Association of Alcohol or Other Drug Dependence with Alleles of the μ Opioid Receptor Gene (OPRM1)

Opioidergic neurotransmission and, specifically, the μ opioid receptor have been implicated in the reinforcing effects of a variety of drugs of abuse. Consequently, the present study examined the association of a polymorphic (CA)n repeat at the OPRM1 locus (the gene coding for the μ opioid receptor) to alcohol or drug dependence in 320 Caucasian and 108 African-American substance-dependent or control subjects. Among Caucasians, suggestion of a modest association, which could be interpreted as statistically significant ( p = 0.03), was observed between OPRMl alleles and substance (alcohol, cocaine, or opioid) dependence. Analysis by specific substance showed only a trend level association to alcohol dependence. Comparisons among African Americans yielded no evidence for association. Further studies of the association between alleles of the OPRM1 gene and substance dependence appear warranted, particularly if they use a family-based approach to control for population stratication. Phenotypes other than a broad diagnostic categorization, such as opioid antagonist effects on drinking behavior in alcoholics, may provide more consistent evidence of a role for OPRMl in behavioral variability.     

Associations Among GABRG1, Level of Response to Alcohol, and Drinking Behaviors

Background:  Recent studies of the genetics of alcoholism have focused on a cluster of genes encoding for γ-aminobutyric acid (GABA_A) receptor subunits, which is thought to play a role in the expression of addiction phenotypes. This study examined allelic associations between 2 single nucleotide polymorphisms (SNPs) of the GABRG1 gene (rs1391166 and rs1497571) and alcohol phenotypes, namely level of response to alcohol, alcohol use patterns, and alcohol-related problems.
Method:  Participants were non-treatment-seeking seeking hazardous drinkers ( n  = 124) who provided DNA samples, participated in a face-to-face interview for level of response to alcohol, and completed a series of drinking and individual differences measures.
Results:  Analyses revealed that a SNP of the GABRG1 gene (rs1497571) was associated with level of response to alcohol and drinking patterns in this subclinical sample. Follow-up mediational analyses were also conducted to examine putative mechanisms underlying these associations.
Discussion:  These findings replicate and extend recent research suggesting that genetic variation at the GABRG1 locus may underlie the expression of alcohol phenotypes, including level of response to alcohol.     

Effects of Alcohol Cue Exposure on Response Inhibition in Detoxified Alcohol‐Dependent Patients

Background: There is evidence that exerting self‐control during alcohol craving can diminish performance on subsequent tasks that require self‐control. Based on the resource depletion model (Muraven and Baumeister, 2000), we examined the influence of alcohol cue exposure on detoxified alcohol‐dependent patients’ ability to inhibit ongoing responses. Methods: Twenty alcohol‐dependent patients were randomly assigned to an alcohol‐cue exposure and a control‐cue exposure condition and thereafter had to perform an inhibition task (i.e., stop‐signal task). Results: Participants who sniffed alcohol before performing the inhibition task reported a stronger urge to drink alcohol than the control group that sniffed water. Participants who sniffed alcohol were also impaired in their inhibitory performance but not in their noninhibitory performance on the stop‐signal task. Conclusions: The urge to drink presumably reduced participants' self‐control, and this interfered with their ability to inhibit responding.     

Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: results from the VA Cooperative Study

BACKGROUND: Pharmacotherapy of alcohol dependence (AD) is at an early stage of development; currently available medications have limited efficacy. It would be clinically valuable to identify, before initiation of a course of treatment, those patients who, based on genetic markers, are most likely to respond to a specific pharmacotherapy. A previous report suggested that a functional variant at the genetic locus encoding the mu opioid receptor (Asn40Asp) is such a marker, in short-term (3-month) treatment with the opioid-blocking drug naltrexone (NTX). METHODS: We studied polymorphic variants at each of the 3 opioid receptor genes--OPRM1, OPRD1, and OPRK1, which encode the mu, delta, and kappa opioid receptors, respectively--including the OPRM1 Asn40Asp variant--as predictors of response to NTX or placebo in 215 alcohol-dependent male subjects who participated in Veterans Affairs Cooperative Study 425, "Naltrexone in the Treatment of Alcohol Dependence." RESULTS: At the 3-month time point, treatment condition, age, and the pretreatment number of drinks per drinking day were all significant (p<0.05) predictors of the rate of relapse and time to relapse. Although NTX had no significant effect on relapse to heavy drinking in the overall sample in CSP 425, it significantly reduced relapse in the subgroup that provided DNA for analysis (i.e., the present study sample). There were no significant interactions between any individual single nucleotide polymorphisms studied and NTX treatment response. CONCLUSIONS: These results do not support association of the OPRM1 Asn40Asp polymorphism with NTX treatment response for AD.     

Naltrexone Selectively Elevates GABAergic Neuroactive Steroid Levels in Heavy Drinkers With the ASP40 Allele of the OPRM1 Gene: A Pilot Investigation

Background: Preclinical studies have implicated GABAergic neurosteroids in behavioral responses to alcohol. Naltrexone is thought to blunt the reinforcing effects of alcohol, and a few studies have found that the effects of naltrexone are moderated by the Asn40Asp polymorphisms of the OPRM1 gene. The present study seeks to integrate these lines of research by testing (i) the moderating role of the functional Asn40Asp polymorphism of the OPRM1 gene on naltrexone‐induced alternations in GABAergic neurosteroid levels, namely (3α,5α)‐3‐hydroxypregnan‐20‐one (allopregnanolone, ALLO); and (ii) the combined effects of naltrexone or genotype with alcohol administration on neurosteroid levels in a sample of at‐risk drinkers. Methods: Participants were 32 (9 females) nontreatment‐seeking heavy drinkers who completed a placebo‐controlled laboratory study of naltrexone (50 mg/d for 3 days) and provided complete sets of serum samples for ALLO assays before and after alcohol administration under both naltrexone and placebo conditions. Results: Naltrexone treatment raised ALLO levels among carriers of the Asp40 allele, but not homozygotes for the Asn40 allele. The Asn40Asp polymorphism did not moderate effects of naltrexone on cortisol levels. Ethanol infusion modestly reduced ALLO levels in all subjects, independent of genotype or naltrexone exposure. Conclusions: Naltrexone increased ALLO levels among individuals with the Asn40Asp allele suggesting a potential neurosteroid contribution to the neuropharmacological effects of naltrexone among Asp40 carriers.     

Association of Markers in the 3' Region of the GluR5 Kainate Receptor Subunit Gene to Alcohol Dependence

Background:  Glutamate neurotransmission plays an important role in a variety of alcohol-related phenomena, including alcohol self-administration by both animals and humans. Because the risk for alcohol dependence (AD) is genetically influenced, genes encoding glutamate receptors are candidates to contribute to the risk for AD. We examined the role of variation in the 3' region of GRIK1 , the gene that encodes the GluR5 receptor subunit of the kainic acid glutamate receptor, on risk for AD. We focused specifically on this gene because topiramate, a glutamate modulator that binds to the GluR5 subunit, has shown robust efficacy in the treatment of AD.
Methods:  We genotyped 7 single nucleotide polymorphisms (SNPs) in the 3'-half of GRIK1 , which includes 3 differentially spliced exons, in a sample of EA control subjects ( n  = 507) and subjects with AD ( n  = 1,057).
Results:  We found nominally significant evidence of association to AD for 3 SNPs (rs2832407 in intron 9, rs2186305 in intron 17, and rs2832387 in the 3'UTR). Empirical p -value estimation revealed that only rs2832407 was significantly associated to phenotype ( p  = 0.043).
Discussion:  These findings provide support for the hypothesis that variation in the 3' portion of the gene encoding the GluR5 kainate receptor subunit contributes to the risk for AD. Further research is needed to ascertain whether this SNP is itself functional or whether the association reflects linkage disequilibrium with functional variation elsewhere in the gene and whether this SNP moderates topiramate's effects in the treatment of AD.     

A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.