PATHOMORPHOLOGICAL CORRELATES OF PSYCHOSIS

精神分裂症是一种以精神错乱和 相当数量的病例出现脑部病理形态改变。NMDA 拮抗剂(如苯环利定和氯胺酮)会导致精神分裂症样 人类精神病与边缘皮质神经元的病理形态变化 成年大鼠的。拟议的研究重点是通过以下机制 NMDA拮抗剂可诱导这些神经元的改变。特定的药物， 抑制NMDA拮抗剂的精神效应的药物和 几种缓解精神分裂症精神症状的药物也 抑制NMDA拮抗剂对大鼠脑内的神经毒性作用 皮质(Olney等人，1991年；Farber等人，1993a)。易感性的开始 对NMDA拮抗剂的神经毒性直到很晚才发生 青春期(Farber等人，1992,1994 b)，这与人类 易受NMDA拮抗剂诱导的精神反应和 精神分裂症。在过去的18个月里，申请人一直在与 奥尔尼博士在研究中发现了几个 递质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，申请者提议 为了继续进行这项研究，组织了大约3个具体的 目标。在前两个目标下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， 包括哪些脑区、递质系统和受体亚型 以及特定发射机在电路中的什么位置相互作用 特定受体亚型。在第三个目标中，申请者将测试 对提议的电路的预测，通过激活 特定的受体，被认为是近端的媒介。 神经毒性反应将有可能重现神经毒性 而不使用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 因为这将有助于研究细胞内的机制 来调节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 药物诱导的和特发性的精神病过程包括 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.