Limbic Dopaminergic System in Major Depression

大量的研究表明，含有中枢多巴胺（DA）的系统是与奖励寻求、动机和环境反应相关的广泛行为的神经基质。这些行为的破坏会导致快感缺乏、社会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）在调节情绪和情感方面的关键作用几乎没有争议，但边缘DA在抑郁症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与边缘结构的关系，但很少有人关注多巴胺能指数。此外，利用死后脑组织对抑郁症进行的神经化学研究也很缺乏。使用死后脑组织的研究提供了比功能成像更高的解剖分辨率。在初步研究中，我们发现，与精神正常对照相比，重度抑郁症患者在杏仁核基底核和中央核中多巴胺转运蛋白（DAT）水平较低，D2受体水平上调，但在这一复杂区域的其他核中没有。这些和其他的发现迫使我们研究在被诊断为重度抑郁症的受试者（死于自杀或自然原因）中DA神经传递减少的可能性。这一提议的中心假设是，重度抑郁症患者的中边缘多巴胺能活动减少，这可以通过中边缘多巴胺能系统离散区域的神经化学异常来揭示。这些神经化学测量将在杏仁核（Aim 1）、伏隔核（Aim 2）、腹侧被盖区（VTA, Aim 3）、大脑核心边缘区域的离散区域进行。我们还假设，边缘结构内的神经化学异常是重度抑郁症特有的（Aim 4），并将区分重度抑郁症与自杀或精神分裂症的病理生物学。研究对象将分为：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)非精神病控制的猝死患者，d)非自杀死亡的精神分裂症患者。这项拟议的研究将是第一个利用精神病学特征受试者对重度抑郁症中边缘DA的潜在异常进行重点调查。这项研究将建立神经化学研究结果在抑郁症和脑区域解剖学方面的特异性。揭示DA在抑郁症病理生物学中的潜在作用可能会导致重度抑郁症的药理学和可能的遗传干预的进展。

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.