A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology
2016 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 6, no e861Article in journal (Refereed) Published
It has been proposed that vulnerability to nicotine addiction is moderated by variation at the mu-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.
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2016. Vol. 6, no e861
IdentifiersURN: urn:nbn:se:liu:diva-132082DOI: 10.1038/tp.2016.132ISI: 000383420800003PubMedID: 27459726OAI: oai:DiVA.org:liu-132082DiVA: diva2:1038382
Funding Agencies|Bundesministerium fur Bildung und Forschung (BMBF) [FKZ 01EW1112, 01ZX1311A]; Deutsche Forschungsgemeinschaft (DFG) [SPP1226, SP 383/4-1]; DFG2016-10-182016-10-172016-11-11