Alcohol in Humans

University of Colorado, Boulder, CO 80309-0345, USA.
Alcoholism Clinical and Experimental Research (Impact Factor: 3.21). 01/2005; 28(12):1789-95. DOI: 10.1097/01.ALC.0000148114.34000.B9
Source: PubMed


Recent research has implicated the endogenous opioid system in the development of alcohol use disorders. The A118G polymorphism of the OPRM1 gene has been shown to confer functional differences to mu-opioid receptors, such that the G variant binds beta-endorphin three times more strongly than the A variant. The goal of this study was to test whether the A118G polymorphism is associated with sensitivity to the effects of alcohol.
Participants who were either homozygous for the A allele (n = 23) or heterozygous (n = 15) received intravenous doses of alcohol designed to reach three target levels of breath alcohol concentration: 0.02, 0.04, and 0.06. The testing procedure consisted of measures of subjective intoxication, stimulation, sedation, and mood states at baseline and at each of the three target breath alcohol concentrations.
The results suggested that individuals with the G allele reported higher subjective feelings of intoxication, stimulation, sedation, and happiness across trials as compared with participants with the A allele. Furthermore, participants with the G allele were almost three times more likely to report a positive family history of alcohol use disorders than participants with the A allele.
These findings may help to explain previous research suggesting that naltrexone is more effective among individuals with the G allele. A medication that reduces feelings of euphoria after alcohol consumption may be more successful among individuals with a genetic predisposition to greater feelings of euphoria after consuming alcohol.

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    • "The OPRM1 gene encodes for the µ-opioid receptor (MOR, receptor of endogenous opioids including heroin, morphine, and methadone). The OPRM1 polymorphism consists of an adenine to guanine substitution which affects the reinforcing (thus addictive) effect of drugs in various brain regions ( Ray et al., 2011) This polymorphism has been linked to a variety of substance use characteristics including sensitivity to the effects of alcohol (Ray & Hutchison, 2004) and adolescent alcohol misuse (Miranda et al., 2010), heroin addiction (Shi et al., 2002), and nicotine reinforcement ( Ray et al., 2006). OPRM1 has also been associated with neural sensitivity to social rejection (Way, Taylor, & Eisenberger, 2009). "

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    • "In one study, the ability of naltrexone to decrease the " high " induced by alcohol was stronger in subjects that were carriers of the G allele variant (Ray and Hutchison, 2007 ). In another study, evaluating sensitivity of different doses of alcohol administered intravenously in order to control for blood alcohol levels with great precision, it was found that the G carriers had higher subjective feeling of intoxication, stimulation , sedation, and happiness, suggesting enhanced sensitivity to the effects of alcohol (Ray and Hutchison, 2004). Interestingly, a functional analogue of the A118G polymorphism has been found in nonhuman primates. "
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    ABSTRACT: The field of neuroscience is rapidly growing as evidenced by the mapping of the human genome, the progress in brain imaging technologies, and the refinement of sophisticated molecular tools that can be combined with innovative preclinical models. With these advances, it seems that our understanding of processes underlying addiction has never been so great. In comparison, the clinical domain has evolved at a much slower pace. Nonetheless, the addiction medical field has seen some gradual improvements in clinical care with the availability of a larger range of pharmacological options. Notably, several therapeutic alternatives are now offered for the treatment of nicotine, alcohol, and opioid use disorders. Some of these developments in treatment regimens have directly emerged from basic neuroscience research and represent a success story for the bench to beside translational approach. However, the clinical and research needs in addiction medicine are huge. There are still no pharmacological interventions available for psychostimulant and cannabis use disorders. Further, major questions remain unanswered: Would a better understanding of the neurocircuitry of addiction lead to therapeutic intervention? Would a better understanding of the neurochemical signature of addiction lead to the validation of a therapeutic target? Will pharmacogenetics hold its promise as a personalized medicine treatment approach? Using recent research developments, we will illustrate the potential of neuroscience to address some of the pressing questions in Addiction Medicine.
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    • "An experimental study focusing on behavioral mechanisms of alcohol reward in a sample of heavy drinkers has shown that compared with A-allele homozygotes, G-allele carriers report greater subjective reinforcement from alcohol in the laboratory (Ray and Hutchison, 2004). Similar results were obtained in a naturalistic study of the effects of alcohol (Ray et al., 2010b). "
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    ABSTRACT: Subjective response to alcohol represents a marker of alcoholism risk. The A118G single-nucleotide polymorphism (SNP) of the mu opioid receptor (OPRM1) gene has been associated with subjective response to alcohol. Recently, the dopamine transporter (DAT1) variable number of tandem repeat (VNTR; SLC6A3) has been found to interact with the OPRM1 A118G SNP in predicting neural and behavioral responses to naltrexone and to alcohol. This exploratory study examines the OPRM1 × DAT1 interaction on subjective responses to alcohol. Non-treatment-seeking problem drinkers (n = 295) were assessed in the laboratory for alcohol dependence. Following prospective genotyping for the OPRM1 gene, 43 alcohol-dependent individuals were randomized to two intravenous infusion sessions, one of alcohol (target BrAC = 0.06 g/dl) and one of saline. Measures of subjective responses to alcohol were administered in both infusion sessions. Analyses revealed significant Alcohol × OPRM1 × DAT1 interactions for alcohol-induced stimulation, vigor and positive mood as well as significant Alcohol × OPRM1 × DAT1 × Time interactions for stimulation and positive mood. These effects were such that, compared with other genotype groups, OPRM1 G-allele carriers + DAT1 A10 homozygotes reported steeper increases in stimulation and positive mood across rising BrAC, when compared with placebo. All Alcohol × OPRM1 × DAT1 interactions remained significant when analyses were restricted to a subsample of Caucasian participants (n = 34); however, 4-way interactions did not reach statistical significance in this subsample. This study suggests that the contribution of OPRM1 genotype to alcohol-induced stimulation, vigor and positive mood is moderated by DAT1 genotype. These findings are consistent with the purported interaction between opioidergic and dopaminergic systems in determining the reinforcing properties of alcohol.
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