Nicotinic Control of Forebrain Serotonin

描述（由申请人提供）：项目总结在美国，通过烟草使用对尼古丁上瘾是可预防的主要死亡原因，每年造成近50万人死亡。有20多种疾病与吸烟有关，包括肺癌、慢性阻塞性肺病、心血管疾病和中风。许多吸烟者都希望减少或停止使用烟草；然而，只有不到7%的人能坚持一年或更长时间。越来越多的证据表明，血清素神经传递在尼古丁成瘾的建立和维持中起作用。改良的血清素能神经传递被认为有助于急性尼古丁给药的奖励和抗焦虑特性，以及尼古丁戒断症状。因此，了解尼古丁如何作用于血清素能神经元，可以深入了解烟草使用对健康负面影响的成瘾行为的机制。本提案的目的是系统地确定急性和慢性尼古丁治疗或尼古丁戒断如何影响上升的血清素能途径。采用神经解剖学和药理学方法建立大鼠模型。在目的1中测试的假设是，尼古丁给药和戒断对上升raphe有地形组织和明显的影响。随后的目的是研究这些地形效应背后的机制。在Aim 2中，将确定5-HT-1A受体在促进上升中叶激活的地形控制中的作用。在Aim 3中，我们通过使用免疫标记技术结合超微结构分析，验证了α 4尼古丁受体亚基的不同亚细胞分布可能有助于地形选择效应的假设，以及α 4含受体在亚细胞分布中作为尼古丁暴露的结果而发生变化的假设。对尼古丁如何作用于血清素上行通路的进一步了解，将有助于深入了解尼古丁在大脑中产生的与成瘾行为有关的基本神经化学变化。这一信息很可能与理解血清素如何导致药物成瘾有关。拟议的研究旨在帮助理解尼古丁成瘾如何发展的神经生物学基础，以及为什么它经常与情绪障碍同时发生。研究结果可能为这两个重要的健康问题提供治疗策略。

DESCRIPTION (provided by applicant): Project Summary Addiction to nicotine through tobacco use is the leading preventable cause of death in the US, contributing to almost half a million deaths per year. There are over 20 diseases associated with smoking include lung cancer, chronic obstructive pulmonary disease, cardiovascular disease, and stroke. Many smokers have the desire to reduce or stop using tobacco; however less then 7% are successful for a year or more. Accumulating evidence suggests that serotonin neurotransmission plays a role in the establishment and maintenance of nicotine addiction. Modified serotonergic neurotransmission is thought to contribute to the rewarding and anxiolytic properties of acute nicotine administration, as well as to symptoms of nicotine withdrawal. Therefore understanding how nicotine acts on serotonergic neurons may give insight into the mechanisms participating in addictive behavior that underlie the negative health impact of tobacco use. The Aims of this proposal are designed to systematically determine how acute and chronic nicotine treatment or nicotine withdrawal influences ascending serotonergic pathways. Neuroanatomical and pharmacological methods in a rat model are used. The hypothesis tested in Aim 1 is that nicotine administration and withdrawal have topographically organized and distinct effects on the ascending raphe. Subsequent Aims investigate the mechanisms underlying these topographic effects. In Aim 2, the role of 5-HT-1A receptors have in contributing to the topographic control of activation of the ascending raphe will be determined. In Aim 3 is test the hypotheses that the differential subcellular distribution of the alpha4 nicotinic receptor subunit could contribute t to the topographically selective effects, and that alpha4 containing receptors shift in subcellular distribution as a consequence of nicotine exposure by using immunolabeling techniques coupled with ultrastructural analysis. A further understanding of how nicotine acts on the ascending serotonergic pathways will give insight into the basic neurochemical changes nicotine produces in the brain that are implicated in addictive behavior. This information will likely have relevance for understanding how serotonin contributes to drug addiction in general.Project Narrative The proposed studies are designed to help understand the neurobiological basis of how nicotine addiction develops and why it often co-occurs with mood disorders. The results may suggest treatment strategies for both of these important health issues.