PET STUDIES OF NEUROTRANSMITTER INTERACTIONS IN HUMANS

本建议书是一个r 01资助的竞争性续期申请 1993年4月，NIMH。 该项目的重点是开发 使用PET研究多巴胺（DA）活性的研究策略 和DA调制在正常对照受试者中进行后续研究 精神分裂症患者的调查。 这些方法 开发来解决假设，即DA不能 调节其他功能相关和病因相关的 大脑皮层和边缘区的神经递质 精神分裂症的治疗 过去三年， 实现了以下具体目标：1）一个范例， 通过测量乙酰胆碱对DA的调节， M胆碱能受体阻断剂对Da受体影响 可用性2）一种范式，最初是为了衡量 DA系统的反应性，与 毒蕈碱胆碱能受体放射性示踪剂测定DA 乙酰胆碱的调节; 3）开发的测量 通过测量5-羟色胺对多巴胺的调节作用 增加DA受体利用率; 4）结合特性 5-HT 2A放射性示踪剂（18 F）-阿坦色林的重复试验变异性 5）开发了一种测量血清素的范例 通过测量血清素增加对 5-羟色胺受体可用性。 PET的应用 方法学代表了最直接、无创和定量的 测量活体中神经递质活性的方法 个脑袋 在本申请中提出的研究代表了最初的研究之一。 PET方法学的临床应用， 这个项目为期三年， DA和5-羟色胺反应性的调节 精神分裂症患者 多巴胺和血清素代表了 重点研究基于死后日期，这些系统的作用 在抗精神病药物的作用机制和基本 神经解剖学和神经生理学数据。 的结果 建议的研究将决定未来研究的方向， 精神分裂症患者在病程早期和之前， 神经抑制剂的暴露 这些研究将作为一种模式， 未来的研究，以检查DA调制的其他 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。 的 拟议研究的结果可能对 精神分裂症的药物治疗的完善，并将导致一个 更好地理解这些系统与特定方面的关系 的医学。

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.