PET: BIOCHEMICAL MECHANISMS OF ALTERATIONS IN MOOD'

该提案的总体目标是开发和应用方法 用于多巴胺能系统的示踪动力学放射分析 哺乳动物的大脑。这种方法将结合动物实验 以及用正电子发射断层扫描(PET)进行的人体研究。这个 拟议的研究将建立在我们目前获得资助的工作基础上，以 扩大生化探针(例如底物)的可获得性 类似物、受体结合配体和酶自杀抑制剂) 对健康和疾病中的多巴胺能功能的研究。 将使用示踪剂动力学建模方法来确定 脑部能量代谢监测的有效方法 行为任务，并增强专一性、传递性和 多巴胺特异性示踪剂在中枢神经系统的定位 系统。我们开发的一种新的人体PET仪器将 应用于这些研究；它将提供前所未有的空间 分辨率和采样能力。一种动物PET设备将是 开发(资金来自其他来源：能源部)并应用于 提案；它将提供接近 PET仪器的理论极限。数据的解剖学方法 分析将优化神经化学部位的定位 人类和动物的大脑。经过验证的生物化学探针 多巴胺能功能将在扰动期间进行测试 大脑中的多巴胺网络(例如，电刺激， 化学刺激、退化性状态(MPTP)、损伤、 行为任务和神经精神障碍)。这个 多巴胺能部位的分布及其定量功能 突触前和突触后都将在正常状态下进行评估， 在运动任务中，在多巴胺兴奋剂的影响下 药物，以及自发性(抑郁症和强迫症-)患者 强迫症)和药物引起的(可卡因和苯丙胺 上瘾)情绪的变化。

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.