SIGMA RECEPTORS AND DOPAMINE NEUROTRANSMISSION

描述（改编自申请人的摘要）：Sigma受体，一种新的 类假定的神经递质受体，已被广泛 特征在于结合研究，但相对较少了解 它们在中枢神经系统中的功能。事实上， 这些地点的功能将大大加强这样一种论点， 它们是大脑中的信号传递机制。之前作品和 研究人员实验室的工作支持了这一假设 sigma受体的一个功能是调节多巴胺 神经传递sigma-多巴胺相互作用的研究很重要 有几个原因：（1）多巴胺活性被假设为 参与精神分裂症症状的表达，（2）运动侧 抗精神病药物治疗的影响，如迟发性运动障碍， 与多巴胺神经传递的改变有关，（3） 产生迟发性运动障碍的抗精神病药物，如 氟哌啶醇对多巴胺和西格玛受体都具有高亲和力， (4)σ配体已显示影响多巴胺神经传递。 拟议的研究将分析sigma受体的作用， 黑质纹状体系统内的多巴胺神经传递。 这些 研究将从三个方面讨论相互作用的性质， 观点：（1）行为，使用大鼠翻转模型，（2） 神经化学，使用微透析与电化学检测， 测量体内多巴胺释放;和（3）电生理学， 给药后的放电率和模式的测量 σ配体。拟议的研究旨在阐明这些地点， 黑质纹状体多巴胺内σ配体的作用机制 系统拟议的研究探讨了假定的西格玛的影响， 拮抗剂以及sigma和NMDA之间相互作用的可能性 受体在黑质纹状体系统这些问题将在 细胞体和终端区域通过检查多巴胺的影响， 和NMDA拮抗剂，以及σ配体对NMDA诱发的 生理学或神经化学的变化。的结果予以 实验可以提供对sigma的作用的更好理解。 受体作为黑质纹状体系统内的信号传导机制， sigma-活性抗精神病药物产生 运动障碍

DESCRIPTION (Adapted from applicant's abstract): Sigma receptors, a novel class of putative neurotransmitter receptors, have been extensively characterized in binding studies, but relatively less is known about their functions in the central nervous system. Indeed, establishment of the function of these sites would greatly strengthen the argument that they serve as a signalling mechanism in the brain. Previous work and work from the investigators laboratories has supported the hypothesis that one function of sigma receptors is to regulate dopamine neurotransmission. The study of sigma-dopamine interactions is important for several reasons: (1) dopamine activity has been hypothesized to be involved in the expression of schizophrenic symptoms, (2) the motor side effects of antipsychotic drug treatment, such as tardive dyskinesia may be related to alterations in dopamine neurotransmission, (3) antipsychotic drugs that produce tardive dyskinesia, such as haloperidol, have high affinity for both dopamine and sigma receipts, (4) sigma ligands have been shown to affect dopamine neurotransmission. The proposed studies will analyze the role of sigma receptors in dopamine neurotransmission within the nigrostriatal system. These studies will address the nature of the interaction from three perspectives: (1) behavioral, using the rat turning model, (2) neurochemical, using microdialysis with electrochemical detection to measure in vivo dopamine release; and (3) electrophysiological, with measurements of firing rate and pattern following administration of sigma ligands. The proposed studies aims to elucidate the sites and mechanisms of action of sigma ligands within the nigrostriatal dopamine system. The proposed research examines the effects of putative sigma antagonists and the possibility of interactions between sigma and NMDA receptors in the nigrostriatal system These issues will be addressed in both cell body and terminal regions by examining the effects of dopamine and NMDA antagonists, and the effects of sigma ligands on NMDA-evoked changes in physiology or neurochemistry. The results of these experiments may provide a better understanding of the role of sigma receptors as a signalling mechanism within the nigrostriatal system and the possible mechanisms by which sigma-active antipsychotics produce movement disorders.