MOLECULAR MECHANISMS OF PCP AND SIGMA DRUG ACTION

PCP 和 Sigma 药物作用的分子机制

• 批准号: 6350483
• 负责人: LINDA L WERLING
• 金额: $ 24.64万
• 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 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350483
• 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.

描述： 摄入滥用药物产生的生理影响 苯基二肽（PCP）是由PCP介导的，该PCP通过多种受体作用， 离子通道和神经递质再摄取转运蛋白。 在 PCP激活的受体是位于运动中的Sigma受体 啮齿动物，非人类灵长类动物和人类大脑的边缘区域。 在啮齿动物中 纹状体，伏隔核，前额叶皮层，海马和小脑， 我们已经表明，Sigma受体的一个作用是调节 儿茶酚胺释放。 儿茶酚胺多巴胺对 增强，运动和精神病；儿茶酚胺去甲肾上腺素是 参与情绪稳定，注意力和认知。 干扰 PCP通过Sigma受体作用的这些神经递质系统 可能预计会导致精神病和烦躁不安 来自pcp滥用。 涉及刺激的几个第二个使者 已经鉴定出从脑组织和细胞释放的儿茶酚胺，但是 关于介导Sigma的信号转导途径尚无 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 第二使者的释放将在 细胞模型，包括人类神经母细胞瘤细胞SK-N-SH和SH-SY5Y 去甲肾上腺素释放和大鼠嗜铬细胞瘤的调节研究 （PC12）调节多巴胺释放的细胞。 这些细胞系具有 事实证明，在理解儿茶酚胺释放机制方面被证明很有价值 过去和许多第二信使系统都在其中进行了研究。 在某些人中 实验不涉及儿茶酚胺释放，我们将使用大鼠新生儿 小脑颗粒细胞培养。 我们使用了这种单元格 广泛研究Sigma-1受体抑制蛛网膜酸 发布。 Sigma-1亚型的Sigma受体被认为是耦合的 通过G蛋白到其传感器。 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 确定与Sigma-1介导的反应有关的G蛋白。 这 确定的第二使者耦合Sigma的生理相关性 细胞模型中的儿茶酚胺释放的受体将在细胞模型中确定 使用我们已建立的超级灌注方法的脑切片。 我们的发现 应该有助于设计滥用PCP的适当疗法，并且 相关的精神病综合征。