PET STUDIES OF NEUROTRANSMITTER INTERACTIONS IN HUMANS

该提案是R01资助的竞争续订申请 由NIMH于1993年4月提出。那个项目的重点是开发 使用PET研究多巴胺(DA)活性的研究策略 正常对照受试者的DA调制用于随后的 对精神分裂症患者的调查。这些方法是 开发的目的是解决DA无法 调节其他与功能相关和病因学相关的 皮质区和边缘区的神经递质 精神分裂症的症状学。在过去三年中， 实现了以下具体目标：1)一个范例 通过测量来测量乙酰胆碱对多巴胺的调制 阻断M胆碱能受体对DA受体的影响 可用性2)一种范式，最初是为了衡量 发展议程系统的响应性，与 M胆碱能受体放射性示踪剂测定多巴胺 乙酰胆碱的调节；3)开发用于测量的范例 5-羟色胺对多巴胺的调节作用 增加DA受体的可用性；4)结合特性 和5-HT2A放射性示踪剂(18F)-Altanserin的测试-再测试变异性 5)开发了一种测量5-羟色胺的范例 通过测量5-羟色胺增加对 5-羟色胺受体的可用性。聚酯的这一应用 方法论代表了最直接、最非抽象和最定量的 活体人体神经递质活性的测量方法 大脑。 在本申请中提出的研究代表了最初的 首例正电子发射计算机断层扫描方法学的临床应用 该项目已进行了三年，并将重点研究5-羟色胺的特性 未用药患者多巴胺和5-羟色胺反应性的调节 精神分裂症患者。DA和5-羟色胺代表了逻辑 以死后日期为研究重点，这些系统的作用 抗精神病药物的作用机制及基础研究进展 神经解剖学和神经生理学数据。评选结果 拟议的研究将决定未来研究的方向 精神分裂症患者病程较早且在 暴露于抗精神病药。这些研究将作为 未来研究以检查DA对其他物质的调制 神经递质(如乙酰胆碱、去甲肾上腺素和 谷氨酸)和它们在体内调节DA释放的能力。这个 建议的研究结果可能会对 改善精神分裂症的药理作用，并将导致 更好地了解这些系统与特定方面的关系 症状学的。

This proposal is a competing renewal application of an r01 funded by NIMH in April 1993. That project focused on the development of a research strategy using PET to study dopamine (DA) activity and DA modulation in normal control subjectsfor subsequent investigation in schizophrenic patients. These methods were developed to address the hypothesis taht the inabilityof DA to modulate other functionally-linked and etiologically relevant neurotransmitters in cortical and limbic areas underlies symptomatology in schizophrenia. Over the past three years, the following specific aims were accomplished: 1) a paradigm was developed to measure acetylcholine modulatio of DA by measuring the effect of muscarinic cholinergic reeptor blockade on Da receptor availability 2) a paradigm, developed originally to measurethe responsiveness of the DA system, was used in combination with muscarinic cholinergic receptor radiotracer to measure DA modulation of acetylcholine; 3) a paradigm as developed to measure serotonin modulation of DA by measuring the effect of serotonin increase on DA receptor availability; 4) the binding characteristics and test-retest variability of the 5-HT2A radiotracer (18F)-altanserin were measured; 5) a paradigm was developed to measure serotonin responsiveness by measuring the effect of serotonin increase on serotonin receptor availability. This application of PET methodology represents the most direct, nonivasive and quantitative method of measuring neurotransmitter activity in the living human brain. The studies proposed in this application represent one of the initial clinical applications of the PET methodology developed in the first three years of this project and will focus on characterizing serotonin modulation of DA and serotonin responsiveness in unmedicated schizophrenic patients. DA and serotonin represented the logical focus for study based on postmortem date, the role of these systems in mechanism of action of antipsychotic medications and basic neuroanatomic and neurophysioligic data. The results of the proposed studies will determine the direction of future studies of schizophrenic patients earlier in the diseae course and prior to neuroleptic exposure. These studies will serve as a model for future studies to examine DA modulation of other neurotransmitters(such as acetylcholine, norepinephrine and glutamate) and their ability to modulate DA release in vivo. The results of the proposed studies may hve implications for the refinement of pharmacotherpy in schizophrenia and will lead to a better understanding ofhow these systems relate to specific aspects of symptomatology.