MOLECULAR MECHANISM OF PCP- AND SIGMA-DRUG ACTIONS

本应用程序的目标是调查 苯环己哌啶（PCP）和σ受体在各种生理 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，以及与兴奋性 氨基酸神经递质系统 虽然曾被认为是一个 由于原始药物的非选择性， 用于表征sigma和PCP受体介导的效应，现在 显然，这两个受体是独立的实体，基于几个 包括差异定位在内的证据线。 五氯苯酚仍然是一种主要的滥用药物， 它产生的感觉是非常不愉快的。 独特的后遗症 由五氯苯酚和苯并吗啡烷引起，它们与五氯苯酚和西格玛相互作用 受体与精神分裂症的症状非常相似。 的 开发这两种受体类型的拮抗剂可以提供 五氯苯酚滥用和精神分裂症的治疗基础。 临床使用的 被认为至少部分发挥其抗精神病作用的化合物 通过其对σ受体的拮抗作用是氟哌啶醇， 最初被鉴定为多巴胺拮抗剂。 Sigma协会 某些脑区的多巴胺能系统受体可能会影响 精神分裂症的多巴胺假说 目前无人 已知的PCP受体拮抗剂，但在 了解这个部位的生理功能， 在阳离子通道内的定位， 兴奋性氨基酸NMDA。 这是否是PCP唯一的位置 受体仍有待确定。 这两种受体类型在细胞内的广泛定位 大脑在神经过程中具有重要意义， 但相对来说，很少有人被描述，尤其是那些 受到sigma受体激活的影响 该项目将集中于 探索两种受体类型在它们所在组织中的作用 已经被确认，并且有证据表明他们的活动。 私家侦探 有初步证据表明sigma和PCP激动剂 抑制NMDA刺激的放射性标记多巴胺从豚鼠释放 猪纹状体 将尝试将通过以下方式调解的行动分开： 通过使用σ的选择性拮抗剂 受体。 结果将与NMDA刺激的 海马释放放射性标记的去甲肾上腺素。 放射配 结合将被用来调查潜在的关系，σ NMDA受体与PCP和NMDA受体的描述进行比较。 小脑颗粒或其他细胞培养将用于探索西格玛 和PCP受体对几种第二信使系统的影响， 不存在由完整的神经网络引起的潜在并发症。 最后， 试图将σ和PCP受体定位在中间神经元上， 将利用河豚毒素制备儿茶酚胺能末端， 选择性中间神经元递质拮抗剂。

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.