Association of OPRM1 A118G variant with the relative reinforcing value of nicotine (original) (raw)
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Association of opioid receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) with nicotine dependence
Oncotarget
Background and Object: Whether opioid-receptor mu 1 (OPRM1) A118G polymorphism (rs1799971) is associated with nicotine dependence is controversial. We analyzed the combined results from published studies of this possibility. Methods: Literature reviews were performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Web of Science, Chinese National Science Infrastructure (CNKI), PubMed, Embase and Google Scholar database searches using MeSH terms were conducted to find all relevant researches up to October 2016. Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated in allele, homozygote, heterozygote, dominant and recessive models. Ethnicity-specific subgroup meta-analysis, heterogeneity, sensitivity analysis and publication bias were considered. Results: Seven eligible studies with 3313 patients were included. The ORs in the five genetic models mentioned above were 1.
The Pharmacogenomics Journal, 2004
To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n ¼ 82) were significantly more likely than those homozygous for the Asn40 variant (n ¼ 238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.
Proceedings of the National Academy of Sciences, 2011
Evidence points to the endogenous opioid system, and the muopioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the human MOR gene (OPRM1 A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of OPRM1 A118G genotype on MOR binding potential (BP ND or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two [ 11 C]carfentanil positron emission tomography (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels of MOR BP ND than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BP ND difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics. genetics | neuroimaging | tobacco W ith 1 billion tobacco users worldwide, nicotine dependence has a major impact on global health. Advances in medication development for nicotine dependence require an improved understanding of the neurobiology of this complex, relapsing brain disorder (1). Although multiple neurobiological mechanisms have been implicated, a growing body of evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the reinforcing effects of drugs of abuse, including nicotine (2-5). Nicotine upregulates MOR mRNA and protein expression in brain regions important in drug reward in rodents (4, 6) and stimulates endogenous opioid release (7, 8), resulting in MOR activation and dopamine release (9).
A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology
Translational Psychiatry
It has been proposed that vulnerability to nicotine addiction is moderated by variation at the μ-opioid receptor locus (OPRM1), but results from human studies vary and prospective studies based on genotype are lacking. We have developed a humanized mouse model of the most common functional OPRM1 polymorphism rs1799971_A4G (A118G). Here we use this model system together with a cohort of German youth to examine the role of the OPRM1 A118G variation on nicotine reward. Nicotine reinforcement was examined in the humanized mouse model using i.v. self-administration. Male (n = 17) and female (n = 26) mice homozygous either for the major human A allele (AA) or the minor G allele (GG) underwent eight daily 2 h sessions of nicotine self-administration. Furthermore, male (n = 104) and female (n = 118) subjects homozygous for the A allele or carrying the G allele from the Mannheim Study of Children at Risk were evaluated for pleasurable and unpleasant experiences during their initial smoking experience. A significant sex-by-genotype effect was observed for nicotine self-administration. Male 118GG mice demonstrated higher nicotine intake than male 118AA mice, suggesting increased nicotine reinforcement. In contrast, there was no genotype effect in female mice. Human male G allele carriers reported increased pleasurable effects from their first smoking experience, as compared to male homozygous A, female G and female homozygous A allele carriers. The 118G allele appears to confer greater sensitivity to nicotine reinforcement in males, but not females.
Nicotine & Tobacco Research, 2007
Extending a previous finding of an association between functional genetic variation in the mu-opioid receptor gene and response to nicotine replacement therapy, we explored the role of genetic variants in two genes encoding muopioid-receptor-interacting proteins, namely ARRB2 and HINT1. Participants were 374 smokers treated for nicotine dependence with either transdermal nicotine or nicotine nasal spray for 8 weeks in an open-label randomized trial. In a logistic regression model controlling for OPRM1 genotype, treatment type, and other covariates, we found no significant main effect of ARRB2 genotype on abstinence at either end of treatment or 6month follow-up. Participants with the HINT1 TT genotype had significantly higher abstinence rates at 6-month follow-up, but this may not be a pharmacogenetic effect, given that the participants were drug free during this time. Haplotype analysis did not reveal any significant associations for either gene. We found an interaction of ARRB2 and OPRM1 genotype on abstinence at 6 months that approached significance; however, interpretation of this finding is limited by the small number of participants with the minor alleles for both genes. Although these data do not provide support for the role of genetic variation in these mu-opioid-receptor-interacting proteins and smoking cessation, further exploration of opioid pathway genes in larger prospective pharmacogenetic trials may be warranted.
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2015
The current study examined whether the presence of the G allele of the A118G polymorphism of the OPRM1 gene (rs1799971) and the long allele of exon 3 VNTR polymorphism of the DRD4 gene moderate the effect of alcohol administration on urge to smoke. These polymorphisms have been associated with greater alcohol induced-urge to drink. Urge to drink and alcohol consumption increase urge to smoke. Therefore, these polymorphisms may also sensitize urge to smoke after alcohol consumption. Individuals smoking 10-30 cigarettes per day and reporting heavy drinking were recruited from the community. Caucasians (n = 62), 57.3% male, mean age 39.2, took part in a three-session, within-subjects, repeated-measures design study. Participants were administered a placebo, 0.4 g/kg, or 0.8 g/kg dose of alcohol. A118G genotype, exon 3 VNTR genotype, and urge to smoke (baseline and 3 times after receiving alcohol) were assessed. Gallele carriers showed greater urge to smoke across all assessments. Addit...
Gene and gene by sex associations with initial sensitivity to nicotine in nonsmokers
Behavioural Pharmacology, 2008
Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 μg/kg) was administered via nasal spray followed by mood, nicotine reward (e.g. "liking") and perception (e.g. "feel effects") measures, physiological responses, sensory processing (pre-pulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine vs. placebo spray choice procedure. For the dopamine D4 receptor (DRD4 VNTR), presence of the 7 repeat allele was associated with greater aversive responses to nicotine (decreases in "vigor", positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased "feel effects" and greater startle response, but in men only. Also observed in men but not women were other genetic associations, such as greater "feel effects" and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T SNP) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G SNP (OPRM1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine prior to the onset of dependence and may do so differentially between men and women.
Addiction Biology, 2013
a db_422 1..10 Smoking and alcohol use often co-occur during adolescence, but little is known about the codevelopment of these substances. In the search for etiological factors that help to explain the development of adolescent substance use patterns, studies have revealed substantial heritability for both alcohol use and smoking. In this regard, the m-opioid receptor gene (OPRM1, chromosome 6q24-q25) has been linked to both substances. This study examined the predictive relationships between initial level and growth of smoking and drinking in 311 early adolescents (13-15 years old) over a 4-year period. In addition, the effects of the A118G polymorphism of the OPRM1 gene on the initial values and the development over time of alcohol use and smoking were assessed. Finally, as prevalence and heritability estimates for both alcohol-and smoking-related behaviors differ between males and females, OPRM1 by sex interactions were tested. We found that high initial levels of early adolescent alcohol consumption were related to a stronger increase in smoking levels over time. In contrast, high initial levels of smoking were not related to growth of alcohol use. No main OPRM1 effects were found, but sex-specificity of the gene was found for smoking development. Male A-allele carriers showed a faster development in smoking behavior, whereas in females, the G-allele led to a faster development in smoking. Thus, in addition to high levels of alcohol as a risk factor for the development of smoking behavior, sexspecific effects exist for OPRM1, which may additionally have consequences for the development of adolescent smoking.