The role of the Asn40Asp polymorphism of the mu opioid receptor gene (OPRM1) on alcoholism etiology and treatment: a critical review

The endogenous opioid system has been implicated in the pathophysiology of alcoholism as it modulates the neurobehavioral effects of alcohol. A variant in the mu opioid receptor gene (OPRM1), the Asn40Asp polymorphism, has received attention as a functional variant that may influence a host of behavioral phenotypes for alcoholism as well as clinical response to opioid antagonists. This paper will review converging lines of evidence on the effect of the Asn40Asp SNP on alcoholism phenotypes, including: (i) genetic association studies; (ii) behavioral studies of alcoholism; (iii) neuroimaging studies; (iv) pharmacogenetic studies and clinical trials; and (v) preclinical animal studies. Together, these lines of research seek to elucidate the effects of this functional polymorphism on alcoholism etiology and treatment response.     

Genetic moderators of naltrexone's effects on alcohol cue reactivity

BACKGROUND: Naltrexone (NTX) reduces drinking and craving in alcoholic individuals in treatment and also in heavy drinkers. Polymorphisms in the D4 dopamine receptor (DRD4) gene and mu-opiate receptor gene (OPRM1) may moderate NTX's effects on craving. This study examined these candidate genes as moderators of the effects of NTX on cue-elicited urge to drink in non-treatment-seeking heavy drinkers. METHOD: Data from the subset of 93 participants who consented for genetic testing in a larger study of medication effects were used to examine pharmacogenetic hypotheses. The non-treatment-seeking male and female heavy drinkers (62% alcohol dependent) were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene [L=7 or more (n=34), S=less than 7 (n=56)] and Asn40Asp single-nucleotide polymorphism in the OPRM1 gene [29 aspartate (Asp) carriers and 59 asparagine (Asn) homozygotes]. Ten days after randomization to NTX (50 mg) or placebo, participants completed an alcohol cue reactivity assessment. RESULTS: Any medication effects were all accounted for by interaction with genotype. Naltrexone increased urge for alcohol in Asp carriers across alcohol and neutral beverage cue trials and had no effect on homozygous Asn carriers. Asp40 carriers on either medication had greater decreases (from resting baseline) in mean arterial blood pressure across all beverage cue trials compared with Asn carriers. For DRD4, no differential medication effects by DRD4 polymorphism were found. Alcohol dependence diagnosis did not moderate the effects of gene and medication on cue-elicited measures. DISCUSSION: The differential responses to NTX due to variation in the OPRM1 gene may help explain conflicting results in clinical trials and suggest directions for patient-treatment matching.     

Effects of opioid receptor gene variation on targeted nalmefene treatment in heavy drinkers

Background:  Recent studies examining the moderating effects of polymorphic variation in opioid receptor genes have yielded conflicting results. We examined opioid receptor gene polymorphisms as moderators of the therapeutic effects of the opioid antagonist nalmefene.
Methods:  Participants ( n  = 272) were subjects who consented to the pharmacogenetic analysis of a multi-site, randomized, placebo-controlled trial of targeted nalmefene for the reduction of heavy drinking. We genotyped two single nucleotide polymorphisms (SNPs) in OPRM1 (including A118G, a commonly studied SNP that encodes an Asn40Asp amino acid substitution), two SNPs in OPRD1 , and one SNP in OPRK1 , which encode the μ-, δ-, and κ-opioid receptors, respectively. Regression analysis served to examine the moderating effects of these SNPs on medication response.
Results:  As previously described by Karhuvaara et al. (2007) , nalmefene significantly reduced the number of heavy drinking and very heavy drinking days per week, compared with placebo. There were no main or moderating effects of the genotypes examined on these outcomes.
Conclusions:  Our finding that the therapeutic effects of targeted nalmefene were not moderated by polymorphic variation in opioid receptor genes is consistent with two recent reports showing that variation in opioid receptor genes does not moderate the response to naltrexone. However, these findings contrast with those from two other studies, in which the Asn40Asp polymorphism in OPRM1 moderated the naltrexone treatment response. Additional research is needed to clarify the role of variation in opioid receptor genes on the response to opioid antagonist treatment of alcoholism.     

OPRM1 Asn40Asp Predicts Response to Naltrexone Treatment: A Haplotype-Based Approach

Background:  Individualized pharmacotherapy requires identification of genetic variants predictive of treatment response. In OPRM1, Asn40Asp has been reported to be predictive of response to naltrexone treatment. Nevertheless, the in vitro function of the polymorphism remains elusive and over 300 OPRM1 sequence variants have been identified to date. Therefore we used a haplotype-based approach to capture information of other genetic variants that might predict treatment response to naltrexone in the COMBINE Study.
Methods:  5' nuclease genotyping assays (TaqMan^®) were applied for 10 SNPs. Five-locus haplotypes in 2 OPRM1 haplotype blocks were assigned to Caucasian participants. The relationship of the haplotypes to medication reflected by "good clinical outcome" was analyzed in 306 Caucasians treated without Combined Behavioral Intervention and with either naltrexone or placebo.
Results:  A significant haplotype by medication interaction ( p  = 0.03) was found in OPRM1 block 1. Naltrexone-treated alcoholics with haplotype AGCCC, the single haplotype carrying the Asp40 allele had the highest percent of good clinical outcome. When interaction of genotypes at each of the 5 loci comprising block 1 with medication was examined, only the Asn40/Asp40 and Asp40/Asp40 genotypes were found to significantly interact with naltrexone treatment. No haplotype by medication interaction was documented in OPRM1 block 2.
Conclusions:  Our haplotype-based approach confirms that the single OPRM1 locus predictive of response to naltrexone treatment is Asn40Asp in exon 1. A substantial contribution of any other OPRM1 genetic variant to interindividual variations in response to naltrexone treatment (at least in terms of good clinical outcome) is not supported by our findings.     

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.     

Naltrexone alone and with sertraline for the treatment of alcohol dependence in Alaska natives and non-natives residing in rural settings: a randomized controlled trial

Background: Access to specialty alcoholism treatment in rural environments is limited and new treatment approaches are needed. The objective was to evaluate the efficacy of naltrexone alone and in combination with sertraline among Alaska Natives and other Alaskans living in rural settings. An exploratory aim examined whether the Asn40Asp polymorphism of the μ‐opioid receptor gene (OPRM1) predicted response to naltrexone, as had been reported in Caucasians. Methods: Randomized, controlled trial enrolling 101 Alaskans with alcohol dependence, including 68 American Indians/Alaska Natives. Participants received 16 weeks of either (1) placebo (placebo naltrexone + placebo sertraline), (2) naltrexone monotherapy (50 mg naltrexone + sertraline placebo) and (3) naltrexone + sertraline (100 mg) plus nine sessions of medical management and supportive advice. Primary outcomes included Time to First Heavy Drinking Day and Total Abstinence. Results: Naltrexone monotherapy demonstrated significantly higher total abstinence (35%) compared with placebo (12%, p = 0027) and longer, but not statistically different, Time to First Heavy Drinking Day (p = 0.093). On secondary measures, naltrexone compared with placebo demonstrated significant improvements in percent days abstinent (p = 0.024) and drinking‐related consequences (p = 0.02). Combined sertraline and naltrexone did not differ from naltrexone alone. The pattern of findings was generally similar for the American Indian/Alaska Native subsample. Naltrexone treatment response was significant within the group of 75 individuals who were homozygous for OPRM1 Asn40 allele. There was a small number of Asp40 carriers, precluding statistical testing of the effect of this allele on response. Conclusions: Naltrexone can be used effectively to treat alcoholism in remote and rural communities, with evidence of benefit for American Indians and Alaska Natives. New models of care incorporating pharmacotherapy could reduce important health disparities related to alcoholism.     

Association of functional opioid receptor genotypes with alcohol dependence in Koreans

BACKGROUND: The functional polymorphism (A118G) of the mu-opioid receptor gene (OPRM1) is thought to have clinical significance in the treatment of alcohol dependence. This study compared Koreans with one or two copies of the A118G polymorphism seeking treatment for alcohol dependence with a group of non-alcohol-dependent controls. METHODS: Patients hospitalized for alcohol dependence (n = 112) and a group of non-alcohol-dependent controls (n = 140) were interviewed on aspects of drinking history and psychiatric history. Patients and controls were excluded if they met criteria for any other major psychiatric disorder. Participants were genotyped at the OPRM1 locus. RESULTS: The allele frequency of the Asp40 allele was 0.397 in the alcohol-dependent group, which is consistent with other literature demonstrating this polymorphism to be common in Asian populations. Within the alcohol-dependent subjects, being homozygous for the Asp40 allele was associated with more days drinking than those heterozygous or homozygous for the Asn40 allele. Differences in the allele frequencies between alcohol-dependent and non-alcohol-dependent controls were not significant. CONCLUSIONS: These results suggest that having one or two copies of the A118G allele is common among Koreans and may be an important genetic factor in the etiology of alcohol dependence and the frequency of alcohol consumption.     

Stress-induced and cue-induced craving for alcohol in heavy drinkers: Preliminary evidence of genetic moderation by the OPRM1 and CRH-BP genes

Background: Neurobiological theories of addiction have highlighted disruption in stress pathways as a central feature of addictive disorders, and pharmacological treatments targeting stress mechanisms hold great promise. This study examines genetic determinants of stress‐induced and cue‐induced craving in heavy drinkers by testing single‐nucleotide polymorphisms (SNPs) of the corticotrophin‐releasing hormone binding protein (CRH‐BP) gene and the mu‐opioid receptor (OPRM1) gene. Methods: This study combines guided imagery stress exposure and in vivo alcohol cue exposure in a sample of 64 (23 women) non‐treatment‐seeking heavy drinkers. Results: Analyses, uncorrected for multiple comparisons, revealed that a tag SNP of the CRH‐BP gene (rs10055255) moderated stress‐induced craving in this sample. The same SNP predicted greater affective responses to the stress manipulation, including greater levels of subjective tension and negative mood. The Asp40 allele of the OPRM1 was associated with greater cue‐induced alcohol craving following the neutral imagery condition. Conclusions: These initial results extend recent preclinical and clinical findings implicating the CRH‐BP in stress‐related alcoholism and confirm the role of the Asp40 allele of the OPRM1 gene in reward‐driven alcohol phenotypes. Human laboratory models of stress and cue‐induced craving may be useful in pharmacotherapy development targeting dysregulation of stress systems. Larger studies are needed to validate these preliminary findings, which should also be extended to clinical samples.     

Moderators of naltrexone's effects on drinking, urge, and alcohol effects in non-treatment-seeking heavy drinkers in the natural environment

Background:  Naltrexone (NTX) has proven to be effective with alcoholics in treatment, with most controlled clinical trials showing beneficial effects on heavy drinking rates. However, little is known about the behavioral mechanisms underlying the effects of NTX on drinking, or about patient characteristics that may moderate NTX's effects on drinking. In this study, ecological momentary assessment (EMA) techniques were used to investigate some of the putative mechanisms of naltrexone's effects on drinking in heavy drinkers who were not seeking treatment for alcohol problems. Polymorphisms in the D4 dopamine receptor (DRD4) gene and the μ-opiate receptor (OPRM1) gene, family history of alcohol problems, age of onset of alcoholism and gender were explored as potential moderators of NTX's effects.
Methods:  After a 1-week placebo lead-in period, heavy drinkers ( n  = 180), 63% of whom were alcohol-dependent, were randomized to 3 weeks of daily naltrexone (50 mg) or placebo. Throughout the study, participants used EMA on palm-pilot computers to enter, in real time, drink data, urge levels, and subjective effects of alcohol consumption.
Results:  Naltrexone reduced percentage drinking days in all participants and reduced percent heavy drinking days in DRD4-L individuals; NTX decreased urge levels in participants with younger age of alcoholism onset; NTX increased time between drinks in participants who had more relatives with alcohol problems; and NTX reduced the stimulating effects of alcohol in women. OPRM1 status did not moderate any of NTX's effects.
Conclusions:  These results confirm earlier findings of NTX's effects on drinking and related subjective effects, and extend them by describing individual difference variables that moderate these effects in the natural environment, using data collected in real time.     

Human μ-Opioid Receptor Variation and Alcohol Dependence

μ-Opioid receptor-mediated neurotransmission is involved in the reward, tolerance, and withdrawal effects of alcohol. The present association study tested the hypothesis that the common Asn40Asp substitution polymorphism in the N-terminal domain of the human fi-opioid receptor (OPRM) confers vulnerability to subtypes of alcohol dependence. The genotypes of the AsrvWAsp substitution polymorphism were assessed in 327 German alcohol-dependent subjects (according to ICD-10) and in 340 control subjects of German descent, using an assay based on allele-specific polymerase chain reaction. To select alcoholics with a presumed high genetic load, three subgroups were delineated, marked by (1) a family history of parental alcoholism ( n = 114); (2) the inability to abstain from alcohol before the age of 26 years (n = 73); and (3) a history of alcohol withdrawal seizure or delirium (n = 107). The frequency of the Asp40 allele did not differ significantly between the controls [f(Asp40) = 0.078] and either the entire group of alcoholics [f(Asp40) = 0.107; p = 0.066], or the alcoholics with parental alcoholism [f(Asp40) = 0.114; p = 0.094], or the early-onset alcoholics [f (Asp40) = 0.096; p = 0.471] or the alcoholics with severe withdrawal symptoms [f(Asp40) = 0.098; p = 0.350]. Our results do not provide evidence that the common Asn40Asp substitution polymorphism of the OPRM gene contributes a major effect to the pathogenesis of alcohol dependence. Key Words: Alcohol Dependence, OPRM fi-Opioid Receptor, Association, Genetics.     

Variation in OPRM1 and risk of suicidal behavior in drug-dependent individuals

Completed suicide and nonfatal suicide‐related outcomes (SROs), such as suicidal ideation and attempts, are heritable. A recent genetic association study in a sample of suicide victims reported a protective effect of the G allele of Asn40Asp (rs1799971) on risk for completed suicide. We examined the association of three OPRM1 single nucleotide polymorphisms (SNPs) (rs1799971, rs609148, and rs648893) with SRO in 426 European Americans, using GEE logistic regression analysis to examine the association of a lifetime history of SRO. There was no allelic association with the SRO phenotypes. A larger sample may be needed to identify risk variants that convey SRO risk. OPRM1 may not be important in the risk of SRO. (Am J Addict 2011;21:5–10)     

Naltrexone and Cue Exposure With Coping and Communication Skills Training for Alcoholics: Treatment Process and 1-Year Outcomes

BACKGROUND: Promising treatments for alcoholics include naltrexone (NTX), cue exposure combined with urge-specific coping skills training (CET), and communication skills training (CST). This study investigated the effects of combining these elements as treatment adjuncts. METHODS: A 2 x 2 design investigated the effects of CET combined with CST, as compared with an education and relaxation control treatment, during a 2-week partial hospital program (n = 165) followed by 12 weeks of NTX (50 mg/day) or placebo during aftercare (n = 128). Drinking outcomes were assessed at 3, 6, and 12 months after discharge from the partial hospital. Process measures included urge, self-efficacy (confidence about staying abstinent in risky situations), and self-reported coping skills. Medically eligible alcohol-dependent patients were recruited. RESULTS: Among those compliant with medication on at least 70% of days, those who received NTX had significantly fewer heavy drinking days and fewer drinks on days that they drank than those receiving placebo during the medication phase but not during the subsequent 9 months. CET/CST-condition patients were significantly less likely to report a relapse day and reported fewer heavy drinking days at the 6- and 12-month follow-ups than patients in the control treatment. Interactions of medication with behavioral treatments were not significant. Process measures showed that NTX resulted in lower weekly urge ratings, and those in CET/CST used more of the prescribed coping skills after treatment, reported fewer cue-elicited urges, and reported more self-efficacy in a posttest role-play test. Drinking reductions at 3, 6, and 12 months correlated with more use of coping skills, lower urge, and higher self-efficacy. CONCLUSIONS: The results suggest the probable value of keeping alcoholics on NTX for longer periods of time and the importance of increasing compliance with NTX. They also support the earlier promising effects of CET and CST as adjuncts to treatment programs for alcoholics by maintaining treatment gains over at least a year. The value of the urge-specific and general coping skills and of self-efficacy and urge constructs was demonstrated in their association with drinking outcomes.     

OPRM1 and Diagnosis-Related Posttraumatic Stress Disorder in Binge-Drinking Patients Living with HIV

Posttraumatic stress disorder (PTSD) has been linked to numerous negative outcomes in persons living with HIV (PLH) and there is evidence that PTSD symptoms may play a role in maintaining alcohol use problems. The opioid receptor mu-1 (OPRM1) gene may play a role in both PTSD and alcohol use. We examined the association between PTSD and drinking motives as well as variation in the OPRM1 as a predictor of both PTSD and drinking motives in a sample of 201 PLH reporting recent binge drinking. Self-reported PTSD symptom severity was significantly associated with drinking motives for coping, enhancement, and socialization. OPRM1 variation was associated with decreased PTSD symptom severity as well as enhancement motives for drinking.     

Differential neural response to alcohol priming and alcohol taste cues is associated with DRD4 VNTR and OPRM1 genotypes

Background:  Studies suggest that polymorphisms in the D4 dopamine receptor (DRD4) and opioid receptor, μ1 (OPRM1) genes are involved in differential response to the effects of alcohol and to alcohol cues. However, to date, the mechanisms that underlie these differences remain largely unknown.
Methods:  Using functional magnetic resonance imaging, hemodynamic response in mesocorticolimbic structures after exposure to alcohol tastes was contrasted with a control taste and compared between DRD4 variable number of tandem repeats (VNTR) genotypes and OPRM1 A118G genotypes. Additionally, the effects of a priming dose of alcohol on this response were examined.
Results:  The results indicated that DRD4 VNTR >7 repeat individuals (DRD4.L) had significantly greater response to alcohol cues in the orbitofrontal cortex, anterior cingulate gyrus, and striatum compared with individuals with <7 repeats (DRD4.S) prior to a priming dose of alcohol ( p  < 0.05), but not after a priming dose. In the OPRM1 comparisons, results showed that individuals with at least 1 copy of the OPRM1 + 118 G allele had greater hemodynamic response in mesocorticolimbic areas both before and after priming compared with those who were homozygous for the OPRM1 + 118 A allele. For the DRD4.L and OPRM1 + 118 G groups, brain response in the striatum was highly correlated with measures of alcohol use and behavior such that greater activity corresponded with greater frequency and quantity of alcohol use.
Conclusions:  The DRD4 VNTR and OPRM1 A118G polymorphisms are associated with functional neural changes in mesocorticolimbic structures after exposure to alcohol cues. This provides evidence for the contributions of the DRD4 and OPRM1 genes in modulating neural activity in structures that are involved in the motivation to drink.     

The effect of naltrexone on alcohol's stimulant properties and self-administration behavior in social drinkers: influence of gender and genotype

Background: Few pharmacological treatments for alcohol dependence are available. Moreover, the best supported treatment, naltrexone hydrochloride, appears to work for only some. Methods: To investigate potential predictors of these differential responses, 40 social drinkers (20 women) were administered 6 days of treatment with naltrexone vs. placebo in a double‐blind, counterbalanced, crossover design. At the end of each treatment period, participants received a single dose of their preferred alcoholic beverage followed by the opportunity to work for additional alcohol units using a progressive ratio (PR) breakpoint paradigm. All subjects but one were genotyped for the A118G polymorphism of the mu opioid receptor gene (OPRM1). Results: Naltrexone decreased the ethanol‐induced ‘euphoria’ to a priming dose of alcohol in two subgroups: (i) in women, and (ii) in subjects with the A118G polymorphism of the mu opioid receptor gene (OPRM1). Naltrexone did not decrease motivation to work for additional alcoholic beverages on the PR task regardless of gender or genotype. Conclusions: The results add to the evidence that naltrexone decreases positive subjective effects of alcohol, with preferential effects in distinct subgroups. Similar effects in heavier drinkers might decrease alcohol use.     

Endogenous opioid receptor genes and alcohol dependence among Taiwanese Han

BACKGROUND: Nonselective opioid antagonists reduce alcohol consumption under various experimental situations, and several association studies have examined possible roles of opioid receptor mu (OPRM), delta (OPRD), and kappa (OPRK) genes in the development of alcohol dependence. METHODS: We examined 20 single nucleotide polymorphisms (SNPs) across the OPRM, OPRD, and OPRK genes in 158 alcohol-dependent subjects and 149 controls. Differences in allele frequency and genotype distribution between case subjects and controls, as well as the deviation from Hardy-Weinberg equilibrium, were examined using Fisher's exact tests. RESULTS: No significant difference in either allele or genotype frequency was found between case subjects and controls for each of the SNPs. CONCLUSIONS: Our findings do not support a possible role of the opioid receptor genes for the proclivity to alcohol dependence in the Taiwanese Han.     

Interaction between family history of alcoholism and Locus of Control in the opioid regulation of impulsive responding under the influence of alcohol

Background: Naltrexone (NTX) is an opioid antagonist indicated for the treatment of alcoholism, which is not universally effective. Thus, identifying individual predictors of NTX’s behavioral effects is critical to optimizing its therapeutic use. Moreover, given the high rate of relapse during treatment for alcoholism, understanding NTX’s behavioral effects when combined with moderate ethanol intake is important. Our previous study of abstinent alcoholics and control subjects showed that a more internal Locus of Control score predicted increased impulsive choice on NTX ( Mitchell et al., 2007 , Neuropsychopharmacology 32:439–449). Here, we tested whether this predictive relationship remains in the context of moderate alcohol intake. Methods: In this study, we tested the effect of acute NTX (50 mg) on impulsive choice, motor inhibition, and attentional bias after ingestion of moderate ethanol (～0.3 g/kg, n = 30 subjects). Subjects included those recruited from a pool of ～1,200 UC Berkeley undergraduates on the basis of scores on the Barratt Impulsiveness Scale (BIS). Results: Impulsive choice was positively correlated with breath alcohol concentration in placebo sessions. Locus of Control was again the sole predictor of NTX’s effect on decision making among subjects with a family history of alcoholism. We also found a weak interaction between BIS scores and NTX’s effect on impulsive choice. Conclusions: Our results reinforce the predictive relationship between Locus of Control and NTX’s effect on decision making in those with a family history of alcoholism, suggesting a possible biological basis to this relationship.     

Oral Ethanol-Reinforced Responding in Rhesus Monkeys: Effects of Opioid Antagonists Selective for the μ-,κ-, or δ-Receptor

To determine the mechanism by which naltrexone (NTX) reduces oral ethanol-reinforced responding, opioid antagonists that show μ-, κ-, or δ-selectivity were evaluated. Rhesus monkeys ( n = 6) were given opportunities to respond and receive ethanol (1 % or 2%) or water during daily 3-hr drinking sessions. Before some drinking sessions, the monkeys received intramuscular injections of saline or the following drugs: the μ-selective irreversible antagonist clocinnamox (CCAM), the κ-selective long-lasting antagonist nor-binaltorphimine (nor-BNI), or the δ-selective antagonist naltrindole. Also, NTX was administered along with either CCAM or nor-BNI. When given alone, CCAM (0.1 mg/kg) had no effect on ethanol-reinforced responding. When NTX (0.32 mg/kg) was given with CCAM, responding maintained by ethanol was decreased. Nor-BNI (3 mg/kg) reduced ethanol-reinforced responding only on the day of injection. On subsequent days, when other studies report continued κ-antagonism, responding maintained by ethanol returned to control levels. Also, NTX (0.32 mg/kg), administered in the presence of nor-BNI, was still able to reduce ethanol-reinforced responding. Naltrindole failed to alter responding maintained by ethanol. Because selective antagonism at the μ-, κ-, or δ-receptor did not reduce ethanol-reinforced responding, NTX's ability to reduce ethanol consumption may not be mediated by these previously characterized opioid receptors. NTX may exert its effects through an uncharacterized opioid binding site or through a nonopioid mechanism.     

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.     

A functional polymorphism of the mu-opioid receptor gene (OPRM1) influences cue-induced craving for alcohol in male heavy drinkers

BACKGROUND: The mu-opioid receptor gene (OPRM1) codes for the mu-opioid receptor, which binds beta-endorphin. The A118G polymorphism in this gene affects beta-endorphin binding such that the Asp40 variant (G allele) binds beta-endorphin 3 times more tightly than the more common Asn40 variant (A allele). This study investigated the influence of the A118G polymorphism on cue reactivity after exposure to an alcoholic beverage in male heavy drinkers. METHODS: Participants were either homozygous for the A allele (n=84) or carrying at least 1 copy of the G allele (n=24). All participants took part in a cue-reactivity paradigm where they were exposed to water and beer in 3-minute trials. The dependent variables of main interest were subjective craving for alcohol, subjective arousal, and saliva production. RESULTS: G allele carriers reported significantly more craving for alcohol than the A allele participants (as indicated by the within-subject difference in craving after beer vs after water exposure). No differences were found for subjective arousal and saliva. Both groups did not differ in family history of alcoholism. Participants with the G allele reported a significantly higher lifetime prevalence of drug use than participants homozygous for the A allele. CONCLUSIONS: A stronger urge to drink alcohol after exposure to an alcoholic beverage might contribute to a heightened risk for developing alcohol-related problems in individuals with a copy of the G allele. The G allele might also predispose to drug use in general.