The a5 nicotinic subunit & drug withdrawal

a5烟碱亚基

• 批准号: 7754719
• 负责人: Erika Edith Perez
• 金额: $ 3.48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7754719
• 关键词: Address; Affect; Agitation; Alcohol Withdrawal Delirium; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Animals; Anxiety; Area; Attenuated; Back; Behavior; Behavioral; Biological; Boxing; Brain; Brain region; Complex; Data; Development; Diagnosis; Disease; Doctor of Philosophy; Drosophila acetylcholine receptor alpha-subunit; Epidemiology; Ethanol; Ethanol Metabolism; Event; Fellowship; Fostering; Frustration; Genes; Genetic; Goals; Habenula; Head; Health Educators; Healthcare Systems; Human; Individual; Injection of therapeutic agent; Knockout Mice; Laboratory Finding; Laboratory Study; Lead; Lentivirus Vector; Literature; Measures; Medial; Mentorship; Microinjections; Minority-Serving Institution; Molecular; Monitor; Morbidity - disease rate; Mus; National Research Service Awards; Neurons; Neurosciences; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Pharmaceutical Preparations; Play; Population; Postdoctoral Fellow; Process; Proteins; Reporting; Research; Role; Seizures; Series; Single Nucleotide Polymorphism; Smoke; Smoker; Stress; Students; Subfamily lentivirinae; Symptoms; System; Testing; Thinking; Time; Tobacco; Tobacco use; Training; Tremor; Universities; Water; Withdrawal; Withdrawal Symptom; addiction; alcohol exposure; base; cancer risk; career; cigarette smoking; coping; craving; depression; design; drug withdrawal; experience; health disparity; insight; interest; interpeduncular nucleus; knock-down; neuromechanism; professor; public health relevance; receptor; research study; response; reward processing; success; tool

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.

描述（由申请人提供）：焦虑水平增加通常是在乙醇戒断期间报告的，被认为是停止乙醇消费的有力威慑。该建议的中心假设是，含aS （a5*）烟碱乙酰胆碱受体（nAChRs）是酒精戒断焦虑相关表现的重要调节剂。这一假设基于实验室数据，表明缺乏a5 nAChR亚基可以降低基础条件和乙醇戒断期间的焦虑水平。此外，据估计，酒精依赖人群中吸烟的比例超过80%，这表明尼古丁可能是为了减轻酒精戒断带来的焦虑。目的1将通过对长期酒精治疗的a5 +/+和a5 -/-小鼠进行一系列行为实验，研究a5* nachr在酒精戒断焦虑相关表现中的作用。目的2将检查尼古丁和酒精之间的相互作用，通过检查乙醇和尼古丁治疗的动物在一次戒断一种药物或同时戒断两种药物时的焦虑反应。实验将在野生型和a5 -/-小鼠中进行，以评估aS nAChR亚基在尼古丁/乙醇相互作用中的作用。目的3将探讨在内侧束/脚间核（MHb/IPN）轴上表达的a5* nachr对乙醇戒断的焦虑样表现至关重要的假设。这些实验的基础是MHb/IPN轴对尼古丁戒断的表达至关重要，而habenular复合体参与了人类的压力和抑郁反应。实验将使用慢病毒结构将a5敲回到aS -/-小鼠的MHb/IPN中，或将a5敲低到C57BI/6J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，给卫生保健系统带来负担。识别和理解潜在戒断的神经元回路将有助于设计更好的戒烟策略，使酒精和尼古丁同时滥用。基于最近的文献，我们的研究特别有趣，这些文献强调了a5单核苷酸多态性在酒精和尼古丁依赖中的作用。公共卫生相关性：这次NRSA奖学金培训的目标是进一步发展我作为一名神经科学家，并为自己在研究型大学或少数民族服务机构的教授生涯做好准备。我对神经科学的兴趣源于我的本科研究经历和作为健康教育者的经历，我对健康差异的兴趣，以及我在研究生课程中的经历。我目前对成瘾的神经机制很感兴趣，特别是对尼古丁和酒精。我在这个申请中提出的实验可以让我通过提出假设，设计实验来使用现代分子生物学工具来验证这些假设，并从结果数据中得出适当的结论，从而培养我的批判性思维能力。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，我希望作为一名博士后继续我在成瘾方面的研究，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，通过互补的分子/细胞和系统神经科学方法来研究成瘾，并为其他学生提供为我的成功铺平道路的指导。我的科学事业目标是进一步加深我们对成瘾的理解，从分子事件的水平到促进滥用的潜在过程。