The Role of Serotonin in Alcohol-Withdrawal Induced Anxiety

描述(申请人提供)：酗酒是一个巨大的公共卫生问题，虽然我们对这种疾病的了解已经有了很大的进步，但我们对导致其慢性复发性质的基本生物学机制的了解仍然存在差距。有人假设，酒精暴露会改变大脑中对情绪调节至关重要的区域的功能，而这些变化是行为持续变化的基础。5-羟色胺系统与一系列精神疾病的病理生理学有关，最明显的是焦虑症和抑郁症。为了与这些情况的共同发病保持一致，5HT系统被认为参与了酒精中毒的发展。改变的5-羟色胺信号被认为有助于渴望和复发，以及增加的负面影响，表现为与酗酒有关的焦虑样行为和焦虑不安的增加。BNST是一种结构，被认为是这些行为改变背后的神经适应部位。此外，BNST内的5HT信号与焦虑样行为有关。然而，5HT调节BNST中突触传递的能力，以及这种调节在酒精暴露后可能发生改变的可能性，尚未得到深入研究。彻底了解酒精暴露对BNST中5HT功能的影响，将为研究酒精戒断引起的焦虑提供重要的机制见解。在初步研究中，我们发现5HT通过激活5HT2C-R来调节BNST的突触传递，酒精暴露改变了BNST中的5HT水平和受体的表达。这些结果支持我们的中心假设：慢性酒精暴露后BNST中5HT2C-R信号的失调与酒精戒断所致的行为障碍有关。以下三个独立但综合的特定目标被提出来检验我们的中心假说：SA#1.检验5HT2C-R增加GABA释放到重要的前馈抑制神经元的假说。SA#2.检验酒精暴露增强BNST中5HT2C-R功能的假设。SA#3.测试酒精暴露后通过激活5HT2C-R而增加焦虑样行为的假设。总之，这项拟议的研究将提供有关5HT2C-R在酒精诱导的神经功能和行为失调中所起作用的重要信息。此外，考虑到5HT2激动剂mCPP能够增加酗酒者的渴望，这项研究可能对渴望和复发都有重要的帮助。了解这些过程背后的分子机制可能会导致更有效的治疗干预。 与公共健康相关：该项目的重点是了解酒精暴露如何改变情绪行为。这个项目的成功完成将使人们更好地理解酒精是如何改变大脑功能的。此外，这些研究可能为如何开发更有效的酒精中毒和焦虑症治疗方法提供洞察力。

DESCRIPTION (provided by applicant): Alcohol abuse is an enormous public health problem and while there have been significant gains in our knowledge of this disorder, there remains a gap in our knowledge of the fundamental biological mechanisms that contribute to its chronic relapsing nature. It has been hypothesized that alcohol exposure modifies function in brain regions critical for regulation of emotion, and that these changes underlie the persistent alterations in behavior. The 5HT system has been implicated in the pathophysiology of a range of psychiatric conditions, most notably anxiety disorders and depression. In keeping with the co-morbidity of these conditions, the 5HT system is proposed to be involved in the development of alcoholism. Altered 5HT signaling has been suggested to contribute to cravings and relapses as well as the increased negative affect, manifested as increased anxiety-like behavior and dysphoria, that is associated with alcohol abuse. The BNST is a structure that has been proposed to be a site of neuroadaptations underlying these behavioral alterations. Further, 5HT signaling within the BNST has been associated with anxiety-like behavior. The ability of 5HT to modulate synaptic transmission in the BNST, and the possibility that this modulation may be altered following ethanol exposure, however, has not been studied in depth. A thorough understanding of the effects of alcohol exposure on 5HT function in the BNST will provide critical mechanistic insight in to alcohol-withdrawal induced anxiety. In preliminary studies, we show that 5HT modulates synaptic transmission in the BNST via activation of 5HT2C-R and that alcohol exposure alters 5HT levels and receptor expression in the BNST. These results support our central hypothesis that: Dysregulation of 5HT2C-R signaling in the BNST following chronic ethanol exposure is associated with alcohol withdrawal induced behavioral deficits. The following three separate but integrated Specific Aims are proposed to test our central hypothesis: SA#1. Test the hypothesis that 5HT2C-R increases GABA release on to an important population of feed- forward inhibitory neurons. SA#2. Test the hypothesis that alcohol exposure enhances 5HT2C-R function in the BNST. SA#3. Test the hypothesis that anxiety-like behavior is increased following alcohol exposure through activation of 5HT2C-R. In total, the proposed research will provide essential information concerning the role that the 5HT2C-R plays in alcohol-induced dysregulation of neuronal function and behavior. Further, given the ability of the 5HT2 agonist, mCPP, to increase craving in alcoholics, this study could shed important light on both craving and relapse. Understanding molecular mechanisms that underlie these processes could lead to more effective therapeutic interventions. PUBLIC HEALTH RELEVANCE: The focus of this project is to understand how alcohol exposure alters emotional behavior. Successful completion of this project will result in a greater understanding of how alcohol changes brain function. Further, these studies may provide insight as to how to develop more useful treatments for alcoholism and anxiety disorders.