Abstract
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_A>G (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.
Highlights
Despite notable success in decreasing rates of smoking, tobacco use remains a major public health issue and the leading cause of preventable death worldwide.[1,2] The addictive properties of tobacco are largely attributable to nicotine,[3,4] and a resounding reminder of this is the rapid increase in the use of e-cigarettes, electronic delivery systems that enable long-term use of tobaccofree nicotine, which are increasingly popular among smokers
Using a humanized mouse model, we isolated the influence of the OPRM1 A118G variation from potential confounds commonly present in human studies and identified a sex-specific influence of the G allele on nicotine self-administration, which provided a basis for investigation of reported initial smoking experiences in a human population sample, in which we further demonstrated that male carriers of the 118G allele showed higher initial rewarding effects of nicotine compared with male 118A homozygous and females regardless of genotype
The convergent genetic findings obtained using this translational strategy support a role for the 118G allele as a key predictor of increased nicotine reward in males but not females
Summary
Despite notable success in decreasing rates of smoking, tobacco use remains a major public health issue and the leading cause of preventable death worldwide.[1,2] The addictive properties of tobacco are largely attributable to nicotine,[3,4] and a resounding reminder of this is the rapid increase in the use of e-cigarettes, electronic delivery systems that enable long-term use of tobaccofree nicotine, which are increasingly popular among smokers The ramifications of this recent development for tobacco control are a matter of intense debate.[5] According to a recent US survey, e-cigarettes are increasing youth nicotine use,[6] and may lead to smoking and nicotine addiction. The rewarding properties of nicotine are mediated in part by μ-opioid receptors (MOR) encoded by the OPRM1 locus.[3,18] The reinforcing effects of nicotine are attenuated in mice lacking
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