Examining nicotine relapse in the habenulo-interpeduncular system

项目摘要 长期接触烟草制品中的尼古丁会导致许多健康后果（肺癌， 肺气肿、高血压等）每年有超过600万人因此死亡复发率很高， 那些试图戒烟的人，以及寻求促进戒烟的药物治疗， 有效性因此，对于治疗尼古丁依赖的更有效的策略存在显著未满足的需求。 尼古丁暴露会产生身体依赖性，身体和/或情绪上的尼古丁戒断 症状-与尼古丁的奖励作用相比-通常是最重要的贡献者， 复发重要的是，尼古丁渴望和复发风险往往在开始吸烟后1至2周达到峰值。 禁欲不幸的是，很少有研究探讨了如何/为什么复发的重要问题， 行为发展。事实上，在我们对慢性病如何发生的理解方面， 尼古丁暴露会鼓励禁欲期间寻求尼古丁。在这个项目中，我们将使用大鼠尼古丁自我- 给药模型，以研究内侧缰核（MHb）和脚间核（IPN），它们共同 包括尼古丁相关行为的关键途径。烟碱乙酰胆碱受体（nAChR）， 尼古丁药理学靶点在该途径中密集表达，并负责尼古丁的 精神活性和成瘾特性。在这个项目中，我们打算确定相关的nAChRs和大脑 在戒烟期间参与尼古丁寻求的回路。三个独立和互补的目标是 提出，其中每一个探针复发样行为的一个特定的机制方面。在AIM 1中，我们将使用 生物物理技术、双光子成像和纤维光度法来探讨MHb与 戒断期间的神经元活动和尼古丁寻求。AIM 2将使用电生理学，双光子成像， 和DREADD方法来检查IPN神经元在尼古丁寻求中的作用。最后，AIM 3将识别 特异性IPN nAChRs参与尼古丁寻求并决定烟碱胆碱能受体的重要性 产生尼古丁渴望和由此产生的尼古丁寻求的活动。这些目标将帮助我们 了解停止尼古丁摄入如何导致大脑产生厌恶的身体和情绪 不可避免地导致复发的戒断反应。解决这个问题可能会导致新的策略或药物 来促进戒烟。

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. Importantly, nicotine cravings and the risk for relapse tend to peak 1 to 2 weeks after the beginning of abstinence. Unfortunately, few research studies have probed the important question of how/why relapse behavior develops. Indeed, a critical gap in knowledge exists regarding our understanding of how chronic nicotine exposure encourages nicotine seeking during abstinence. In this project, we will use a rat nicotine self- administration model to study the medial habenula (MHb) and interpeduncular nucleus (IPN), which together comprise a crucial pathway involved in nicotine-related behaviors. Nicotinic acetylcholine receptors (nAChRs), the pharmacological target of nicotine, are densely expressed in this pathway and are responsible for nicotine's psychoactive and addictive properties. In this project, we intend to identify the relevant nAChRs and brain circuits involved in nicotine seeking during abstinence. Three independent and complementary AIMs are proposed, each of which probes a specific mechanistic aspect of relapse-like behavior. In AIM 1, we will use biophysical techniques, 2-photon imaging, and fiber photometry to probe the relationship between MHb neuronal activity and nicotine seeking during abstinence. AIM 2 will use electrophysiology, 2-photon imaging, and a DREADD approach to examine the role of IPN neurons in nicotine seeking. Finally, AIM 3 will identify specific IPN nAChRs involved in nicotine seeking and determine the importance of nicotinic cholinergic receptor activity in producing nicotine craving and resultant nicotine seeking. Together, these AIMs will help us understand 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.