Integrity of the Dorsal Raphe Serotonin System in Alcohol Dependence and Suicide

描述（由申请人提供）：多项证据表明，5-羟色胺神经传递功能障碍使个体易产生酒精依赖，并有助于维持过量饮酒。各种研究提供的证据表明，酒精依赖受试者和偏爱酒精的动物大脑中的血清素神经传递减少。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导致酒精依赖中5-羟色胺神经传递的缺陷，或者在表现出自杀行为的患有重度抑郁症的酒精依赖受试者中，多巴胺能调节是否进一步减弱。该建议旨在检验以下假设：相对于非自杀、非抑郁的酒精依赖和正常对照受试者，诊断为酒精依赖和重度抑郁的自杀受试者中脑5-羟色胺神经元中5-羟色胺神经传递存在缺陷，这是由5-羟色胺生物合成的一种或多种关键神经元调节剂的改变引起的。该建议将检查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-HTiA受体和特定的血清素转录因子在中缝背核的人死后标本的两个酒精使用受试者组和正常对照组。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。

DESCRIPTION (provided by applicant): 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 proposal is intended to 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. This proposal will examine gene and protein expression of several serotonin molecules including tryptophan hydroxylase, 5-HTiA receptors and specific serotonin transcription factors in the dorsal raphe nucleus of human postmortem specimens of two alcohol-use subject groups 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.