MOLECULAR MECHANISM OF PCP- AND SIGMA-DRUG ACTIONS

PCP 和 Sigma 药物作用的分子机制

• 批准号: 2118861
• 负责人: LINDA L WERLING
• 金额: $ 10.36万
• 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/2118861
• 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.

这个应用程序的目标是调查角色 苯环利定(PCP)和Sigma受体在不同生理过程中的作用 过程，包括调节儿茶酚胺的释放、激活或 第二信使系统的抑制及其与兴奋性的关系 氨基酸神经递质系统。尽管曾经被认为是一种 由于原始药物的非选择性，导致单一受体类型 用来描述Sigma和PCP受体介导的效应，现在是 明确这两个受体是独立的实体，基于几个 包括差异定位在内的一连串证据。 五氯苯酚仍然是滥用的主要药物，尽管通常 它产生的感觉是非常不舒服的。独一无二的后遗症 由与五氯苯酚和西格玛相互作用的五氯苯酚和苯并吗啉引发 受体与精神分裂症的症状明显相似。这个 这两种受体类型的拮抗剂的开发可以提供 五氯酚滥用和精神分裂症的治疗基础。一种临床使用的 至少部分发挥其抗精神病特性的化合物思想 通过它对西格玛受体的拮抗作用是氟哌啶醇， 最初被鉴定为多巴胺拮抗剂。西格玛的关联 在某些脑区有多巴胺能系统的受体可能会影响 “精神分裂症的多巴胺假说”。目前没有 已知的PCP受体拮抗剂，但在 了解这个部位的生理功能一直是它的 选择性地激活阳离子通道内的局部化 兴奋性氨基酸NMDA。这是否是五氯苯酚的唯一位置 受体仍有待确定。 这两种受体在体内的广泛定位 大脑在神经过程中具有重要意义， 但其中相对较少的特征被描述出来，特别是那些 受Sigma受体激活的影响。这个项目将集中在 探索这两种受体类型在组织中的作用 已经被确认，并有证据表明他们的活动。私家侦探。 有初步证据表明西格玛和五氯酚激动剂 抑制NMDA刺激的豚鼠放射性标记多巴胺释放 猪纹状体。将尝试通过调解将行动分开 选择性Sigma拮抗剂对两种受体类型的影响 感受器。结果将与NMDA刺激的结果进行比较 放射性标记的去甲肾上腺素从海马区的释放。放射性配体 结合将被用来研究西格玛与 NMDA受体与PCP和NMDA受体的比较。 小脑颗粒或其他细胞培养物将用于探索Sigma 和PCP受体在脑内几个第二信使系统中的作用 一个完整的神经网络没有潜在的并发症。最后， 尝试将Sigma和PCP受体定位于中间神经元或 儿茶酚胺能终末将利用河豚毒素和 选择性神经元间递质拮抗剂。