A gene-by-sex interaction for nicotine reward: Evidence from humanized mice and epidemiology

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Bernardi RE1, Zohsel K2, Hirth N1, Treutlein J3, Heilig M4, Laucht M2, Spanagel R1, Sommer WH1,5

1Institute of Psychopharmacology, Departments of 2Child and Adolescent Psychiatry, 3Genetic Epidemiology, and 5Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany; 4Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden

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 intravenous 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 8 daily 2hr 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 confers greater sensitivity to nicotine reinforcement in males, but not females.