MOLECULAR MECHANISM OF PCP- AND SIGMA-DRUG ACTIONS

PCP 和 Sigma 药物作用的分子机制

• 批准号: 3461256
• 负责人: LINDA L WERLING
• 金额: $ 9.9万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3461256
• 关键词: NMDA receptors; PCP receptor; arachidonate; catecholamines; cerebellum; corpus striatum; cyclic AMP; cyclic GMP; dopamine; drug interactions; drug receptors; electrostimulus; excitatory aminoacid; glutamates; glycine; guinea pigs; haloperidol; hippocampus; interneurons; laboratory rat; ligands; maleimides; newborn animals; norepinephrine; opiate alkaloid; opioid receptor; pentazocine; pertussis toxin; phosphatidylinositols; potassium; radioassay; receptor binding; second messengers; statistics /biometry; tetrodotoxin; thin layer chromatography; tissue /cell culture; tritium

The objectives of this application are to investigate the roles of phencyclidine (PCP) and sigma receptors in various physiological processes, including regulation of catecholamine release, activation or inhibition of second messenger systems, and relationship to excitatory amino acid neurotransmitter systems. Although once thought to be a single receptor type due to the non-selectivity of the original drugs used to characterize sigma and PCP receptor-mediated effects, it is now clear that the two receptors are separate entities, based upon several lines of evidence including differential localization. PCP remains a major drug of abuse, although often the sensations it produces are extremely unpleasant. The unique sequelae elicited by PCP and benzomorphans, which interact with PCP and sigma receptors are markedly similar to symptoms of schizophrenia. The development of antagonists for these two receptor types could provide the basis for treatment of PCP abuse and schizophrenia. A clinically used compound thought to exert its antipsychotic properties at least partially through its antagonist action at the sigma receptor is haloperidol, originally identified as a dopamine antagonist. The association of sigma receptors with dopaminergic systems in some brain areas may factor into the "dopamine hypothesis of schizophrenia". There are at present no known antagonists for the PCP receptor, but a major advance in understanding the physiological function of this site has been its localization within the cation channel activated selectively by the excitatory amino acid NMDA. Whether this is the only location of the PCP receptor remains to be determined. The widespread localization of the two receptor types within the brain is suggestive of major significance in neurological processes, but relatively few of these have been characterized, especially those affected by sigma receptor activation. This project will concentrate on exploring the actions of the two receptor types in tissues where they have been identified and there is evidence of their activity. The P.I. has preliminary evidence suggesting that both sigma and PCP agonists inhibit the NMDA-stimulated release of radiolabeled dopamine from guinea pig striatum. Attempts will be made to separate actions mediated through the two receptor types by use of selective antagonists for sigma receptors. Results will be compared to those found for NMDA-stimulated release of radiolabeled norepinephrine from hippocampus. Radioligand binding will be used to investigate potential relationship of sigma to NMDA receptors compared to that described for PCP and NMDA receptors. Cerebellar granule or other cell cultures will be used to explore sigma and PCP receptor effects on several second messenger systems in the absence of potential complication by an intact neural network. Finally, an attempt to localize sigma and PCP receptors on interneurons or catecholaminergic terminals will be made utilizing tetrodotoxin and selective interneuron transmitter antagonists.

此应用程序的目标是调查角色 各种生理学 过程，包括调节儿茶酚胺释放，激活或 抑制第二信使系统以及与兴奋性的关系 氨基酸神经递质系统。 虽然曾经被认为是 由于原始药物的非选择性，单个受体类型 用于表征Sigma和PCP受体介导的效果，现在是 显然，两个受体是单独的实体，基于几个。 包括差分定位的证据线。 PCP仍然是一种主要的滥用药物，尽管通常 它产生的感觉极为不愉快。 独特的后遗症 由PCP和Benzomorphans引起的，它们与PCP和Sigma相互作用 受体明显类似于精神分裂症的症状。 这 这两种受体类型的拮抗剂的发展可以提供 治疗PCP滥用和精神分裂症的基础。 临床上使用的 被认为至少部分部分施加其抗精神病药的化合物 通过其在Sigma受体中的拮抗作用是氟哌啶醇， 最初被鉴定为多巴胺拮抗剂。 西格玛的协会 在某些大脑区域中具有多巴胺能系统的受体可能会导致 “精神分裂症的多巴胺假说”。 目前没有 PCP受体已知的拮抗剂，但在 了解该站点的生理功能是它的 阳离子通道内的定位是由 兴奋性氨基酸NMDA。 这是否是PCP的唯一位置 受体仍有待确定。 两种受体类型的广泛定位 大脑暗示着神经过程中的重要意义， 但是其中很少有特征，尤其是那些 受Sigma受体激活的影响。 这个项目将集中于 探索两种受体类型在组织中的作用 已经确定了其活动的证据。 P.I. 有初步证据表明Sigma和PCP激动剂既 抑制几内亚的NMDA刺激的放射性标记多巴胺的释放 猪纹状体。 将尝试分开通过介导的动作 通过使用选择性拮抗剂进行Sigma这两种受体类型 受体。 结果将与NMDA刺激的结果进行比较 从海马释放放射性标记的去甲肾上腺素。 放射线 结合将用于研究Sigma与 与PCP和NMDA受体所述的NMDA受体相比。 小脑颗粒或其他细胞培养物将用于探索Sigma 以及PCP受体对几个第二个Messenger系统的影响 完整的神经网络没有潜在的并发症。 最后， 试图将Sigma和PCP受体定位在中间神经元或 使用四毒素和 选择性中间神经元发射器拮抗剂。