MODEL OF SCHIZOPHRENIA GATING DEFICITS: NMDA EFFECTS

精神分裂症门控缺陷模型：NMDA 效应

• 批准号: 3429388
• 负责人: ROBERT S. MANSBACH
• 金额: $ 6.89万
• 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 1992-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3429388
• 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.

该提案旨在调查 N-甲基-D-天冬氨酸 (NMDA) 受体复合物在病理生理学中的作用 精神分裂症。最近的药理学、生理学和行为研究 已经表明，苯环己哌啶（PCP）的精神作用是 由 NMDA 复合物的一个成分介导。 PCP 是一种滥用药物，已被 几项研究指出，会产生一种有毒的精神病，这种病在很多方面 类似于精神分裂症。我们提出的研究将采用前脉冲 大鼠感觉运动门控抑制（PPI）模型，研究如何 NMDA 受体扰动可能与信息处理缺陷有关 常见于精神分裂症。我们在初步研究中发现，PCP 产生类似于精神分裂症患者的 PPI 缺陷 以及用多巴胺激动剂治疗的动物。具体来说，我们打算 通过分离负责 PPI 缺陷的受体成分 测试 NMDA 三个主要已知成分的特定配体 受体复合物：NMDA 位点、PCP 位点和甘氨酸位点。 现有证据表明 NMDA 和甘氨酸位点的活性可以 深刻影响 PCP 的效果，从而操纵这些网站 可能揭示该复合物调节感觉的整体机制 门控功能。老鼠将按照先前开发的程序进行测试 大声的声刺激要么单独出现，要么先出现 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。通常呈现较弱的刺激或前脉冲 减少或阻止主要令人震惊的事件的影响。的拮抗剂 NMDA 位点和甘氨酸位点，在某些方面模仿了 将施用 PCP，并将所得效果与 五氯苯酚和五氯苯酚类药物。我们还将探讨西格玛的影响 阿片受体产生门控缺陷。一些西格玛阿片类药物 据报道，它会对人类产生类似精神病的影响，最近 有证据表明，许多西格玛行为行动可能确实是 介导于 PCP 受体。我们将测试拟心理阿片类药物和 与高亲和力和低亲和力西格玛位点结合的其他药物 努力阐明该系统在生产中的重要性 由 PCP 控制赤字。我们希望这些研究能够提供更好的 对精神分裂症感觉门控障碍的总体了解 NMDA 功能对这种毁灭性疾病发生的影响。 这些信息可能会导致新药物治疗的开发 精神分裂样精神病的治疗方法。