Role of NMDAR Regulation in Phencyclidine-Induced Neurotoxicity

NMDAR 调节在苯环己哌啶诱导的神经毒性中的作用

• 批准号: 7222076
• 负责人: Noelle C Anastasio
• 金额: $ 2.93万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2009-09-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7222076
• 关键词: frontal lobe /cortex; neurotoxicology; perinatal; phencyclidine; proteins; receptor; role

DESCRIPTION (provided by applicant): Clinical use of phencyclidine (PCP), a potent dissociative anesthetic, was abandoned because of reports of post-operative hallucinations and disoriented behavior. Due to its hallucinogenic effects, PCP appeared on the drug of abuse scene in the mid-1960's known as "angel dust" but its illicit use has substantially diminished because of its psychotomimetic properties. PCP intoxication in humans has also been shown to mimic both the positive and negative symptoms of schizophrenia as well as exacerbate psychoses in schizophrenics. PCP elicits its major actions as a noncompetitive NMDAR antagonist, a member of the ionotropic glutamate family of receptors. PCP administration in immature rats has been shown to cause.. neurotoxicity and later in development, aberrant behaviors. Preliminary experiments have shown that two distinct mechanisms of receptor trafficking and protein synthesis are likely involved in the differences in NMDAR up-regulation that exist between perinatal acute and sub-chronic PCP administration and that this may underlie regional- and dosage-dependent differences in the mechanism of PCP-induced neurotoxicity. The purpose of this study is to determine the mechanism and functional consequences of PCP-induced regulation of the NMDAR in association with neurotoxicity in the frontal cortex and striatum in perinatal rats. The specific aims of this project will focus on delineating the mechanisms of regulation of the NMDAR, specifically the role of synthesis and trafficking of the receptor following acute and sub-chronic PCP administration through the use of selective inhibitors of synthesis and trafficking pathways and analysis via Western blot. In addition, we plan to investigate the role of indirect activation of DA and 5-HT receptors on the NMDAR using 3H-MK-801 binding. Finally, in order to relate regulation and function of the NMDAR to NMDA-mediated cell death, we plan to incorporate double-labeled immunohistochemistry of the NR1 and NR2A/B subunits and a known marker of neurotoxicity, cleaved caspase-3. Lay Summary: PCP, also known as "angel dust", is a powerful psychoactive substance that is mainly abused in urban regions of several large cities in the United States. It elicits its actions through blockade of the NMDA receptor in brain regions responsible for memory, emotions, and higher thought processes. This project aims to further clarify the actions of PCP at the NMDA receptor in order to gain insight into the mechanisms underlying its hallucinogenic, psychotomimetic, and neurotoxic properties.

描述（由申请人提供）：苯环己哌啶（PCP）是一种强效解离麻醉剂，由于有报道称术后出现幻觉和迷失方向行为，因此被放弃临床使用。由于其致幻作用，五氯苯酚在 20 世纪 60 年代中期出现在滥用药物的场景中，被称为“天使之尘”，但由于其拟精神病特性，其非法使用已大大减少。人类中毒五氯苯酚也被证明会模仿精神分裂症的阳性和阴性症状，并加剧精神分裂症患者的精神病。 PCP 作为非竞争性 NMDAR 拮抗剂（离子型谷氨酸受体家族的成员）发挥其主要作用。未成熟大鼠服用五氯苯酚已被证明会导致神经毒性，并在随后的发展中导致异常行为。初步实验表明，受体运输和蛋白质合成的两种不同机制可能与围产期急性和亚慢性 PCP 给药之间存在的 NMDAR 上调差异有关，这可能是 NMDAR 上调差异的基础。 PCP 诱导神经毒性的机制。本研究的目的是确定 PCP 诱导的 NMDAR 调节与围产期大鼠额叶皮层和纹状体神经毒性相关的机制和功能后果。该项目的具体目标将侧重于描绘 NMDAR 的调节机制，特别是通过使用合成和运输途径的选择性抑制剂并通过以下方法进行分析，在急性和亚慢性 PCP 给药后受体的合成和运输的作用：蛋白质印迹。此外，我们计划研究利用 3H-MK-801 结合间接激活 NMDAR 上的 DA 和 5-HT 受体的作用。最后，为了将 NMDAR 的调节和功能与 NMDA 介导的细胞死亡联系起来，我们计划结合 NR1 和 NR2A/B 亚基的双标记免疫组织化学以及已知的神经毒性标记物 cleaved caspase-3。摘要：五氯苯酚（PCP）又称“天使尘”，是一种强效精神活性物质，主要在美国几个大城市的市区滥用。它通过阻断负责记忆、情绪和高级思维过程的大脑区域的 NMDA 受体来引发其作用。该项目旨在进一步阐明 PCP 对 NMDA 受体的作用，以深入了解其致幻、拟精神病和神经毒性特性的机制。