Role of Brain Nicotinic Receptors in Addiction Behaviors

大脑烟碱受体在成瘾行为中的作用

• 批准号: 7575264
• 负责人: STEPHEN FOX HEINEMANN
• 金额: $ 35.39万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575264
• 关键词: Affinity; Agonist; Animal Model; Behavior; Behavioral; Binding; Binding Sites; Biochemical; Biological Models; Brain; Chronic; Cigarette; Country; Dependence; Drug Addiction; Epidemic; Excision; Exposure to; Family; Genetic; Health; Heart Diseases; Human; In Vitro; Knowledge; Lead; Malignant neoplasm of lung; Mediating; Methods; Molecular; Mus; Mutation; Neurobiology; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Pharmaceutical Preparations; Physiological; Process; Property; Proteins; Receptor Up-Regulation; Recovery; Research; Rodent; Role; Self Administration; Smoker; Smoking; Smoking Behavior; Societies; System; Testing; Time; Tobacco use; United States; Up-Regulation; addiction; cholinergic; combat; depressed; desensitization; design; neurotransmission; novel therapeutic intervention; receptor; response; smoking cessation; tissue culture

Cigarette use has led to an epidemic of lung cancer and heart disease and is the major preventable cause of poor health in the U.S.This epidemic is driven by the desire to feel the effects of nicotine, which are likely mediated by binding of nicotine to neuronal nicotinic acetylcholine receptors (nAChRs). The mechanisms of nicotine dependence are unknown, however, we have discovered a large family of nAChRs expressed in brain. nAChRs with a.4 and (32 subunits have the highest affinity for nicotine and chronic nicotine exposure (smoking) produces an increase, or up-regulation, of these nAChRs in human smokers and animal models. We proposed that long term nicotine exposure changes the properties of nAChRs in brain, and these changes underlie the molecular mechanism of dependence. Initial exposure to nicotine activates nAChRs, but chronic exposure depresses nAChR function (desensitization). Compensatory mechanisms (up-regulation) are induced by chronic nicotine, potentiallyto maintain normal levels of neurotransmission. Removal of agonist via smoking cessation allows recovery of nAChRs, producing an excess of active nAChRs which may contribute to the physiological desire to continue smoking. To test this hypothesis we will examine the mechanism(s) by which nicotine regulates the function and expression of the high affinity a4/|32 nAChRs using tissue culture model systems and lines of genetically altered mice. We propose to investigate the underlying molecular mechanism(s) of nAChR up-regulation using an in vitro expression system in combination with genetic and biochemical methods to characterize several proteins that we have identified that interact with cx4/|32 nAChRs. We will also explore the role of nAChR desensitization in the induction of up-regulation and its effects on behaviors related to nicotine addiction by capitalizingon the effects of several mutations identified in cx4and [32subunits which have contrasting effects on receptor desensitization and may therefore alter receptor up-regulation differently.

吸烟已导致肺癌和心脏病的流行，并且是吸烟的主要可预防原因。 这种流行病是由渴望感受尼古丁的影响所驱动的，这很可能是 通过尼古丁与神经元烟碱乙酰胆碱受体（nAChR）的结合来介导。的机制 尼古丁依赖是未知的，然而，我们已经发现了一个大家族的nAChRs表达在 个脑袋具有α 4和β 2亚基的nAChR对尼古丁和慢性尼古丁暴露具有最高的亲和力 在人类吸烟者和动物模型中，吸烟引起这些nAChR的增加或上调。 我们提出，长期尼古丁暴露改变了大脑中nAChRs的特性，这些变化 依赖的分子机制。最初接触尼古丁会激活nAChR，但慢性 暴露抑制nAChR功能（脱敏）。补偿机制（上调）是 由慢性尼古丁诱导，潜在地维持正常的神经传递水平。除去激动剂 通过戒烟可以恢复nAChRs，产生过量的活性nAChRs， 有助于继续吸烟的生理欲望。为了验证这一假设，我们将研究 尼古丁调节高亲和性A4/A5蛋白的功能和表达的机制|32个nAChR 使用组织培养模型系统和遗传改变的小鼠品系。我们建议调查 使用体外表达系统研究nAChR上调的潜在分子机制， 结合遗传和生物化学方法来表征我们已经鉴定的几种蛋白质， 与cx4/|32个nAChR。我们还将探讨nAChR脱敏在诱导 上调及其对尼古丁成瘾相关行为的影响 在CX 4和[32]亚基中发现的突变对受体脱敏具有相反的作用， 因此不同地改变受体上调。