Characterizing Alpha5* Nicotinic Receptors in Alcohol and Nicotine Co-Dependence

描述(申请人提供)：烟草使用是可预防的疾病、残疾和死亡的主要原因。在美国，过度饮酒是可预防死亡的第三大原因。尽管成瘾占大脑相关疾病的40%以上，但创新的治疗方法却很匮乏。酒精和尼古丁成瘾通常被视为独立的疾病，尽管大多数有酒精使用障碍的人也吸烟，在戒酒期间继续吸烟会导致显著更高的复发率。这些发现表明，酒精和尼古丁成瘾可能形成并依赖于共同的途径。最近，大量的人类遗传关联研究表明，神经元尼古丁受体(NAChRs)，如a5nAChR亚单位在酒精和尼古丁依赖过程中起关键作用，最近的分子研究表明，a5nAChR亚单位改变了a4b2*nAChRs的活性。我们的主要目标是应用一种整合基础和临床研究的多学科方法，以确定nAChRs在酒精和尼古丁消费以及物质使用障碍中作用的分子基础，目的是产生药物和治疗策略。在项目的第一部分，我们将结合行为和电生理学研究，有两个目标：1)表征a5*nAChRs在乙醇、尼古丁和varenicline的行为效应中的作用；2)测量腹侧被盖区多巴胺神经元中a4b2*nAChRs的表达和突触特性，腹侧被盖区是大脑中在尼古丁和乙醇增强特性中发挥关键作用的区域。我们开发的一种创新的饮酒模式极大地促进了这些研究，该模式使乙醇和尼古丁可以一起消费，而不需要糖精。在项目的第二部分，我们将结合临床研究和遗传学来确定nAChRs的遗传变异是否与临床特征为尼古丁依赖和危险饮酒的队列中对varenicline的反应相关。有两个主要目标：1)测量varenicline作为危险饮酒治疗的有效性，2)对受试者进行基因分型，并评估编码nAChRs的基因多态是否缓和了varenicline减少酗酒的效果。将遗传分析与人类对varenicline的反应联系起来，将为我们提供一种手段，用来衡量varenicline减少酒精使用障碍的有效性，并确定对varenicline的反应是否存在潜在的遗传差异。我们的总体目标是加快开发更有效的药物，并改进和个性化药物使用障碍的治疗策略。 公共卫生相关性：我们开发了一个多学科合作研究计划，重点是确定神经元尼古丁受体(NAChRs)在酒精和尼古丁消费和物质使用障碍中作用的分子基础，目标是产生药物和治疗策略。我们建议结合行为学和电生理学来确定a5*nAChRs在酒精和尼古丁消费中作用的分子基础，并在临床特征为尼古丁依赖和危险饮酒的队列中确定nAChRs的遗传变异是否与对varenicline的反应相关。从这项提案中获得的研究将促进针对nAChRs的药物的开发，用于治疗酒精和物质使用障碍。

DESCRIPTION (provided by applicant): Tobacco use is the leading cause of preventable disease, disability, and death. Excessive alcohol consumption is the number-three cause of preventable death in the United States. Despite the fact that addiction represents more than 40% of brain-related illnesses, there is a dearth of innovative treatments. Alcohol and nicotine addiction are often treated as separate disorders even though most people with alcohol use disorders also smoke, and continued tobacco use during abstinence from alcohol leads to significantly higher relapse rates. These findings suggest that alcohol and nicotine addictions may develop, and depend on, common pathways. Recently, a large number of human genetic association studies have implicated the neuronal nicotinic receptors (nAChRs), such as the a5 nAChR subunit as playing a critical role in developing alcohol and nicotine dependence processes and recent molecular studies indicate that the a5 nAChR subunit changes the activity of a4b2* nAChRs. Our main objective is to apply a multidisciplinary approach that integrates basic and clinical research to define the molecular basis of the role of nAChRs in ethanol and nicotine consumption and substance use disorders with the goal of generating medications and treatment strategies. In the first part of the project, we will combine behavior and electrophysiology studies and there are two objectives: 1) to characterize the role of the a5* nAChRs in the behavioral effects of ethanol and nicotine and varenicline and 2) to measure the expression and synaptic properties of a4b2* nAChRs responses in dopamine neurons in the ventral tegmental area, a brain region that plays a key role in the reinforcing properties of nicotine and ethanol. These studies have been greatly facilitated by an innovative drinking model we developed that enables ethanol and nicotine to be consumed together without the need for saccharin. In the second part of the project, we will combine clinical studies and genetics to determine whether genetic variants in nAChRs correlate with response to varenicline in a cohort clinically characterized for nicotine dependence and hazardous alcohol use. There are two major objectives: 1) to measure the effectiveness of varenicline, as a treatment for hazardous alcohol use and 2) to genotype the subjects and assess whether polymorphisms in the genes encoding for nAChRs moderate the effect of varenicline to reduce heavy drinking. The linking of genetic analyses with human responses to varenicline will provide a means by which we can measure both the efficacy of varenicline for diminishing alcohol use disorders and to determine whether there are underlying genetic differences in responses to varenicline. Our overall goal is to accelerate the development of more effective medications, and to improve and personalize treatment strategies for substance use disorders. PUBLIC HEALTH RELEVANCE: We have developed a multidisciplinary collaborative research program focused on defining the molecular basis of the role of neuronal nicotinic receptors (nAChRs) in ethanol and nicotine consumption and substance use disorders with the goal of generating medications and treatment strategies. We propose to combine behavior and electrophysiology to define the molecular basis of the role of a5* nAChRs in ethanol and nicotine consumption and determine whether genetic variants in nAChRs correlate with response to varenicline in a cohort clinically characterized for nicotine dependence and hazardous alcohol use. The research garnered from this proposal will facilitate the development of medications that target nAChRs for the treatment of alcohol and substance use disorders.