The a5 nicotinic subunit & drug withdrawal

描述（由申请人提供）：在乙醇戒断期间通常报告焦虑水平增加，并被认为是停止乙醇消耗的有效威慑因素。该提议的中心假设是含α 5的（α 5 *）烟碱乙酰胆碱受体（nAChR）是酒精戒断的焦虑相关表现的重要调节剂。这一假设是基于实验室的数据，表明缺乏α 5 nAChR亚基可以降低基础条件下和乙醇戒断期间的焦虑水平。此外，酒精依赖人群中的吸烟率估计超过80%，这表明尼古丁可能是为了减轻酒精戒断所产生的焦虑。目的1将通过在长期用酒精处理的a5 +/+和a5 -/-小鼠中的一系列行为实验来检查a5* nAChR在乙醇戒断的焦虑相关表现中的作用。目的2将通过检查乙醇和尼古丁处理动物中的焦虑样反应来检查尼古丁和酒精之间的相互作用，这些动物一次戒断一种药物或同时戒断两种药物。将在野生型和α 5-/-小鼠中进行实验以评估aS nAChR亚基在尼古丁/乙醇相互作用中的作用。目的3将解决的假设，在内侧缰/脚间核（MHb/IPN）轴中表达的α 5 * nAChR是关键的焦虑样表现的乙醇戒断。这些实验基于以下事实：MHb/IPN轴对于尼古丁戒断的表达至关重要，并且缰复合体参与人类的应激和抑郁反应。实验将使用慢病毒构建体将α 5敲回到aS -/-小鼠的MHb/IPN中或将α 5敲回到C57 BI/6 J小鼠的MHb/IPN中。同时滥用酒精和烟草会增加患癌症和其他疾病的风险，给保健系统造成负担。识别和理解引起戒断的神经回路将有助于在酒精和尼古丁共滥用受试者中设计更好的戒烟策略。我们的研究是特别感兴趣的基础上，最近的文献突出的作用，α 5单核苷酸多态性的酒精和尼古丁依赖。公共卫生相关性：这个NRSA奖学金培训的目标是进一步发展我作为一个神经科学家，并为自己的职业生涯做好准备，无论是在研究型大学或少数民族服务机构的教授。我对神经科学的兴趣始于我的本科研究经验和健康教育工作者，我对健康差异的兴趣，以及我在研究生课程中的经验。我目前对成瘾的神经机制感兴趣，特别是尼古丁和酒精。我在本申请中提出的实验将使我能够通过制定假设，设计实验来测试这些假设，并从所得数据中得出适当的结论，来培养我的批判性思维能力。当我被神经科学领域解释人类行为的潜力所吸引时，在我获得博士学位后，我希望继续我在成瘾方面的研究，作为一名博士后研究员，在遗传和系统水平上研究这种疾病。最终，我计划领导我自己的研究实验室，通过互补的分子/细胞和系统神经科学方法研究成瘾，并提供指导，为我的成功铺平了道路。我的科学生涯的目标是进一步我们的成瘾从分子事件的水平，以促进滥用的潜在过程的理解。

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.