Examining nicotine relapse in the habenulo-interpeduncular system

项目总结 长期接触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)每年造成600多万人死亡。复发率很高，在 那些试图戒烟的人和寻求促进戒烟的药物疗法都是有限的 有效性。因此，对治疗尼古丁依赖的更有效策略的需求仍未得到满足。 尼古丁暴露会产生身体依赖，身体和/或情感上的尼古丁戒断 症状--与尼古丁的有益效果相比--往往是导致 旧病复发。重要的是，尼古丁的渴望和复发的风险往往在戒烟开始后1到2周达到顶峰。 禁欲。不幸的是，很少有研究探讨如何/为什么复发这一重要问题。 行为就会发展。事实上，在我们对慢性疾病的理解方面，存在着严重的知识差距 在戒烟期间，尼古丁暴露会鼓励人们寻求尼古丁。在这个项目中，我们将使用一种老鼠尼古丁自身 内侧缰核和脚间核给药模型的研究 构成尼古丁相关行为的关键途径。烟碱型乙酰胆碱受体(NAChRs)， 尼古丁的药理靶标，在这一途径中密集表达，并与尼古丁的 具有精神活性和成瘾性。在这个项目中，我们打算识别相关的nAChRs和Brain 在戒烟过程中参与尼古丁寻求的回路。三个独立和互补的目标是 其中每一个都探讨了复发行为的一个特定的机制方面。在目标1中，我们将使用 生物物理技术、双光子成像和纤维光度法探索MHB之间的关系 戒酒过程中的神经元活动和尼古丁寻求。目标2将使用电生理学，双光子成像， 以及一种DREADD方法来研究IPN神经元在尼古丁寻找中的作用。最后，AIM 3将确定 烟碱寻找过程中的特异性IPN nAChRs及烟碱胆碱能受体的重要性 产生尼古丁渴求和由此产生的尼古丁寻求的活动。共同努力，这些目标将帮助我们 了解停止尼古丁摄取如何导致大脑产生令人厌恶的身体和情绪 不可避免地导致旧病复发的戒断反应。解决这个问题可能会带来新的策略或药物 以促进戒烟。

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.