NEUROPATHOLOGY OF DOPAMINE SYSTEMS IN SCHIZOPHRENIA

描述（由申请人提供）：本提案是我们之前研究精神分裂症多巴胺病理学的R 01竞争性更新的第二次修订。基于这些研究的结果，我们已经将我们的兴趣转向治疗反应或抵抗的解剖学和神经化学基础。精神分裂症的典型症状是精神病、认知障碍和阴性症状，可用的治疗是基于使用抗精神病药物，其主要作用是在一定程度上阻断多巴胺受体。不幸的是，并不是所有的患者都对治疗有反应，在那些有反应的患者中，通常只有精神病症状得到改善。事实上，大约30%的患者对这些治疗完全没有反应，被认为是治疗无反应者或治疗抵抗者。这清楚地指出，需要找到这些治疗反应差异的基础，以开发新的治疗方法。这些差异的基础目前尚不清楚，但一些证据（包括我们小组进行的工作）表明治疗应答者与治疗无应答者的多巴胺异常（“多巴胺表型”）不同（Abi-Dargham et al，2000; Roberts et al，2009）。 该建议的总体目标是确定多巴胺能传递的组分，这些组分可能是治疗应答者与治疗无应答者中存在不同“多巴胺表型”的基础。我们提出了一种多层次的方法来分析死后黑质腹侧被盖区（SN/VTA）的多巴胺病理学，[大脑中容纳大多数多巴胺能细胞的区域]，在精神分裂症治疗反应者与治疗无反应者中，也与健康对照组进行比较。我们将测试这些多巴胺神经元产生多巴胺的能力，多巴胺细胞群的健康状况，以及多巴胺能系统对这些细胞的调节，所有这些都是为了识别与治疗反应成功/失败有关的特定异常。 即使多巴胺在精神分裂症的病理学中起着核心作用，也很少有关于精神分裂症SN/VTA异常的研究，更少的是关于死后人脑治疗反应的研究，这两个事实使我们的项目独一无二。更重要的是，发现治疗反应的神经解剖学和神经化学生物标志物应该允许识别用于开发新的和更具体的疗法的潜在靶点，以及为旨在预测治疗反应结果的神经成像工具的开发提供框架。

DESCRIPTION (provided by applicant): This proposal is the second revision of our competing renewal of our previous R01 studying dopamine pathology in schizophrenia. Based on the results of those studies we have turned our interest to the anatomical and neurochemical basis of treatment response or resistance. The typical symptoms of schizophrenia are psychosis, cognitive impairments and negative symptoms, and the treatment available is based in the use of antipsychotic medications, which primarily act blocking dopamine receptors in some degree. Unfortunately, not all patients respond to treatment, and in those who do, only psychotic symptoms are usually improved. In fact, approximately 30% of patients do not respond to these treatments at all, and are considered treatment-non-responders or treatment resistant. This clearly points out the need of finding the basis of these differences in treatment response in order to develop new therapies. The basis of these differences are currently unknown but some lines of evidence (including work performed by our group), point towards different dopamine anomalies ('dopamine phenotypes") in treatment-responders vs treatment-non- responders (Abi-Dargham et al, 2000; Roberts et al, 2009). The overall goal of this proposal is to identify components of the dopaminergic transmission that may underlie the existence of different "dopamine phenotypes" in treatment-responders vs treatment-non- responders. We propose a multitier approach to analyze dopamine pathologies in postmortem substantia nigra-ventral tegmental area (SN/VTA), [the area of the brain that houses the majority of the dopaminergic cells], in schizophrenia treatment-responders vs treatment-non-responders, comparing also with healthy controls. We will test the capability of these dopamine neurons to produce dopamine, the health of the dopamine cell populations, and the modulation of these cells by the glutamatergic system, all with the common goal of identifying specific anomalies that can be linked to success/failure in treatment response. Even when dopamine has a central role in schizophrenia pathology, there are very scarce studies on anomalies of the SN/VTA in schizophrenia, and even rarer is the study of treatment response in postmortem human brain, both facts making our project unique. More importantly, finding neuroanatomical and neurochemical biomarkers of treatment response should allow the identification of potential targets for the development of new and more specific therapies, as well as provide a framework for the development of neuroimaging tools aimed to the prediction of treatment response outcomes.