NEUROPATHOLOGY OF DOPAMINE SYSTEMS IN SCHIZOPHRENIA

精神分裂症多巴胺系统的神经病理学

• 批准号: 8197443
• 负责人: Miguel Melendez-Ferro
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197443
• 关键词: Affect; Antipsychotic Agents; Appearance; Area; Autopsy; Behavior; Biological; Biological Markers; Brain; Brain region; Cell Death; Cells; Corpus striatum structure; Data; Delusions; Development; Disease; Dopamine; Dopamine Receptor; Dopaminergic Cell; Dose; Enzymes; Failure; Glutamate Receptor; Glutamates; Goals; Grant; Hallucinations; Health; Housing; Human; Image; Impaired cognition; Intervention; Knowledge; Label; Learning; Length; Link; Measurement; Measures; Metabolic; Mitochondria; Neurons; Outcome; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Population; Proteins; Psychotic Disorders; Public Health; Recovery; Resistance; Role; Schizophrenia; Source; Speech; Substantia nigra structure; Symptoms; Synapses; System; Testing; Therapeutic Effect; Treatment outcome; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Work; base; dopamine system; dopaminergic neuron; experience; improved; innovation; interest; neurochemistry; neuroimaging; neuropathology; neurotransmission; partial response; public health relevance; receptor density; response; success; tool; transmission process; treatment response

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. PUBLIC HEALTH RELEVANCE: Identifying the neuroanatomical and neurochemical substrates underlying treatment response/resistance to the currently available antipsychotic medications in schizophrenia should provide new potential targets for treatment intervention, as well as a framework to develop tools for the prediction of treatment outcomes.

描述（由申请人提供）：该提案是我们对先前研究精神分裂症多巴胺病理的R01的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耐药性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，可用的治疗方法是使用抗精神病药物，其主要作用是在某种程度上阻断多巴胺受体。不幸的是，并不是所有的病人都对治疗有反应，而在那些有反应的病人中，通常只有精神病症状得到改善。事实上，大约30%的患者对这些治疗根本没有反应，被认为是治疗无反应或治疗耐药。这清楚地指出，为了开发新的治疗方法，需要找到这些治疗反应差异的基础。这些差异的基础目前尚不清楚，但一些证据（包括我们小组的工作）指出，在治疗反应者和治疗无反应者中，多巴胺异常（“多巴胺表型”）不同（Abi-Dargham等人，2000；Roberts等人，2009）。本提案的总体目标是确定多巴胺能传递的成分，这些成分可能是治疗反应者与治疗无反应者存在不同“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，[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和治疗无反应者中，并与健康对照进行比较。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，以及谷氨酸系统对这些细胞的调节，所有这些都有一个共同的目标，即确定与治疗反应成功/失败相关的特定异常。即使多巴胺在精神分裂症病理中起着核心作用，关于精神分裂症SN/VTA异常的研究也非常少，而对死后人脑治疗反应的研究就更少了，这两个事实都使我们的项目与众不同。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确定新的和更特异性治疗的潜在靶点，并为开发旨在预测治疗反应结果的神经影像学工具提供框架。