NMDA Antagonist-induced Neurotoxicity in Schizophrenia

描述：(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 苯环利定(PCP)模型显示的分裂症样精神病 精神分裂症。然而，NMDAR拮抗剂产生的机制 精神分裂样精神病还没有被很好地理解。系统性的 非竞争性和竞争性NMDAR拮抗剂的给药也 诱导包括海马区在内的边缘前脑神经元损伤。几个 一系列证据表明，这种NMDAR拮抗剂引起的神经毒性可能 与NMDAR拮抗剂诱导的精神病密切相关。证据来自 人类研究表明，海马体紊乱可能起着核心作用。 在精神分裂症的病理生理学方面。由于NMDAR拮抗剂诱导 精神分裂样精神病，并在海马区产生神经毒性， 最有文献记载的精神分裂症病理部位，这项研究 NMDAR拮抗剂诱导海马区神经毒性的机制 可能对理解病理生理学有很大贡献。 精神分裂症的症状。 在这项提案中，我将研究活体暴露的神经毒性后果。 对PCP的影响及S-氨基丁酸激动剂的预防作用 海马区研究NMDAR拮抗剂诱导 神经毒性与三个具体目标：1)评估形态损伤 五氯苯酚致大鼠中毒及GABA能的预防作用 激动剂，2)评估由以下因素引起的电生理损害 PCP的给药和GABA激动剂的预防作用，以及3)评估 五氯苯酚和丙二醛对谷氨酸和GABA释放的影响 GABA能激动剂的预防作用。

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.