PATHOMORPHOLOGICAL CORRELATES OF PSYCHOSIS

精神分裂症是一种以精神病为特征的疾病， 病理形态学脑变化在相当数量的情况下。 NMDA 拮抗剂（例如苯环己哌啶和氯胺酮）引起精神分裂样 人类精神病和皮质边缘神经元的病理形态学变化 成年老鼠的 拟议的研究重点是机制， NMDA拮抗剂诱导这些神经元的变化。 特定药物， 抑制NMDA拮抗剂精神病作用的抑制药物， 几种改善精神分裂症精神症状的药物， 抑制NMDA拮抗剂的神经毒性作用 皮质（Olney等人，1991; Farber等人，1993年a）。 易感性发作 NMDA拮抗剂的神经毒性在大鼠中直到晚期才发生 青春期（Farber等人，1992年，1994年b），这是同一年龄时，人类 变得对NMDA拮抗剂诱导的精神病反应敏感， 精神分裂症 在过去的18个月里，申请人一直在与 博士奥尔尼在研究中发现， 传递系统和受体亚型似乎参与了 这种神经毒性反应 在接下来的五年里，申请人提出 继续在围绕3个具体的研究中进行这项研究， 目标。 根据前两个目标提出的研究将提供一个更好的 理解神经毒性反应背后的复杂电路， 包括哪些大脑区域、递质系统和受体亚型 以及在电路中特定发射器与 特异性受体亚型。 在第三个目标中，申请人将测试一个 预测所提出的电路，预测，通过激活 特异性受体，puronectin作为近端介质， 神经毒性反应将有可能重现神经毒性 而不施用NMDA拮抗剂。 目标#3的终极目标 实验的目的是开发一种可靠的方法来重现反应， 因为这将有助于研究细胞内机制 介导这种类型的细胞损伤。 建议的意义 研究在于它可能阐明潜在的机制， 药物诱导和特发性精神病过程，包括 精神分裂症

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.