Nicotinic Control of Forebrain Serotonin

描述(由申请者提供)：项目摘要通过烟草使用尼古丁成瘾是美国最主要的可预防的死亡原因，每年导致近50万人死亡。与吸烟有关的疾病有20多种，包括肺癌、慢性阻塞性肺疾病、心血管疾病和中风。许多吸烟者都有减少或停止吸烟的愿望；然而，在一年或更长时间内成功戒烟的不到7%。越来越多的证据表明，5-羟色胺的神经传递在尼古丁成瘾的建立和维持中发挥了作用。修饰的5-羟色胺能神经传递被认为有助于急性尼古丁给药的回报和缓解焦虑的特性，以及尼古丁戒断的症状。因此，了解尼古丁如何作用于5-羟色胺能神经元，可能有助于深入了解参与成瘾行为的机制，这些成瘾行为是烟草使用对健康造成负面影响的基础。这项建议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5-羟色胺能上升通路。采用神经解剖学和药理学方法制作大鼠模型。在目标1中检验的假设是尼古丁的给药和戒断在地形图上对上升中缝有组织和明显的影响。随后的目的是研究这些地形效应背后的机制。在目标2中，将确定5-羟色胺-1A受体在激活上行中缝的地形图控制中所起的作用。在目标3中，用免疫标记技术结合超微结构分析来检验假设，即α4尼古丁受体亚单位的不同亚细胞分布可能有助于地形图选择效应，以及含有α4受体的亚细胞分布因尼古丁暴露而发生变化的假设。进一步了解尼古丁如何作用于上升的5-羟色胺能通路，将使我们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。这些信息可能会对了解5-羟色胺如何导致药物成瘾具有相关性。项目叙述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并存。这一结果可能会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.