The a5 nicotinic subunit & drug withdrawal

描述(由申请者提供)：在酒精戒断过程中，焦虑水平的增加通常被报道，并被认为是停止酒精消费的有效威慑。这一建议的中心假设是，含砷(a5*)的烟碱型乙酰胆碱受体(NAChRs)是酒精戒断焦虑相关表现的重要调节器。这一假说是基于实验室的数据，数据显示，缺乏a5 nAChR亚单位可以降低基础状态和酒精戒断期间的焦虑水平。此外，据估计，酒精依赖人群中的吸烟率超过80%，这表明人们可能会摄入尼古丁，试图缓解戒酒带来的焦虑。目的1通过对长期酒精处理的a5+/+和a5-/-小鼠的一系列行为学实验，研究a5*nAChRs在酒精戒断焦虑相关表现中的作用。目标2将通过检测酒精和尼古丁处理的动物的焦虑样反应来检查尼古丁和酒精之间的相互作用，这些动物一次停用一种药物或同时停用两种药物。实验将在野生型和a5-/-小鼠身上进行，以评估AS nAChR亚单位在尼古丁/乙醇相互作用中的作用。目的3提出的假设是，在内侧缰核/脚间核(MHB/IPN)轴表达的a5*nAChRs是酒精戒断焦虑样表现的关键。这些实验是基于这样一个事实，即MHB/IPN轴对尼古丁戒断的表达至关重要，缰核复合体参与人类的应激和抑郁反应。这些实验将使用慢病毒构建物将a5反击到AS-/-小鼠的MHB/IPN中，或者将A5反击到C57BI/6J小鼠的MHB/IPN中。酒精和烟草的共同滥用会增加患癌症和其他疾病的风险，从而给医疗保健系统带来负担。识别和理解戒断背后的神经元回路将有助于设计更好的戒酒和尼古丁联合滥用患者的戒烟策略。我们的研究特别令人感兴趣，基于最近的文献，强调了a5单核苷酸多态在酒精和尼古丁依赖中的作用。公共卫生相关性：NRSA奖学金培训的目标是促进我作为一名神经学家的发展，并为我在研究型大学或少数族裔服务机构担任教授的职业生涯做好准备。我对神经科学的兴趣始于我的本科研究和健康教育经验，我对健康差距的兴趣，以及我在研究生课程中的经验。目前，我对成瘾的神经机制很感兴趣，尤其是尼古丁和酒精。我在本申请中提出的实验将使我能够通过制定假设、设计实验来使用现代分子生物学工具来检验这些假设，并从结果数据中得出适当的结论来培养我的批判性思维能力。由于我被神经科学领域解释人类行为的潜力所吸引，在获得博士学位后，我希望继续我的成瘾研究，作为一名博士后研究员，从基因和系统层面研究这种疾病。最终，我计划领导自己的研究实验室，通过补充分子/细胞和系统神经科学的方法来研究成瘾，并为其他学生提供为我的成功铺平道路的导师类型。我的科学生涯目标是加深我们对成瘾的理解，从分子事件的层面到助长滥用的潜在过程。

DESCRIPTION (provided by applicant): Increased anxiety levels are commonly reported during ethanol withdrawal and are considered a potent deterrent for the cessation of ethanol consumption. The central hypothesis of this proposal is that aS- containing (a5*) nicotinic acetylcholine receptors (nAChRs) are important modulators of the anxiety-related manifestations of alcohol withdrawal. This hypothesis is based on data from the lab showing that lack of the a5 nAChR subunit reduces anxiety levels in basal conditions and during ethanol withdrawal. In addition, smoking in the alcohol dependent population is estimated to be in excess of 80 percent, suggesting that nicotine might be consumed in the attempt to mitigate the anxiety produced by alcohol withdrawal. Aim 1 will examine the role of a5* nAChRs in the anxiety-related manifestations of ethanol withdrawal through a series of behavioral experiments in a5 +/+ and a5 -/- mice chronically treated with alcohol. Aim 2 will examine the interaction between nicotine and alcohol by examining anxiety-like responses in ethanol and nicotine treated animals undergoing withdrawal of one drug at a time or both drugs simultaneously. Experiments will be conducted in wild type and a5 -/- mice to assess the role of the aS nAChR subunit in the nicotine/ethanol interaction. Aim 3 will address the hypothesis that the a5* nAChRs expressed in the medial habenula/ interpeduncular nucleus (MHb/IPN) axis are critical for the anxiety-like manifestations of ethanol withdrawal. These experiments are based on the fact that the MHb/IPN axis is crucial for the expression of nicotine withdrawal and that the habenular complex participates in stress and depression responses in humans. The experiments will use lentiviral constructs to either knock back a5 into the MHb/IPN of aS -/- mice or knock down a5 into the MHb/IPN of C57BI/6J mice. The co-abuse of alcohol and tobacco leads to an increased risk of cancer and other diseases, resulting in a burden to the health care system. The identification and understanding of the neuronal circuits underlying withdrawal will be useful in the design of better cessation strategies in subjects with alcohol and nicotine co- abuse. Our studies are of particular interest based on the recent literature highlighting the role of a5 single nucleotide polymorphisms in alcohol and nicotine dependence. PUBLIC HEALTH RELEVANCE: The goal of this NRSA fellowship training is to further my development as a neuroscientist and prepare myself for a career as a professor at either a research university or a minority serving institution. My interests in neuroscience began as a result of my undergraduate experience in research and as a health educator, my interest in health disparities, and my experiences in graduate coursework. I am presently interested in the neural mechanisms underlying addiction, in particular to nicotine and alcohol. The experiments that I propose in this application will allow me to cultivate my critical thinking abilities through formulating hypotheses, designing experiments to test these hypotheses using modern molecular biological tools, and drawing appropriate conclusions from resulting data. As I was drawn to the field of neuroscience by its potential to explain human behavior, after graduating with a Ph.D., I hope to continue my research in addiction as a postdoctoral fellow studying this disease at the genetic and systems level. Ultimately, I plan to head my own research laboratory studying addiction through complementary molecular/cellular and systems neuroscience approaches as well as provide the type of mentorship that has paved the way to my success to other students. My scientific career goal is to further our understanding of addiction from the level of molecular events to the underlying processes that foster abuse.