Dopamine levels in postmortem human nucleus accumbens in schizophrenia

描述(申请人提供)：精神分裂症是一种严重的精神疾病，影响约1%的人口，其神经回路的物理连接中断尚不清楚。我们的目标是进一步了解精神分裂症患者神经回路的潜在变化，为更好的治疗提供基础。伏隔核是精神分裂症许多脑区传入的汇聚区，也是中脑边缘多巴胺系统输入基底节的主要部位，使其成为精神分裂症的关键感兴趣区域；背侧纹状体的多巴胺功能亢进是精神分裂症的特征，而多巴胺在精神分裂症中的中枢作用是最被接受的疾病假说之一。虽然有证据表明腹侧纹状体在精神分裂症中的作用，但精神分裂症伏隔核的解剖病理在很大程度上被忽视了。这项拟议的研究将使用死后的人体组织来检验这一假设，即精神分裂症患者与正常对照组相比，伏隔核中的多巴胺能输入增加。我们将用光密度法和蛋白质印迹法来测定对照组与停药和服药精神分裂症患者组的酪氨酸羟基酶免疫标记的密度。这项拟议的研究还将利用电子显微镜水平上的三维立体计数来确定精神分裂症受试者伏隔核神经回路中存在的超微结构异常。最后，长期服用抗精神病药物的大鼠将为解释死后人类研究的结果提供一个背景。拟议的研究结果将提供对可能是精神分裂症的核心特征的异常回路的洞察，进一步阐明疾病的机制，并提供对尚未完全了解的治疗方法的洞察。

DESCRIPTION (provided by applicant): Schizophrenia is a severe mental illness affecting about 1% of the population in which disruptions in the physical connections of neural circuitry are unclear. Our goal is to further understand the underlying changes to neural circuitry that occur in schizophrenia to provide a foundation that is fundamental for better treatment. The nucleus accumbens is a region of convergence for afferents of many brain areas disrupted in schizophrenia, and is the major site of input into the basal ganglia from the mesolimbic dopamine system, making it a key area of interest for schizophrenia; dopamine hyperfunction in the dorsal striatum is a hallmark characteristic of the disorder, and the role of dopamine as central in schizophrenia is one of the most accepted hypotheses of the illness. Although there is evidence for the role of the ventral striatum in schizophrenia, the anatomical pathology of the nucleus accumbens in schizophrenia has largely been overlooked. The proposed research will test the hypothesis that subjects with schizophrenia have increased dopaminergic inputs in the nucleus accumbens compared to normal control cases using postmortem human tissue. The density of tyrosine hydroxylase immunolabeling, the rate limiting synthesizing enzyme of dopamine, will be determined in control subjects compared to groups of off- and on-drug schizophrenia subjects using optical densitometry and western blot assays. The proposed research will also determine the ultrastructural abnormalities present in the nucleus accumbens neurocircuitry of subjects with schizophrenia using 3- dimensional stereological counting at the electron microscopic level. Lastly, chronically antipsychotic drug- treated rats will provide a context for the interpretation of results from the postmortem human studies. Results from the proposed research will provide insight into the abnormal circuitry that may be a core feature of schizophrenia, further elucidate mechanisms of the illness, and offer insight into therapeutics which are not fully understood.