Functional Mapping of Dopamine Systems in Schizophrenia

精神分裂症多巴胺系统的功能图谱

• 批准号: 6610525
• 负责人: MARC A LARUELLE
• 金额: $ 12.27万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610525
• 关键词: NMDA receptors; amphetamines; baboons; bioimaging /biomedical imaging; brain imaging /visualization /scanning; brain mapping; clinical research; corpus striatum; dopamine; dopamine receptor; human subject; magnetic resonance imaging; method development; neuroanatomy; neurochemistry; nuclear magnetic resonance spectroscopy; phencyclidine; positron emission tomography; radiotracer; schizophrenia; single photon emission computed tomography; substantia nigra

DESCRIPTION (provided by applicant): This application is a proposal for the competitive renewal of a K02 grant to support the career development plan of the candidate. The candidate research career is directed toward developing novel brain imaging methods to better characterize neurochemical alterations associated with schizophrenia, the clinical correlates of these alterations, and their relevance to treatment strategies. The candidate previous research experience included postmortem analysis of neurochemical markers in schizophrenic brains (NIMH) and neuroreceptor imaging using single photon computerized tomography (SPECT) (Yale University). The first cycle of this K02 (July 1998 to June 2003) was awarded after the candidate moved to Columbia University in 1996. The primary objective of the first cycle of this K02 was to develop expertise in a brain imaging modality that was new to him, Positron Emission Tomography (PET). In the next cycle of this grant, the candidate will continue to enhance his knowledge of PET, and will also develop expertise in nonhuman primate models of schizophrenia. The long-term goals of the candidate is to use neurochemical imaging as a translational research tool, involving both animal and clinical studies, to characterize neurotransmitter imbalances implicated in schizophrenia. In previous studies, the candidate observed that schizophrenia is associated with an increase in striatal amphetamine-induced DA release. The same dysregulation was induced in healthy volunteers by acute administration of the N-methyl-D-aspartate (NMDA) antagonist, ketamine, suggesting that alterations of DA function in schizophrenia might be secondary to disruptions of glutamate-mediated pathways. The current research plan proposes to: 1) develop a novel imaging method enabling detailed mapping ofpresynaptic DA function in nigro-striatal, mesolimbic and mesocortical DA systems, using the new PET tracer [lsF]fallypride and high resolution PET (specific aims 1 and 2); 2) use this technique to probe these DA systems in patients with schizophrenia, to test the hypothesis that schizophrenia is associated with increased mesolimbic DA function (specific aim 3); 3) use this technique to study, in nonhuman primates, the effect of subchronie phencyclidine (PCP) exposure on DA systems. The hypothesis is that chronic disruption of NMDA transmission by PCP will induce a pattern of DA dysregulations similar to that observed in schizophrenia. Ultimately, better understanding of these dysregulations and their origin will lead to improved treatment strategies.

描述（由申请人提供）：本申请是 K02 补助金竞争性更新的提案，以支持候选人的职业发展计划。候选人的研究生涯旨在开发新型脑成像方法，以更好地表征与精神分裂症相关的神经化学改变、这些改变的临床相关性以及它们与治疗策略的相关性。该候选人之前的研究经验包括对精神分裂症患者大脑神经化学标记物（NIMH）进行尸检分析以及使用单光子计算机断层扫描（SPECT）（耶鲁大学）进行神经感受器成像。 K02 的第一个周期（1998 年 7 月至 2003 年 6 月）是在候选人于 1996 年转到哥伦比亚大学后授予的。K02 第一个周期的主要目标是发展对他来说是新的脑成像模式的专业知识，正电子发射断层扫描 (PET)。在这笔资助的下一个周期中，候选人将继续增强他对 PET 的了解，并将发展非人类灵长类精神分裂症模型的专业知识。候选人的长期目标是使用神经化学成像作为转化研究工具，涉及动物和临床研究，以表征与精神分裂症有关的神经递质失衡。 在之前的研究中，候选人观察到精神分裂症与纹状体安非他明诱导的 DA 释放增加有关。通过急性施用 N-甲基-D-天冬氨酸 (NMDA) 拮抗剂氯胺酮，在健康志愿者中也诱导了相同的失调，这表明精神分裂症中 DA 功能的改变可能继发于谷氨酸介导途径的破坏。目前的研究计划建议：1）开发一种新颖的成像方法，使用新的 PET 示踪剂 [lsF]fallypride 和高分辨率 PET，详细绘制黑质纹状体、中脑边缘和中皮质 DA 系统中的突触前 DA 功能（具体目标 1 和 2） ）； 2) 使用该技术探测精神分裂症患者的这些 DA 系统，以检验精神分裂症与中脑边缘 DA 功能增强相关的假设（具体目标 3）； 3) 使用该技术在非人类灵长类动物中研究亚慢性苯环己哌啶 (PCP) 暴露对 DA 系统的影响。该假设认为，PCP 对 NMDA 传播的长期破坏将导致 DA 失调模式，类似于在精神分裂症中观察到的情况。 最终，更好地了解这些失调及其根源将导致治疗策略的改进。