PET BIOCHEMICAL MECHANISMS OF ALTERATIONS IN MOOD

本提案的总体目标是制定和应用方法， 用于多巴胺能系统的示踪剂动力学放射性测定， 哺乳动物的大脑 这种方法将联合收割机动物实验 和人体研究的正电子发射断层扫描（PET）。 的 拟议的研究将以我们目前资助的工作为基础， 扩展了生物化学探针的可用性（例如，基板 类似物、受体结合配体和酶自杀抑制剂） 研究多巴胺能在健康和疾病中的作用。 示踪剂动力学建模方法将用于确定 有效的方法来监测大脑的能量代谢， 行为任务和提高特异性，交付和 多巴胺特异性示踪剂在中枢神经系统中的定位 系统 我们开发的一种新的人体PET仪器， 它将提供前所未有的空间， 分辨率和采样能力。 动物PET设备将 开发（由其他来源供资：DOE）并应用于 建议;它将提供接近的空间分辨率 PET仪器的理论限值。 数据的解剖方法 分析将优化神经化学位点的定位， 人类和动物的大脑。 经验证的生化探针 多巴胺能功能将在 大脑中的多巴胺网络（例如，电刺激， 化学刺激，退行性状态（MPTP），病变， 行为任务和神经精神障碍）。 的 多巴胺能部位的分布及其定量功能 将在正常状态下评估突触前和突触后， 在运动任务中，在多巴胺兴奋剂的影响下， 药物，并在患者自发（抑郁症和强迫症- 强迫症）和药物引起的（可卡因和安非他明 情绪上的改变。

The overall goal of this proposal is to develop and apply methods for the tracer kinetic radioassay of dopaminergic systems in the mammalian brain. This approach will combine animal experimentation and human studies with positron emission tomography (PET). The proposed studies will build upon our presently funded work to extend the availability of biochemical probes (e.g., substrate analogs, receptor binding ligands, and enzyme suicide inhibitors) to the study of dopaminergic function in health and disease. Tracer kinetic modeling approaches will be used to determine efficient ways of monitoring brain energy metabolism during behavioral tasks and of enhancing the specificity, delivery and localization of dopamine specific tracers in the central nervous system. A new human PET instrument, that we have developed, will be applied to these studies; it will provide unprecedented spatial resolution and sampling abilities. An animal PET device will be developed (funded from other sources: DOE) and applied in this proposal; it will provide spatial resolution approaching the theoretical limit for PET instruments. Anatomical methods for data analysis will optimize the localization of neurochemical sites in both human and animal brains. Validated biochemical probes of dopaminergic function will be tested during perturbations of dopamine networks in the brain (e.g., electrical stimulation, chemical stimulation, degenerative states (MPTP), lesions, behavioral tasks, and neuropsychiatric disorders). The distribution of dopaminergic sites and their quantitative function both pre- and post-synaptically will be evaluated in normal states, during motor tasks, under the influence of dopamine stimulant drugs, and in patients with spontaneous (depression and obsessive- compulsive disorder) and drug-induced (cocaine and amphetamine addiction) alterations in mood.