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

中缝背侧血清素系统的完整性在酒精依赖和自杀中的作用

• 批准号: 7610493
• 负责人: MARK C AUSTIN
• 金额: $ 16.7万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610493
• 关键词: Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Anabolism; Animals; Autopsy; Behavior; Biochemical; Brain; Computer Retrieval of Information on Scientific Projects Database; Condition; Depressed mood; Diagnosis; Dorsal; Exhibits; Functional disorder; Funding; Gene Proteins; Goals; Grant; Heavy Drinking; Human; Individual; Institution; Link; Maintenance; Major Depressive Disorder; Mental Depression; Mental disorders; Midbrain structure; Neurons; Population; Relative (related person); Research; Research Personnel; Resources; Serotonin; Source; Specimen; Suicide; System; Testing; Tryptophan 5-monooxygenase; United States National Institutes of Health; accomplished suicide; neurobiological mechanism; neurochemistry; neurotransmission; prevent; protein expression; raphe nuclei; receptor; serotonergic regulation; suicidal; suicidal behavior; suicide rate; transcription factor

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 几条证据表明，5-羟色胺神经传递的功能障碍使人易于酒精依赖，并有助于维持过度饮酒。各种研究提供了证据，表明在酒精依赖性受试者和饮酒的动物的大脑中，5-羟色胺神经传递减少。依赖酒精的人群的终身自杀率很高，酒精中毒是自杀病例中最常发现的两种精神疾病之一。此外，严重抑郁症是酒精依赖人群的常见合并状况，自杀行为和抑郁症也与5-羟色胺的改变有关。目前尚不清楚哪种神经化学底物或机制是导致酒精依赖性5-羟色胺神经传递缺陷的原因，或者在具有自杀行为的大抑郁症的酒精依赖受试者中，血清素能调节是否进一步减少。 这项研究将检验以下假设：在自杀受试者中，在中脑血清素神经元中血清素神经传递缺陷，这些受试者被诊断出患有酒精依赖性和严重抑郁症相对于非抑郁剂，非抑郁的酒精依赖性和正常控制受试者，这是由一种或多种关键神经元调节剂的改变引起的，这些神经元调节剂的毒素蛋白蛋白生物蛋白蛋白蛋白蛋白质蛋白。我们将进一步研究几种5-羟色胺分子的基因和蛋白质表达，包括色氨酸羟化酶，5-HT（1A）受体和特定的5-羟色胺转录因子，在人类术后的背侧和中位raphe核中，两个癌后核的核核，两个酒精使用受试者，主要抑郁症组和正常对照组组和正常对照组。 该提案的目标是了解5-羟色胺神经传递缺乏的生化机制，专门针对患有酒精依赖和合并症的大抑郁症的受试者。鉴于与酒精依赖性人群中自杀行为相关的严重性，致死性和毁灭性后果，了解促成酒精依赖人的这种有害行为的神经生物学机制可能会为制定新的治疗策略和可能预防酒精中毒的自杀行为提供线索。