title: A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology.
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.
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: R E
authors.initials: RE
authors.lastname: Bernardi
authors.affiliation: Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Zohsel
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Hirth
authors.affiliation: Genetic Epidemiology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Treutlein
authors.affiliation: Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Heilig
authors.affiliation: Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Laucht
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.|Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: W H
authors.initials: WH
authors.lastname: Sommer
mesh_terms: D000293:Adolescent; D000483:Alleles; D000818:Animals; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D051379:Mice; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration; D012737:Sex Factors; D014029:Tobacco Use Disorder / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
chemical_list: D018722:Nicotinic Agonists; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D009538:Nicotine