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.

项目概要 长期接触烟草制品中的尼古丁会导致多种健康后果（肺癌、 肺气肿、高血压等），每年导致超过 600 万人死亡。其中复发率很高 那些试图戒烟的人以及旨在促进戒烟的药物疗法有限 效力。因此，对于治疗尼古丁依赖的更有效的策略存在显着的未满足的需求。 接触尼古丁会产生身体依赖性，以及身体和/或情感上的尼古丁戒断 与尼古丁的奖励作用相比，症状通常是最重要的因素 复发。不幸的是，很少有研究探讨身体依赖性和身体依赖性的重要问题。 尼古丁戒断机制。事实上，我们对以下问题的理解存在着严重的知识差距： 长期接触尼古丁如何建立身体依赖性，从而使吸烟者高度依赖尼古丁 容易复发。在这个项目中，我们将使用小鼠模型来研究内侧缰核（MHB），这是一个小的 最近与尼古丁戒断有关的上丘脑区域的大脑区域 表达异常高水平的几种类型的烟碱乙酰胆碱受体 (nAChR)。乙酰胆碱受体 介导尼古丁的精神活性和成瘾作用，我们打算确定相关的 nAChR 和 MHB 回路涉及尼古丁依赖和戒断。三个独立且互补的 AIM 提出了一些建议，每一项都探讨了 MHB 中尼古丁反应的特定机制。在 AIM 1，我们将利用生物物理和光学技术来确定尼古丁通过什么机制产生急性尼古丁 差异性地激活 MHB 中的特定细胞类型。在 AIM 2 中，我们将采用类似的技术来确定 慢性尼古丁如何选择性地增强戒断途径特定子回路中的神经元活动。 最后，在 AIM 3 中，我们将把生理学技术与新颖的行为/系统方法结合起来，以识别 重要的 MHB 回路参与尼古丁产生身体和/或情绪反应 撤回。这些 AIM 将共同帮助我们解决了解如何戒除尼古丁的问题。 摄入会导致大脑产生厌恶的身体和情感退缩反应，这不可避免地导致 复发。解决这个问题可能会带来新的策略或药物来促进戒烟。