INTEGRITY OF THE DORSAL RAPHE SEROTONIN SYSTEM IN ALCOHOL DEPENDENCE AND SUICIDE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。有几条证据表明，血清素神经传递功能障碍使人容易产生酒精依赖，并有助于维持过量饮酒。各种研究都提供了证据，证明酒精依赖受试者和酒精偏好动物大脑中的5-羟色胺神经传递减少。酒精依赖人群的终生自杀率很高，酒精中毒是自杀病例中最常见的两种精神疾病之一。此外，重度抑郁症是酒精依赖个体中常见的共病，自杀行为和抑郁症也与5-羟色胺的改变有关。目前尚不清楚是什么神经化学底物或机制是负责在酒精依赖中的5-羟色胺神经传递的缺陷，或如果在酒精依赖的受试者中，表现出自杀行为的抑郁症，多巴胺能调节进一步减少。 本研究将测试的假设，有一个赤字，在中脑5-羟色胺神经元的5-羟色胺神经传递在自杀的酒精依赖和抑郁症的诊断相对于非自杀，非抑郁症的酒精依赖和正常对照组，这是由一个或多个关键的神经元调节5-羟色胺生物合成的改变。我们将进一步研究基因和蛋白质表达的几种血清素分子，包括色氨酸羟化酶，5-HT（1A）受体和特定的血清素转录因子的背侧和正中中缝核的人死后标本的两个酒精使用的主题组，一个重性抑郁症组和正常对照组。 这项建议的目标是了解生化机制的不足，血清素神经传递，特别是在主题自杀酒精依赖和共病的严重抑郁症。鉴于酒精依赖人群中自杀行为的严重性，致命性和破坏性后果，了解酒精依赖个体中导致这种有害行为的神经生物学机制可能为开发新的治疗策略和预防酒精中毒自杀行为的可能途径提供线索。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Several lines of evidence suggest that dysfunction of serotonin neurotransmission predisposes individuals to alcohol dependence and contributes to the maintenance of excessive alcohol consumption. A variety of studies have provided evidence that serotonin neurotransmission is reduced in the brain of alcohol-dependent subjects and alcohol-preferring animals. Alcohol-dependent populations have a high lifetime suicide rate, and alcoholism is one of two psychiatric disorders most frequently found in suicidal cases. Furthermore, major depression is a frequent co-morbid condition among individuals with alcohol dependence, and suicidal behavior and depression have also been linked to alterations in serotonin. It remains unclear what neurochemical substrate or mechanism is responsible for the deficit in serotonin neurotransmission in alcohol dependence or if serotonergic regulation is further diminished in alcohol-dependent subjects with major depression that exhibit suicidal behavior. This research will test the hypothesis that there is a deficit in serotonin neurotransmission in midbrain serotonin neurons in suicide subjects diagnosed with alcohol-dependence and major depression relative to non-suicide, non-depressed alcohol-dependent and normal control subjects which is caused by an alteration in one or more key neuronal regulators of serotonin biosynthesis. We will further examine gene and protein expression of several serotonin molecules including tryptophan hydroxylase, 5-HT(1A) receptors and specific serotonin transcription factors in the dorsal and median raphe nucleus of human postmortem specimens of two alcohol-use subject groups, a major depression group and a normal control subject group. The goals of this proposal are to understand the biochemical mechanisms underlying the deficiency in serotonin neurotransmission specifically in subjects committing suicide with alcohol dependence and co-morbid major depression. Given the seriousness, lethality and devastating consequences associated with suicidal behavior in alcohol-dependent populations, understanding the neurobiological mechanisms contributing to such harmful behavior in alcohol-dependent individuals may offer clues for developing new treatment strategies and possible avenues to prevent suicidal behavior in alcoholism.