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

描述（由申请人提供）：一些证据表明，血清素神经传递功能障碍使个体容易产生酒精依赖，并有助于维持过度饮酒。各种各样的研究已经提供了证据，证明血清素神经传递在酒精依赖者和嗜酒动物的大脑中减少。酒精依赖人群的终生自杀率很高，酗酒是自杀案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者的常见合并症，自杀行为和抑郁症也与血清素的改变有关。目前尚不清楚是什么神经化学底物或机制导致了酒精依赖中5 -羟色胺神经传递的缺陷，或者是否5 -羟色胺能调节在酒精依赖受试者中进一步减弱并表现出自杀行为。本研究旨在验证以下假设：与非自杀、非抑郁的酒精依赖者和正常对照者相比，酒精依赖者中脑5 -羟色胺神经元中的5 -羟色胺神经传递存在缺陷，这是由一个或多个5 -羟色胺生物合成的关键神经元调节因子的改变引起的。本研究将检测两组酒精使用受试者和正常对照组人类死后标本中颚背核中几种血清素分子（包括色氨酸羟化酶、5-HTiA受体和特异性血清素转录因子）的基因和蛋白表达。本研究的目的是了解5 -羟色胺神经传递缺乏的生化机制，特别是在酒精依赖和合并重度抑郁症的自杀者中。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，了解导致酒精依赖个体中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依赖人群中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.