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We have developed a humanized mouse model of the most common functional OPRM1 polymorphism rs1799971_A&gt;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 (<jats:italic>n<\/jats:italic>=17) and female (<jats:italic>n<\/jats:italic>=26) mice homozygous either for the major human A allele (AA) or the minor G allele (GG) underwent eight daily 2\u2009h sessions of nicotine self-administration. Furthermore, male (<jats:italic>n<\/jats:italic>=104) and female (<jats:italic>n<\/jats:italic>=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.<\/jats:p>","DOI":"10.1038\/tp.2016.132","type":"journal-article","created":{"date-parts":[[2016,7,26]],"date-time":"2016-07-26T13:45:27Z","timestamp":1469540727000},"page":"e861-e861","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology"],"prefix":"10.1038","volume":"6","author":[{"given":"R E","family":"Bernardi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Zohsel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Hirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Treutlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Heilig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Laucht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Spanagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W H","family":"Sommer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,7,26]]},"reference":[{"key":"BFtp2016132_CR1","unstructured":"WHO Global Health Risks: Morality and Burden of Disease Attributable to Selected Major Risks. 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