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

• Published in: Translational psychiatry Vol. 6; no. 7; p. e861
• Main Authors: Bernardi, R E, Zohsel, K, Hirth, N, Treutlein, J, Heilig, M, Laucht, M, Spanagel, R, Sommer, W H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.07.2016; Nature Publishing Group
• Subjects: 692/699/476/5; Adolescent; Alleles; Animals; Behavioral Sciences; Biological Psychology; Female; Germany - epidemiology; Humans; Male; Medicine; Medicine & Public Health; Mice; Neurosciences; Nicotine - administration & dosage; Nicotinic Agonists - administration & dosage; Original; original-article; Pharmacotherapy; Psychiatry; Receptors, Opioid, mu - genetics; Reinforcement, Psychology; Reward; Self Administration; Sex Factors; Tobacco Use Disorder - epidemiology; Tobacco Use Disorder - genetics; Young Adult; Germany
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2016.132

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.