Nicotine consumption is regulated by a human polymorphism in dopamine neurons

吸烟是全世界范围内可预防的导致发病率和死亡率上升的重要因素。最近的全基因组关联研究表明15号染色体上的一种人类单倍型，该单倍型是烟草依赖和肺癌的潜在风险。几个编码烟碱型乙酰胆碱受体α3、α5和β4亚单位的CHRNA3-CHRNA5-CHRNB4簇的多态性也牵扯其中。我们在小鼠模型中确定了腹侧被盖区多巴胺能神经元中的α5亚单位在控制尼古丁敏感性中起关键作用。首先通过自我给药的方式急性静脉注射尼古丁和对尼古丁诱导的DA细胞激活的体外和体内电生理记录，研究尼古丁对未使用药物的α5−/−小鼠的增强作用。然后设计慢病毒再表达载体，使野生型或突变型α5在VTA或只在多巴胺神经元中定向再表达。结果证实了α5*-nAChRs在多巴胺能神经元中的重要作用。这些受体是决定DA细胞激活和尼古丁强化所需的最小尼古丁剂量的关键调节器。最后，证明了在体内条件下，当错意突变rs16969968存在时（这种突变在很许多人群中都很常见），会导致α5蛋白的部分功能丧失。这导致了在自我给药的实验程式中，尼古丁消费的增加。我们因此定义了一个关键的人类易感标记，将它在多巴胺神经元的表达与尼古丁的摄取联系在一起。

Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and β4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.

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