SIGMA RECEPTORS AND DOPAMINE NEUROTRANSMISSION

描述(摘自申请者的摘要)：西格玛受体，一部小说 一类可能的神经递质受体，已被广泛研究 以约束性研究为特征，但相对鲜为人知 它们在中枢神经系统中的功能。事实上，建立 这些网站的功能将极大地加强以下论点 它们在大脑中起着信号传递机制的作用。以前的工作和 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是重要的。 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现，(2)运动侧 抗精神病药物治疗的效果，如迟发性运动障碍，可能 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有很高的亲和力， (4)Sigma配体已被证明影响多巴胺的神经传递。 拟议的研究将分析Sigma受体在 黑质纹状体系统内的多巴胺神经传递。这些 研究将从三个方面探讨相互作用的性质 观点：(1)行为学，使用大鼠翻身模型，(2) 神经化学，使用微透析和电化学检测来 测量体内多巴胺释放；以及(3)电生理，与 给药后放电频率和模式的测量 西格玛配体。拟议的研究旨在阐明这些地点和 黑质纹状体多巴胺中Sigma配体的作用机制 系统。这项拟议的研究检验了假定的西格玛的影响。 拮抗剂及其与NMDA相互作用的可能性 黑质纹状体系统中的受体这些问题将在 通过检测多巴胺对细胞体和终末区域的影响 和NMDA拮抗剂，以及Sigma配体对NMDA诱导的作用 生理或神经化学方面的变化。这些研究的结果 实验可能会更好地理解西格玛的作用。 受体作为黑质纹状体系统内的信号机制 Sigma活性抗精神病药物产生的可能机制 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.