NMDA Antagonist-induced Neurotoxicity in Schizophrenia

NMDA 拮抗剂诱导的精神分裂症神经毒性

• 批准号: 6621798
• 负责人: SEONG S. SHIM
• 金额: $ 7.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621798
• 关键词: NMDA receptors; brain electrical activity; drug adverse effect; gamma aminobutyrate; glutamates; hippocampus; inhibitor /antagonist; laboratory rat; neurotoxins; organic brain syndrome; phencyclidine; schizophrenia

DESCRIPTION: (provided by applicant) Non-competitive and competitive N-methyl-D-aspartate receptor (NMDAR) antagonists have the ability to induce schizophrenia-like psychosis as shown in the phencyclidine (PCP) model of schizophrenia. However, the mechanism by which NMDAR antagonists produce schizophrenia-like psychosis is not well understood. The systemic administrations of non-competitive and competitive NMDAR antagonists also induce neuronal injury in limbic forebrain including the hippocampus. Several lines of evidence suggest that this NMDAR antagonist-induced neurotoxicity may be closely associated with NMDAR antagonist-induced psychosis. Evidence from human studies indicates that hippocampal disturbances may play a central role in the pathophysiology of schizophrenia. Since NMDAR antagonists induce schizophrenia-like psychosis, and produce neurotoxicity in the hippocampus, the best documented locus of pathology in schizophrenia, this study on the mechanisms by which NMDAR antagonists induce neurotoxicity in the hippocampus may provide a significant contribution toward understanding the pathophysiology of schizophrenia. In this proposal, I will examine the neurotoxic consequences of in vivoexposure to PCP and the preventive action of s-amino butyric acid (GABA) agonists in the hippocampus to investigate the mechanism by which NMDAR antagonists induce neurotoxicity with the three specific aims; 1) assess morphological injury induced by the administration of PCP and the preventive action of GABAergic agonists, 2) assess electrophysiological impairment induced by the administration of PCP and the preventive action of GABA agonists, and 3) assess changes in glutamate and GABA release induced by the administration of PCP and the preventive action of GABAergic agonists.

描述：（由申请人提供）非竞争性和竞争性 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂具有诱导 精神分裂症样精神病，如苯环利定（PCP）模型所示， 精神分裂症然而，NMDAR拮抗剂产生NMDAR的机制并不清楚。 类似精神分裂症的精神病还不太清楚。全身 非竞争性和竞争性NMDAR拮抗剂的施用还 诱导包括海马在内的边缘前脑神经元损伤。几 一系列证据表明，这种NMDAR拮抗剂诱导的神经毒性可能 与NMDAR拮抗剂诱导的精神病密切相关。证据 对人类的研究表明，海马体的紊乱可能在 精神分裂症的病理生理学由于NMDAR拮抗剂诱导 精神分裂症样精神病，并在海马体中产生神经毒性， 精神分裂症病理学最好的记录位点，这项关于 NMDAR拮抗剂诱导海马神经毒性的机制 可能会对理解病理生理学做出重要贡献 精神分裂症 在这个建议中，我将研究体内暴露的神经毒性后果 以及氨基丁酸（GABA）激动剂在五氯苯酚中的预防作用。 海马以研究NMDAR拮抗剂诱导的机制。 神经毒性有三个具体目标：1）评估形态学损伤 与GABA能的预防作用 激动剂，2）评估由激动剂诱导的电生理学损伤， PCP的管理和GABA激动剂的预防作用，以及3）评估 PCP给药引起的谷氨酸和GABA释放的变化， GABA能激动剂的预防作用。