Identifying nicotine withdrawal mechanisms hidden within habenular complexity

识别隐藏在缰核复杂性中的尼古丁戒断机制

• 批准号: 9699459
• 负责人: Ryan Michael Drenan
• 金额: $ 34.88万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9699459
• 关键词: Acute; Affective; Area; Behavior; Behavioral; Biophysics; Brain; Cells; Cessation of life; Chronic; Collection; Data; Dependence; Development; Down-Regulation; Drug Targeting; Drug usage; Effectiveness; Electrophysiology (science); Emotional; Exhibits; Fostering; Genetic; Goals; Habenula; Health; Human; Hypertension; Inferior; Intake; Knock-out; Knowledge; Label; Laboratories; Lateral; Lead; Malignant neoplasm of lung; Medial; Mediating; Methods; Microscopy; Molecular; Mouse Strains; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Optical Methods; Optics; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Physical Dependence; Physiology; Positioning Attribute; Problem Solving; Process; Pulmonary Emphysema; Relapse; Research; Research Project Grants; Resistance; Rewards; Role; Slice; Smoker; System; Techniques; Time; Tobacco Dependence; United States; Universities; Withdrawal; Withdrawal Symptom; addiction; cell type; comparative; desensitization; dopamine system; experience; experimental study; gene gun; genome wide association study; innovation; mouse model; nicotine cessation; nicotine exposure; novel; receptor; receptor expression; research study; response; smoking cessation; tobacco products; tool

PROJECT SUMMARY Chronic exposure to nicotine in tobacco products results in numerous health consequences (lung cancer, emphysema, hypertension, etc.) and accounts for over 6 million deaths per year. Relapse rates are high among those who attempt to quit smoking, and pharmacotherapies that seek to foster smoking cessation have limited effectiveness. Thus, there is a significant unmet need for more effective strategies to treat nicotine dependence. Nicotine exposure produces physical dependence, and the physical and/or emotional nicotine withdrawal symptoms – as compared to the rewarding effects of nicotine – are often the most important contributors to relapse. Unfortunately, few research studies have probed the important question of physical dependence and nicotine withdrawal mechanisms. Indeed, a critical gap in knowledge exists regarding our understanding of how chronic nicotine exposure establishes physical dependence and therefore makes smokers highly susceptible to relapse. In this project, we will use mouse models to study the medial habenula (MHB), a small brain area in the epithalamic region that has recently been implicated in nicotine withdrawal, and which expresses extraordinarily high levels of several types of nicotinic acetylcholine receptors (nAChRs). nAChRs mediate the psychoactive and addictive action of nicotine, and we intend to identify the relevant nAChRs and MHB circuits involved in nicotine dependence and withdrawal. Three independent and complementary AIMs are proposed, each of which probes a specific mechanistic aspect of the response to nicotine in the MHB. In AIM 1, we will use biophysical and optical techniques to determine through what mechanisms acute nicotine differentially activates specific cell types in MHB. In AIM 2, we will employ similar techniques to determine how chronic nicotine selectively enhances neuronal activity in a specific sub-circuit of the withdrawal pathway. Finally, in AIM 3, we will couple physiology techniques with a novel behavioral/systems approach to identify important MHB circuits involved in generating physical and/or emotional responses during nicotine withdrawal. Together, these AIMs will help us solve the problem of understanding how cessation of nicotine intake causes the brain to generate aversive physical and emotional withdrawal responses that inevitably lead to relapse. Solving this problem could lead to new strategies or drugs to foster smoking cessation.

项目摘要 长期暴露于烟草产品中的尼古丁会导致许多健康后果（肺癌， 肺气肿，高血压等），每年死亡超过600万。复发率很高 那些试图戒烟的人以及试图促进戒烟的药物治疗 效力。这是对治疗尼古丁依赖性的更有效策略的重要需求。 尼古丁暴露会产生身体依赖，以及身体和/或情绪尼古丁的戒断 与尼古丁的奖励作用相比，症状通常是最重要的原因 复发。不幸的是，很少有研究调查了身体依赖的重要问题和 尼古丁提取机制。确实，知识存在的重要差距关于我们的理解 慢性尼古丁暴露如何建立身体依赖，因此使吸烟者高度高 容易缓解。在这个项目中，我们将使用鼠标模型来研究内侧Habenula（MHB），这是一个小的 尼古丁戒断中最近隐含的上皮区域的大脑区域 表达几种类型的烟碱乙酰胆碱受体（NACHR）的高水平。 nachrs 调解尼古丁的精神活性和其他作用，我们打算确定相关的nachrs和 MHB电路涉及尼古丁依赖性和退出。三个独立和完整的目标 提出了提出的，每个人都会在MHB中投射出对尼古丁反应的特定机械方面。在 AIM 1，我们将使用生物物理和光学技术来确定哪些机制急性尼古丁 在MHB中激活特定的细胞类型的不同。在AIM 2中，我们将采用类似的技术来确定 慢性尼古丁如何在戒断途径的特定亚电路中选择性增强神经元活性。 最后，在AIM 3中，我们将将生理学技术与一种新颖的行为/系统方法相结合，以识别 在尼古丁期间产生身体和/或情绪反应的重要MHB电路 提取。这些目标在一起将有助于我们解决了解尼古丁的停止的问题 摄入导致大脑产生厌恶性的身体和情感戒断反应，不可避免地会导致 缓解。解决此问题可能会导致新的策略或药物来促进戒烟。