Translational studies of nicotinic receptor genes: alcohol and nicotine behaviors

描述（由申请人提供）：酒精和尼古丁依赖通常同时发生，各种研究表明，其中一些共同发病可能是由于重叠的遗传因素。来自电生理学研究和酒精和烟草相关表型的啮齿动物模型的证据支持神经元尼古丁受体（nAChRs）可能是这些药物的共同作用位点的假设。nachr是配体门控离子通道，含有一个中心阳离子孔，是尼古丁和内源性激动剂乙酰胆碱的主要靶点。酒精似乎在调节尼古丁与nachr结合的药理学特性中起作用，通常是通过增强受体功能。此外，已知多巴胺能神经元上存在几种尼古丁受体亚型，并参与调节对酒精和尼古丁的多巴胺释放。通过中脑边缘多巴胺能通路，这些受体（包括13-7和22-4亚基）可能与物质使用相关的奖励特性有关。最近的研究提供了证据，证明人类nAChR亚基基因与人类酒精和尼古丁行为有关，包括开始饮酒的年龄、早期主观反应和依赖性。这项提议将从三个方面扩展这些人体研究。首先，将使用来自100个个体的DNA样本对13-6和22-4 nAChR亚基的人类基因进行重新测序，以确定新的变异。其次，这些基因的多种变异将在4146人的样本中进行表征，这些样本的DNA、酒精和尼古丁行为数据已经被收集起来，以测试特定DNA变异与这些行为之间的联系。第三，将采用基于实验室的方法，通过细胞培养测定来确定特定变异是否导致基因表达的差异。

DESCRIPTION (provided by applicant): Alcohol and nicotine dependence commonly co-occur and a variety of research suggests some of this co-morbidity may be due to overlapping genetic factors. Converging evidence from electrophysiology studies and rodent models of alcohol- and tobacco-related phenotypes supports the hypothesis that neuronal nicotinic receptors (nAChRs) may be a common site of action for these drugs. The nAChRs are ligand-gated ion channels containing a central cation pore that act as the primary targets for nicotine and the endogenous agonist acytelcholine. Alcohol appears to play a role in modulating the pharmacological properties of nicotine binding at nAChRs, usually by enhancing receptor function. Furthermore, several nicotinic receptor subtypes are known to be present on dopaminergic neurons and involved in mediating the release of dopamine in response to alcohol and nicotine. Through this mesolimbic dopaminergic pathway, these receptors (including the 13-7 and 22-4 subunits) may contribute to the rewarding properties associated with substance use. Recent work has provided evidence that several of the human nAChR subunit genes are associated with alcohol and nicotine behaviors in humans, including age of initiation, early subjective response, and dependence. This proposal will extend these human studies in three ways. First, the human genes for the 13-6 and 22-4 nAChR subunits will be resequenced using DNA samples from 100 individuals to identify novel variations. Second, multiple variations in these genes will be characterized in a sample of 4,146 individuals, for which DNA and alcohol and nicotine behavioral data have already been collected, to test for associations between specific DNA variations and these behaviors. Third, laboratory-based methods will be conducted to determine whether specific variations lead differences in gene expression using cell culture assays. PUBLIC HEALTH RELEVANCE: Results from each of these aims will facilitate a better understanding of how naturally occurring variations in these genes might contribute to the underlying molecular mechanisms responsible for differences in alcohol and nicotine behaviors. Such knowledge should lead to the development of improved prevention and treatment of individuals who suffer from these disorders.