Limbic Dopaminergic System in Major Depression

重度抑郁症的边缘多巴胺能系统

• 批准号: 6826276
• 负责人: GREGORY ALLEN ORDWAY
• 金额: $ 16.97万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-14 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826276
• 关键词: amine oxidase (flavin); amygdala; autoradiography; brain septal area; dopamine; dopamine receptor; dopamine transporter; limbic system; major depression; neural transmission; neurochemistry; neuropathology; nucleus accumbens; postmortem; putamen; schizophrenia; substantia nigra; suicide; western blottings

A vast amount of research reveals that central dopamine (DA) containing systems are neuronal substrates of a broad spectrum of behaviors related to reward-seeking, motivation, and environmental responsivity. Disruption of these behaviors leads to anhedonia, social isolation, and psychomotor retardation that form core symptoms of depression. While there is little debate for a critical role of limbic structures, e.g. amygdala, in the regulation of mood and affect, the role of limbic DA in the pathobiology of depressive illness is not known. Functional imaging studies report involvement of limbic structures in depression, but few have focused on dopaminergic indices. Furthermore, there is a paucity of neurochemical studies of depression that have utilized postmortem brain tissue. Studies using postmortem brain tissue offer much higher anatomical resolution than it is offered by functional imaging. In preliminary studies, we have found lower dopamine transporter (DAT) and up-regulation of D2 receptors in the basal and central nuclei of the amygdala, but not in the other nuclei of this complex region, in major depression as compared to psychiatrically normal controls. These and other findings compel us to examine the possibility that there is diminished DA neurotransmission in subjects diagnosed with major depression (who died of suicide or natural causes). The central hypothesis of this proposal is that subjects with major depression have diminished mesolimbic DA activity that can be revealed by neurochemical abnormalities in discrete regions of the mesolimbic dopaminergic system. These neurochemical measures will be performed in discrete regions of the amygdala, (Aim 1), in the nucleus accumbens (Aim 2), and in the ventral tegmental area (VTA, Aim 3), core limbic regions of the brain. We also hypothesize that a distinct constellation of neurochemical abnormalities within limbic structures is specific for major depression (Aim 4), and will differentiate the pathobiology of major depression from that of suicide or schizophrenia. Groups of subjects to be studied will be: a) subjects with major depression who committed suicide, b) subjects with major depression not dying by suicide, c) sudden death non-psychiatric controls, and d) schizophrenics not dying by suicide. The proposed research will be the first focused investigation of potential abnormalities of limbic DA in major depression utilizing psychiatrically characterized subjects. The research will establish the specificity of neurochemical findings with respect to major depression and with respect to regional brain anatomy. Uncovering the potential role of DA in the pathobiology of depression may lead to advancements in the pharmacological, and possibly genetic, intervention of major depression.

大量研究表明，中枢多巴胺(DA)系统是与奖赏、动机和环境反应相关的广泛行为的神经元底物。这些行为的中断会导致快感缺失、社交孤立和精神运动迟缓，这些都是抑郁症的核心症状。虽然边缘结构(如杏仁核)在情绪和情感调节中的关键作用鲜有争议，但边缘多巴胺在抑郁性疾病的病理生物学中的作用尚不清楚。功能成像研究报告了抑郁症边缘结构的受累，但很少有人关注多巴胺能指标。此外，利用死后脑组织对抑郁症进行的神经化学研究还很少。使用死后脑组织的研究提供了比功能成像提供的更高的解剖分辨率。在初步研究中，我们发现与精神正常对照组相比，重度抑郁症患者杏仁核基底核和中央核的多巴胺转运体(DAT)水平降低，D2受体表达上调，而这个复杂区域的其他核团则没有。这些和其他发现迫使我们研究在被诊断为重度抑郁症(死于自杀或自然原因)的受试者中，DA神经传递减弱的可能性。这一建议的中心假设是，患有严重抑郁症的受试者中脑边缘多巴胺能系统的离散区域的神经化学异常可以揭示出中脑边缘多巴胺活性降低。这些神经化学措施将在杏仁核(目标1)、伏核(目标2)和腹侧被盖区(VTA，目标3)的大脑核心边缘区域进行。我们还假设，边缘结构中的一系列明显的神经化学异常是重度抑郁症特有的(目标4)，并将把重度抑郁症的病理生物学与自杀或精神分裂症区分开来。将研究的对象组包括：a)自杀的重度抑郁症患者，b)非自杀死亡的重度抑郁症患者，c)猝死的非精神控制组，d)非自杀死亡的精神分裂症患者。这项拟议的研究将是首次利用精神病学特征的受试者对严重抑郁症患者的边缘DA潜在异常进行的重点调查。这项研究将确定神经化学结果与重度抑郁症和局部大脑解剖的特异性。揭示DA在抑郁症的病理生物学中的潜在作用可能会导致对重度抑郁症的药理学和可能的遗传干预方面的进展。