PATHOMORPHOLOGICAL CORRELATES OF PSYCHOSIS

精神病的病理形态学相关性

• 批准号: 2116358
• 负责人: NURI B FARBER
• 金额: $ 13.07万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-15 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2116358
• 关键词: NMDA receptors; brain mapping; cytotoxicity; excitatory aminoacid; histopathology; inhibitor /antagonist; laboratory rat; neural degeneration; neurochemistry; neurotoxins; neurotransmitter receptor; neurotransmitter transport; psychopharmacologic agent; psychosis

Schizophrenia is a disorder that is characterized by psychosis and pathomorphological brain changes in a significant number of cases. NMDA antagonists (e.g. phencyclidine and ketamine) cause a schizophrenia-like psychosis in humans and pathomorphological changes in corticolimbic neurons of the adult rat. The proposed research focuses on mechanisms by which NMDA antagonists induce these neuronal changes. Specific drugs that suppress drug that suppress the psychotic effects of NMDA antagonists and several drugs that ameliorate psychotic symptoms in schizophrenia, also suppress the neurotoxic effects of NMDA antagonists in the rat cerebral cortex (Olney et al., 1991; Farber et al., 1993a). Onset of susceptibility to NMDA antagonist neurotoxicity in rats does not occur until late adolescence (Farber et al., 1992, 1994b), which is the same age when humans become susceptible to NMDA antagonist-induced psychotic reactions and to schizophrenia. Over the past 18 months the applicant has been working with Dr. Olney in studies that have resulted in the identification of several transmitter systems and receptor subtypes that appear to be involved in this neurotoxic reaction. Over the next five years, the applicant proposes to continue pursuing this research in studies organized around 3 specific aims. Research proposed under the first two aims will provide a better understanding of the complex circuitry underlying the neurotoxic reaction, including which brain regions, transmitter systems and receptor subtypes are involved and where in the circuit specific transmitters interact with specific receptor subtypes. In the third aim the applicant will test a prediction of the proposed circuit, the prediction that by activating specific receptors that putatively serve as proximal mediators of the neurotoxic reaction it will be possible to reproduce the neurotoxicity without administering a NMDA antagonist. An ultimate objective of Aim #3 experiments is to develop a reliable method for reproducing the reaction in vitro as this would facilitate an investigation of intracellular mechanisms that mediate this type of cellular injury. Significance of the proposed research lies in the possibility that it may clarify mechanisms underlying both drug-induced and idiopathic psychotic processes including schizophrenia.

精神分裂症是一种以精神病为特征的疾病 在相当多的病例中，大脑发生病理形态学变化。 国家MDA 拮抗剂（例如苯环己哌啶和氯胺酮）会导致精神分裂症样症状 人类精神病和皮质边缘神经元的病理形态变化 成年大鼠的。 拟议的研究重点是机制 NMDA 拮抗剂诱导这些神经元变化。 具体药物是 抑制药物抑制 NMDA 拮抗剂的精神病作用， 一些可以改善精神分裂症精神症状的药物 抑制 NMDA 拮抗剂对大鼠大脑的神经毒性作用 皮质（Olney 等人，1991；Farber 等人，1993a）。 出现易感性 NMDA 拮抗剂对大鼠的神经毒性直到晚期才发生 青春期（Farber et al., 1992, 1994b），与人类进入青春期的年龄相同 变得容易受到 NMDA 拮抗剂诱导的精神病反应的影响 精神分裂症。 在过去 18 个月中，申请人一直在与 奥尔尼博士在研究中发现了一些 似乎参与的递质系统和受体亚型 这种神经毒性反应。 申请人建议在未来五年内 继续开展围绕 3 个具体项目组织的研究 目标。 根据前两个目标提出的研究将提供更好的 了解神经毒性反应背后的复杂电路， 包括哪些大脑区域、发射器系统和受体亚型 涉及以及电路中特定发射器相互作用的位置 特定受体亚型。 在第三个目标中，申请人将测试 所提出的电路的预测，通过激活的预测 特定受体被认为是近端介质 神经毒性反应 有可能重现神经毒性 不施用 NMDA 拮抗剂。 目标 #3 的最终目标 实验的目的是开发一种可靠的方法来重现反应 体外，因为这将有助于细胞内机制的研究 介导这种类型的细胞损伤。 拟议的意义 研究在于它可能澄清潜在的机制 药物引起的和特发性精神病过程包括 精神分裂症。