Translational studies of nicotinic receptor genes: alcohol and nicotine behaviors

描述(申请人提供)：酒精和尼古丁依赖通常是同时发生的，各种研究表明，这种共同发病的一些可能是由于重叠的遗传因素造成的。来自电生理学研究和与酒精和烟草相关的表型的啮齿动物模型的聚合证据支持这样的假设，即神经元尼古丁受体(NAChRs)可能是这些药物的共同作用部位。NAChRs是含有一个中心阳离子孔的配体门控离子通道，它是尼古丁和内源性激动剂乙酰胆碱的主要靶点。酒精似乎通过增强受体功能来调节尼古丁与nAChRs结合的药理学特性。此外，已知在多巴胺能神经元上存在几种尼古丁受体亚型，并参与调节多巴胺对酒精和尼古丁的反应。通过这种中脑边缘多巴胺能途径，这些受体(包括13-7和22-4亚基)可能有助于与物质使用相关的奖赏特性。最近的工作提供了证据表明，人类nAChR亚单位的几个基因与人类的酒精和尼古丁行为有关，包括开始年龄、早期主观反应和依赖。这项提案将从三个方面扩展这些人体研究。首先，将使用100个个体的DNA样本对人类13-6和22-4nAChR亚基的基因进行重新测序，以识别新的变异。其次，这些基因的多个变异将在4146个个体的样本中进行表征，已经收集了这些个体的DNA、酒精和尼古丁行为数据，以测试特定DNA变异与这些行为之间的关联。第三，将进行基于实验室的方法，通过细胞培养分析来确定特定的变异是否会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.