A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology
A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology
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DOI：
10.1038/tp.2016.132
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发表时间：
2016-07-26
影响因子：
6.8
通讯作者：
Sommer, W. H.
中科院分区：
文献类型：
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作者：
Bernardi, R. E.;Zohsel, K.;Sommer, W. H.
已经有人提出，对尼古丁成瘾的易感性是通过u-阿片受体基因(OPRM1)的变异来缓解的，但来自人类的研究结果各不相同，缺乏基于基因的前瞻性研究。我们已经建立了最常见的功能性OPRM1多态rs1799971_A4G(A118G)的人源化小鼠模型。在这里，我们使用这个模型系统与一群德国年轻人一起研究OPRM1A118G变异对尼古丁奖励的作用。在人源化的小鼠模型中，通过静脉注射检查尼古丁的强化。自治。雄性(n=17)和雌性(n=26)人类主要A等位基因(AA)或次要G等位基因(GG)纯合子的小鼠每天接受8次2小时的尼古丁自我注射。此外，来自曼海姆风险儿童研究的A等位基因纯合或携带G等位基因的男性(n=104)和女性(n=118)受试者在他们最初的吸烟经历中被评估为愉快和不愉快的经历。观察到尼古丁自身给药存在显著的性别-基因效应。雄性118GG小鼠表现出比雄性118AA小鼠更高的尼古丁摄入量，这表明尼古丁强化增加。相比之下，在雌性小鼠中没有基因效应。人类男性G等位基因携带者报告称，与男性纯合子A、女性G和女性纯合子A等位基因携带者相比，他们第一次吸烟带来的愉悦效果更大。118G等位基因似乎使男性对尼古丁强化更敏感，但女性不是。
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.