The Role of Serotonin in Alcohol-Withdrawal Induced Anxiety

描述（由申请人提供）：酒精滥用是一个巨大的公共卫生问题，虽然我们对这种疾病的了解有了重大进展，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。据推测，酒精暴露会改变大脑中调节情绪的关键区域的功能，而这些变化是行为持续改变的基础。5HT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。与这些疾病的合并症保持一致，5HT系统被认为参与了酒精中毒的发展。改变的5HT信号被认为有助于渴望和复发以及增加的负面影响，表现为增加的焦虑样行为和不安，这与酒精滥用有关。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信号传导与焦虑样行为有关。然而，5HT调节BNST突触传递的能力，以及这种调节在乙醇暴露后可能被改变的可能性，尚未得到深入研究。彻底了解酒精暴露对BNST中5HT功能的影响将为酒精戒断引起的焦虑提供关键的机制见解。在初步研究中，我们发现5HT通过激活5HT2C-R调节BNST中的突触传递，酒精暴露改变了BNST中的5HT水平和受体表达。这些结果支持了我们的中心假设：慢性酒精暴露后BNST中5HT2C-R信号的失调与酒精戒断引起的行为缺陷有关。提出以下三个独立但综合的具体目标来检验我们的中心假设：SA#1。验证5HT2C-R增加GABA释放到重要的前馈抑制神经元的假设。SA # 2。验证酒精暴露增强bst中5HT2C-R功能的假设。SA # 3。通过激活5HT2C-R，验证酒精暴露后焦虑样行为增加的假设。总的来说，拟议的研究将提供有关5HT2C-R在酒精诱导的神经元功能和行为失调中所起作用的重要信息。此外，鉴于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意义。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。

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.