MODEL OF SCHIZOPHRENIA GATING DEFICITS: NMDA EFFECTS

精神分裂症门控缺陷模型：NMDA 效应

• 批准号: 3429389
• 负责人: ROBERT S. MANSBACH
• 金额: $ 7.15万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 1993-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3429389
• 关键词: NMDA receptors; PCP receptor; auditory stimulus; disease /disorder model; glycine receptors; inhibitor /antagonist; laboratory rat; neural information processing; neural inhibition; opioid receptor; phencyclidine; psychotomimetic drug; schizophrenia; sensorimotor system; startle reaction

This proposal seeks to investigate the involvement of the N-methyl-D-aspartate (NMDA) receptor complex in the pathophysiology of schizophrenia. Recent pharmacological, physiological and behavioral studies have indicated that the psychoactive effects of phencyclidine (PCP) are mediated by a component of the NMDA complex. PCP, a drug of abuse, has been noted in several studies to produce a toxic psychosis which in many ways resembles schizophrenia. Our proposed studies will employ the prepulse inhibition (PPI) model of sensorimotor gating in rats to investigate how NMDA receptor perturbation might relate to information processing deficits often noted in schizophrenia. We have found in preliminary studies that PCP produces deficits in PPI similar to those seen in schizophrenic patients and in animals treated with dopamine agonists. Specifically, we intend to isolate the receptor component responsible for PPI deficits through the testing of specific ligands at the three major known components of the NMDA receptor complex: the NMDA site, the PCP site, and the glycine site. Available evidence indicates that activity at NMDA and glycine sites can profoundly influence the effects of PCP, and so manipulation of these sites may reveal the overall mechanism by which this complex regulates sensory gating functions. Rats will be tested in a previously-developed procedure where loud acoustic stimuli are presented either alone or preceded by weaker stimuli. Whole-body startle responses in each condition are recorded and compared. Presentation of the weaker stimulus, or prepulse, typically reduces, or gates, the effects of the main startling event. Antagonists of the NMDA site and glycine site, which in some ways mimic the effects of PCP, will be administered and the resulting effects compared with those of PCP and PCP-like drugs. We will also explore the influence of the sigma opioid receptor in the production of gating deficits. Some sigma opiates have been reported to produce psychosis-like effects in humans, and recent evidence has indicated that many sigma behavioral actions may indeed be mediated at the PCP receptor. We will test psychotomimetic opioids and other drugs which bind to the high- and low-affinity sigma sites in an effort to elucidate the importance of this system in the production of gating deficits by PCP. We hope that these studies will provide a better overall understanding of sensory gating disturbances in schizophrenia and the influences of NMDA function in the genesis of this devastating disease. Such information could lead to the development of new pharmacotherapeutic approaches for schizophreniform psychoses.

这项提案旨在调查 N-甲基-D-天冬氨酸(NMDA)受体复合体在心肌梗死病理生理中的作用 精神分裂症。最近的药理学、生理学和行为学研究 已经表明苯环利定(PCP)的精神活性作用是 由NMDA复合体的一种成分介导。五氯苯酚，一种滥用的药物，一直被 在几项研究中指出会产生一种中毒性精神病，在许多方面 像是精神分裂症。我们提议的研究将采用预脉冲 大鼠感觉运动门抑制(PPI)模型的建立 NMDA受体紊乱可能与信息加工缺陷有关 常见于精神分裂症。我们在初步研究中发现，五氯酚 产生与精神分裂症患者类似的PPI缺陷 在用多巴胺激动剂治疗的动物中也是如此。具体来说，我们打算 通过以下途径分离导致PPI缺陷的受体组件 对NMDA三个主要已知成分的特定配体的测试 受体复合体：NMDA位点、PCP位点和甘氨酸位点。 现有证据表明，NMDA和甘氨酸位点的活动可以 深刻地影响了PCP的效果，因此对这些站点的操纵 可能揭示这种复合体调节感官的整体机制 选通功能。老鼠将在之前开发的程序中进行测试 其中大声的声刺激单独呈现或在其之前呈现 较弱的刺激。记录每种情况下的全身惊吓反应 并进行了比较。呈现较弱的刺激，或预脉冲，通常 减少或关闭主要令人震惊的事件的影响。拮抗剂 NMDA位点和甘氨酸位点，在某些方面模拟了 将实施PCP，并将产生的效果与 五氯苯酚和五氯苯酚类药物。我们还将探讨西格玛的影响 阿片受体在门控缺陷的产生。一些西格玛阿片类药物 据报道在人类身上会产生类似精神病的影响，最近 有证据表明，许多西格玛行为可能确实是 通过PCP受体进行调节。我们将测试精神类阿片类药物和 其他结合高亲和力和低亲和力的Sigma位点的药物 努力阐明这一制度在生产中的重要性 五氯联苯控制赤字。我们希望这些研究将提供更好的 对精神分裂症患者感觉门控障碍的总体认识 NMDA功能在这种毁灭性疾病的发生中的影响。 这些信息可能会导致新药物疗法的发展 精神分裂样精神病的治疗方法。