MOLECULAR MECHANISMS OF PCP AND SIGMA DRUG ACTION

PCP 和 Sigma 药物作用的分子机制

• 批准号: 2872055
• 负责人: LINDA L WERLING
• 金额: $ 23.22万
• 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 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2872055
• 关键词: NMDA receptors; PCP receptor; arachidonate; catecholamines; cyclic AMP; cyclic GMP; drug interactions; excitatory aminoacid; glutamates; haloperidol; laboratory rat; maleimides; neuropharmacology; opioid receptor; pentazocine; phosphatidylinositols; receptor binding; second messengers; tissue /cell culture

DESCRIPTION: Physiological effects produced by ingestion of the drug of abuse phencyclidine (PCP) are mediated by PCP acting through several receptors, ion channels, and neurotransmitter reuptake transporters. Among the receptors activated by PCP is the sigma receptor, located in motor and limbic areas of rodent, non-human primate, and human brains. In rodent striatum, nucleus accumbens, prefrontal cortex, hippocampus and cerebellum, we have shown that one role of the sigma receptors is regulation of catecholamine release. The catecholamine dopamine is critical to reinforcement, movement, and psychosis; the catecholamine norepinephrine is involved in mood stability, attention, and cognition. Interference with these neurotransmitter systems by PCP acting through the sigma receptor might be expected to contribute to the psychosis and dysphoria resulting from PCP abuse. Several second messengers involved in the stimulation of catecholamine release from brain tissue and cells have been identified, but nothing is known about the signal transduction pathways mediating sigma receptor inhibition of catecholamine release. In this project, the relationships among sigma receptor agonist binding, activation or inhibition of second messengers, and release of catecholamines will be established in cell models, including the human neuroblastoma cells SK-N-SH and SH-SY5Y for studies on regulation of norepinephrine release, and in rat pheochromocytoma (PC12) cells for regulation of dopamine release. These cell lines have proved valuable in understanding catecholamine release mechanisms in the past, and many second messenger systems have been studied in them. In some experiments not involving catecholamine release, we will use rat neonatal cerebellar granule cells in culture. We have used this cell type extensively to study sigma-1 receptor inhibition of arachidonic acid release. Sigma receptors of the sigma-1 subtype are thought to be coupled to their transducers via a G protein. By using antisense oligonucleotides to the alpha subunits of various inhibitory G proteins, we have begun to identify G protein(s) involved in sigma-1-mediated responses. The physiological relevance of the identified second messengers coupling sigma receptors to catecholamine release in cell models will be determined in brain slices using our established superfusion methodologies. Our findings should be helpful in designing appropriate therapies for abuse of PCP, and related psychotic syndromes.

说明： 摄入滥用药物所产生的生理效应 苯环利定(PCP)是由PCP通过几种受体介导的。 离子通道和神经递质再摄取转运体。在这些人中 由PCP激活的受体是Sigma受体，位于运动和 啮齿动物、非人类灵长类动物和人脑的边缘区域。在啮齿动物中 纹状体、伏隔核、前额叶皮质、海马体和小脑， 我们已经证明，Sigma受体的一个作用是调节 儿茶酚胺的释放。儿茶酚胺多巴胺对 强化、运动和精神病；儿茶酚胺去甲肾上腺素 与情绪稳定、注意力和认知有关。干扰 PCP通过Sigma受体作用于这些神经递质系统 可能会导致精神病和烦躁不安 五氯酚滥用所致。参与刺激的几个第二信使 已发现脑组织和细胞中儿茶酚胺的释放，但 对介导Sigma的信号转导通路一无所知 儿茶酚胺释放的受体抑制。在这个项目中， Sigma受体激动剂结合、激活或抑制之间的关系 第二信使，儿茶酚胺的释放将在 细胞模型，包括人神经母细胞瘤细胞SK-N-SH和SH-SY5Y 去甲肾上腺素在大鼠嗜铬细胞瘤中释放调控的研究 (PC12)调节多巴胺释放的细胞。这些细胞系有 证明对了解儿茶酚胺的释放机制是有价值的 过去，许多第二信使系统已经在它们中被研究。在一些 不涉及儿茶酚胺释放的实验，我们将使用大鼠新生 培养中的小脑颗粒细胞。我们已经使用了这种细胞类型 广泛研究花生四烯酸对Sigma-1受体的抑制作用 放手。Sigma-1亚型的Sigma受体被认为是偶联的 通过G蛋白传递给他们的换能器。通过使用反义寡核苷酸 对于各种抑制性G蛋白的α亚基，我们已经开始 确定参与Sigma-1介导的反应的G蛋白(S)。这个 识别的第二信使与偶联西格玛的生理相关性 细胞模型中儿茶酚胺释放的受体将在 使用我们已建立的灌流方法进行脑切片。我们的发现 应有助于为滥用五氯苯酚设计适当的治疗方法，以及 相关的精神病综合征。