NORADRENERGIC SYSTEM IN DEPRESSION

抑郁症中的去甲肾上腺素能系统

• 批准号: 2674978
• 负责人: GREGORY ALLEN ORDWAY
• 金额: $ 13.03万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2674978
• 关键词: alpha adrenergic receptor; amine oxidase (flavin); brain disorder diagnosis; brain metabolism; cell death; central neural pathway /tract; clinical research; histology; human tissue; intercellular connection; limbic system; locus coeruleus; major depression; neuroanatomy; neurochemistry; neurotransmitter metabolism; norepinephrine; pathologic process; postmortem; psychopharmacology; radioimmunoassay; suicide; tyrosine 3 monooxygenase; western blottings

Converging evidence from years of intensive research has implicated that a disorder of brain norepinephrine and/or serotonin occurs in major depression. However, the basic neurobiology of major depression has not yet been elucidated. The goal of this research is test the hypothesis that a distinct constellation of neurochemical/neuroanatomical deficits occurs in the noradrenergic system (in particular, the locus coeruleus) in major depression. Experiments are designed to address the issues of (1) the precise neurochemical and/or neuroanatomical alterations and (2) the specificity of alterations with respect to psychiatric illness. To address the first issue, concentrations of a number of proteins and substances will be measured throughout the locus coeruleus, and in a major limbic projection area (amygdala) in post-mortem brains from subjects with major depression and from psychiatrically normal control subjects. In particular, a number of noradrenergic and non-noradrenergic proteins which are sites of action of antidepressant drugs will be studied, along with proteins of which levels are modulated in the locus coeruleus by antidepressant treatment. Preliminary findings demonstrates that noradrenergic cell number is a major determinant of noradrenergic protein concentration in the locus coeruleus. Furthermore, cell loss in the locus coeruleus is associated with aging, Alzheimer's disease, and Parkinson's disease. Thus, if cell number in locus coeruleus is altered in psychiatric disease, such a change could complicate measurements of noradrenergic proteins in the locus coeruleus or lead to misinterpretation of neurochemical alterations in the locus coeruleus from major depressives. Thus, noradrenergic neuron density and number will be estimated stereologically in all subjects in parallel with neurochemical measurements. To address the issue of specificity, 4 groups of subjects will be studied: 1) no psychiatric diagnosis, age-matched control subjects dying of natural or accidental causes, 2) suicide victims with major depression, 3) non-suicide subjects with major depression, and 4) suicide victims with Axis I diagnoses other than major depression. This research will extend and clarify major findings of research in the first grant period. Elucidation of the biochemical and/or anatomical alterations of locus coeruleus neurons associated with major depression may yield important information for the development of more effective treatments for this devastating disorder.

多年来密集研究的综合证据表明 大脑去甲肾上腺素和/或5-羟色胺紊乱 抑郁症。然而，严重抑郁症的基本神经生物学还没有 但还没有被阐明。这项研究的目的是检验这一假设 一系列明显的神经化学/神经解剖学缺陷 发生于去甲肾上腺素能系统(尤其是蓝斑) 严重的抑郁症。实验旨在解决以下问题 (1)精确的神经化学和/或神经解剖学改变；(2) 与精神疾病相关的改变的特殊性。至 解决第一个问题，一些蛋白质和 物质将在整个蓝斑进行测量，并在 人死后大脑主要边缘投射区(杏仁核) 患有重度抑郁症的受试者和精神正常的受试者 研究对象。尤其是一些去甲肾上腺素和非去甲肾上腺素 作为抗抑郁药物作用部位的蛋白质将是 研究了哪些蛋白质的水平在基因座上受到调节 蓝斑通过抗抑郁药物治疗。初步调查结果表明 去甲肾上腺素能细胞数量是去甲肾上腺素能的主要决定因素 蓝斑的蛋白质浓度。此外，信元丢失在 蓝斑与衰老、阿尔茨海默病和 帕金森氏症。因此，如果蓝斑中的细胞数量发生变化 在精神疾病方面，这种变化可能会使测量变得复杂 去甲肾上腺素能蛋白在蓝斑或导致 蓝斑神经化学改变的误读 从严重的忧郁症。因此，去甲肾上腺素能神经元的密度和数量 将在所有科目中同时进行立体评估 神经化学测量。为了解决专一性问题，4个小组 研究对象的比例：1)没有精神疾病诊断，年龄匹配 对照研究对象死于自然或意外原因，2)自杀 患有严重抑郁症的受害者，3)患有严重抑郁症的非自杀受试者 抑郁症，以及4)轴心I诊断为其他重大疾病的自杀者 抑郁症。这项研究将扩展和澄清以下主要发现 在第一个资助期进行研究。阐明生物化学和/或 大脑皮层蓝斑神经元的解剖学改变 抑郁症可能会产生更多的重要信息 对这种毁灭性疾病的有效治疗。