Stress, Anxiety, and Nicotine Withdrawal

压力、焦虑和尼古丁戒断

基本信息

批准号：
7735780
负责人：
Mariella De Biasi
金额：
$ 34.54万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7735780
关键词：
Abstinence Address Affective Affective Symptoms Anxiety Area Back Behavior Behavioral Behavioral Paradigm Biological Factors Boxing Brain Brain region Chronic Cigarette Complex Corticosterone Dimensions Drosophila acetylcholine receptor alpha-subunit Estrus Female Genetic Techniques Genetically Engineered Mouse Goals Habenula Home environment Injection of therapeutic agent Intraperitoneal Injections Investigation Knockout Mice Lentivirus Vector Maintenance Measures Mecamylamine Medial Medical Microinjections Molecular Biology Monitor Mus Nicotine Nicotine Dependence Nicotine Withdrawal Nicotinic Receptors Pharmaceutical Preparations Pharmacology Phase Plasma Play Positioning Attribute Proteins Rewards Role Sex Characteristics Signal Transduction Social Problems Source Stress Subfamily lentivirinae Substance Withdrawal Syndrome Symptoms Tail Suspension Testing Time Tobacco use Validation Wild Type Mouse Withdrawal Withdrawal Symptom aversive conditioning base depression drinking water drug withdrawal genetic manipulation interpeduncular nucleus knock-down male mesolimbic system mutant nicotine abuse novel research study response smoking cessation success tobacco abstinence

项目摘要

Nicotine addiction is a major worldwide medical and social problem that continues to escalate. Affective and somatic symptoms associated with nicotine withdrawal contribute to the difficulty in quitting tobacco use. While current therapies for smoking cessation are helpful, none can claim a very high rate of success. Therefore, there is a great need for a better understanding of the behavioral and biological factors underlying nicotine withdrawal. Stress and anxiety play an important role in the maintenance of nicotine abuse. Anxiety promotes cigarette use and it is also one of the symptoms of withdrawal, making tobacco abstinence more difficult. This application builds on the observation that lack of 4* or α5* nicotinic acetylcholine receptors (nAChRs) significantly reduces somatic signs of withdrawal and reduces anxiety-like responses. 4* and α5* nAChRs are prominently expressed in the medial habenula/interpeduncular nucleus (MHb/IPN) axis. The habenula is a source of negative reward signals and participates in a wide array of behaviors including anxiety and stress. We postulate that 4* and α5* nAChRs in the MHb/IPN axis are in a key position to influence the mesolimbic dopamine system during nicotine withdrawal. Control mice and mice lacking the 4 or the α5 nAChR subunit will be chronically treated with nicotine delivered in the drinking water, and withdrawal will be precipitated by injection of the nAChR antagonist mecamylamine. First, we will examine the role of 4* and α5* nAChRs on anxiety-related responses during withdrawal using a battery of behavioral paradigms. Second, we will ask which manifestations of nicotine withdrawal are directly influenced by the 4* and α5* nAChRs expressed in the MHb/ IPN axis. In those experiments, lentiviral vectors will be used to either re-express 4 or α5 in the MHb or the IPN of 4 and α5 null mice or to knock down the levels of α5 and β4 in MHb and IPN of wild type mice.

尼古丁成瘾是一个全球性的重大医学和社会问题，与尼古丁戒断相关的情感和躯体症状导致戒烟困难，尽管目前的戒烟疗法有帮助，但没有一个可以声称有很高的成功率。因此，非常需要更好地了解尼古丁戒断背后的行为和生物因素。压力和焦虑在尼古丁滥用的维持中发挥着重要作用，焦虑也是尼古丁戒断的症状之一。戒断，使戒烟变得更加困难。该应用建立在以下观察基础上：缺乏 4* 或 α5* 烟碱乙酰胆碱受体 (nAChR) 会显着减少戒断症状和焦虑样反应，4* 和 α5* nAChR 在内侧缰核/脚间核中显着表达。 MHb/IPN）轴是负面奖励信号的来源，参与包括焦虑和压力在内的多种行为。假设 MHb/IPN 轴中的 4* 和 α5* nAChR 在尼古丁戒断过程中处于影响中脑边缘多巴胺系统的关键位置。对照小鼠和缺乏 4 或 α5 nAChR 亚基的小鼠将长期接受饮用水中的尼古丁治疗，并通过注射 nAChR 拮抗剂美加明来促进戒断。首先，我们将检查 4* 和 α5* 的作用。使用一系列行为范式研究 nAChR 对戒断期间焦虑相关反应的影响其次，我们将询问尼古丁戒断的哪些表现直接受到 4* 和 α5* 的影响。在 MHb/IPN 轴中表达的 nAChR 在这些实验中，慢病毒载体将用于在 MHb 或 4 和 α5 缺失小鼠的 IPN 中重新表达 4 或 α5，或降低 MHb 中的 α5 和 β4 水平。和野生型小鼠的IPN。