A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology
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 pol...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
26 July 2016
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| In: |
Translational Psychiatry
Year: 2016, Volume: 6, Issue: 7 |
| ISSN: | 2158-3188 |
| DOI: | 10.1038/tp.2016.132 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/tp.2016.132 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/tp2016132 
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| Author Notes: | R.E. Bernardi, K. Zohsel, N. Hirth, J. Treutlein, M. Heilig, M. Laucht, R. Spanagel and W.H. Sommer |
| Summary: | 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. |
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| Item Description: | Gesehen am 03.07.2019 |
| Physical Description: | Online Resource |
| ISSN: | 2158-3188 |
| DOI: | 10.1038/tp.2016.132 |