Stress, Anxiety, and Nicotine Withdrawal

尼古丁成瘾是一个全球性的重大医学和社会问题，并持续升级。与尼古丁戒断相关的情感和躯体症状导致戒烟困难。虽然目前的戒烟疗法是有帮助的，但没有一种疗法可以声称有很高的成功率。因此，非常需要更好地了解尼古丁戒断的行为和生物学因素。压力和焦虑在维持尼古丁滥用中起着重要作用。焦虑促进吸烟，也是戒断症状之一，使戒烟更加困难。 该应用基于以下观察结果：缺乏4* 或α5* 烟碱乙酰胆碱受体（nAChR）显著减少戒断的躯体体征并减少焦虑样反应。4* 和α5* nAChR主要表达于内侧缰核/脚间核（MHb/IPN）轴。缰核是负面奖励信号的来源，参与了包括焦虑和压力在内的一系列行为。我们推测，在尼古丁戒断过程中，MHb/IPN轴中的4* 和α5* nAChR处于影响中脑边缘多巴胺系统的关键位置。 对照小鼠和缺乏4或α5 nAChR亚基的小鼠将接受在饮用水中递送的尼古丁长期治疗，并通过注射nAChR拮抗剂美加明来促使戒断。首先，我们将使用一系列行为范式来研究4* 和α5* nAChRs在戒断过程中对焦虑相关反应的作用。其次，我们将询问尼古丁戒断的哪些表现直接受到MHb/ IPN轴中表达的4* 和α5* nAChR的影响。在这些实验中，慢病毒载体将用于在4和α5缺失小鼠的MHb或IPN中重新表达4或α5，或者用于敲低野生型小鼠的MHb和IPN中α5和β4的水平。

Nicotine addiction is a major worldwide medical and social problem that continues to escalate. Affective and somatic symptoms associated with nicotine withdrawal contribute to the difficulty in quitting tobacco use. While current therapies for smoking cessation are helpful, none can claim a very high rate of success. Therefore, there is a great need for a better understanding of the behavioral and biological factors underlying nicotine withdrawal. Stress and anxiety play an important role in the maintenance of nicotine abuse. Anxiety promotes cigarette use and it is also one of the symptoms of withdrawal, making tobacco abstinence more difficult. This application builds on the observation that lack of 4* or α5* nicotinic acetylcholine receptors (nAChRs) significantly reduces somatic signs of withdrawal and reduces anxiety-like responses. 4* and α5* nAChRs are prominently expressed in the medial habenula/interpeduncu​lar nucleus (MHb/IPN) axis. The habenula is a source of negative reward signals and participates in a wide array of behaviors including anxiety and stress. We postulate that 4* and α5* nAChRs in the MHb/IPN axis are in a key position to influence the mesolimbic dopamine system during nicotine withdrawal. Control mice and mice lacking the 4 or the α5 nAChR subunit will be chronically treated with nicotine delivered in the drinking water, and withdrawal will be precipitated by injection of the nAChR antagonist mecamylamine. First, we will examine the role of 4* and α5* nAChRs on anxiety-related responses during withdrawal using a battery of behavioral paradigms. Second, we will ask which manifestations of nicotine withdrawal are directly influenced by the 4* and α5* nAChRs expressed in the MHb/ IPN axis. In those experiments, lentiviral vectors will be used to either re-express 4 or α5 in the MHb or the IPN of 4 and α5 null mice or to knock down the levels of α5 and β4 in MHb and IPN of wild type mice.