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.

产品说明： 滥用药物引起的生理效应 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蛋白。 中 PCP激活的受体是sigma受体，位于运动和 啮齿类动物、非人类灵长类动物和人类大脑的边缘区。 在啮齿类动物 纹状体、脑桥核、前额皮质、海马和小脑， 我们已经表明，σ受体的一个作用是调节 儿茶酚胺释放 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是 参与情绪稳定性注意力和认知 干扰 这些神经递质系统由PCP通过σ受体起作用 可能会导致精神病和烦躁不安， 因为滥用五氯酚 几个第二信使参与刺激 已经鉴定出脑组织和细胞释放的儿茶酚胺，但是 对于介导σ的信号转导途径还一无所知 受体抑制儿茶酚胺释放。 本工程 σ受体激动剂结合、激活或抑制之间的关系 第二信使，释放的儿茶酚胺将建立在 细胞模型，包括人神经母细胞瘤细胞SK-N-SH和SH-SY 5 Y， 大鼠嗜铬细胞瘤中去甲肾上腺素释放调节的研究 （PC 12）细胞用于调节多巴胺释放。 这些细胞系具有 证明了在理解儿茶酚胺释放机制的价值， 过去，许多第二信使系统已经在其中进行了研究。 在一些 不涉及儿茶酚胺释放的实验，我们将使用新生大鼠 培养的小脑颗粒细胞。 我们用这种细胞 广泛研究花生四烯酸对sigma-1受体的抑制作用 release. σ-1亚型的σ受体被认为是偶联的 通过G蛋白连接到它们的传感器。 通过使用反义寡核苷酸 到各种抑制性G蛋白的α亚基，我们已经开始 鉴定参与sigma-1介导的应答的G蛋白。 的 所鉴定的第二信使偶联σ的生理相关性 细胞模型中释放儿茶酚胺的受体将在 脑组织切片的方法。 我们的研究结果 应有助于设计适当的五氯苯酚滥用疗法， 相关精神病综合征。