Nicotinic Control of Forebrain Serotonin

通过烟草使用对尼古丁成瘾是美国主要的可预防死亡原因，每年导致近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。许多吸烟者希望减少或停止使用烟草;然而，不到7%的人成功地使用了一年或更长时间。越来越多的证据表明，5-羟色胺神经传递在尼古丁成瘾的建立和维持中起着重要作用。修饰的尼古丁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尼古丁能神经元可能有助于深入了解烟草使用对健康产生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尼古丁能上行通路。使用大鼠模型中的神经解剖学和药理学方法。目标1中检验的假设是，尼古丁给药和戒断对中缝上行具有地形学组织化和独特的影响。随后的目标调查这些地形效应的机制。在目标2中，将确定5-HT-1A受体在促进中缝上行核激活的地形控制中的作用。在目的3中，通过使用免疫标记技术结合超微结构分析，检验以下假设：α 4烟碱受体亚单位的差异亚细胞分布可能有助于地形选择性效应，以及含有α 4受体的亚细胞分布由于烟碱暴露而发生变化。进一步了解尼古丁如何作用于尼古丁能上行通路，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。这些信息可能有助于理解血清素如何促进药物成瘾。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同时发生。研究结果可能为这两个重要的健康问题提出治疗策略。

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.