Phencyclidine (PCP) is a dissociative anesthetic that induces psychotic symptoms and neurocognitive deficits in rodents similar to those observed in schizophrenia patients. PCP administration in healthy human subjects induces schizophrenia-like symptoms such as positive and negative symptoms, and a range of cognitive deficits. It has been reported that PCP, ketamine, and related drugs such as N-methyl-D-aspartate-type (NMDA) glutamate receptor antagonists, induce behavioral effects by blocking neurotransmission at NMDA receptors. Further, NMDA receptor antagonists reproduce specific aspects of the symptoms of schizophrenia. Neurochemical models based on the actions of PCP are well established, with increased focus on glutamatergic dysfunction as a basis for both symptoms and cognitive dysfunction in schizophrenia. On the other hand, the endogenous NMDA receptor antagonist, kynurenic acid (KYNA), which is a product of tryptophan-kynurenine pathway (KP) metabolism, is involved in schizophrenia pathogenesis. KYNA concentrations are elevated in the prefrontal cortex and cerebrospinal fluid of patients with schizophrenia. KYNA elevation affects neurotransmitter release in a similar manner to that of psychotomimetic agents such as PCP, underscoring a molecular basis of its involvement in schizophrenia pathophysiology. This review will highlight the relationship between PCP and KP metabolites based on evidence that both exogenous and endogenous NMDA receptor antagonists are involved in the pathogenesis of schizophrenia, and discuss our current understanding of the mechanisms underlying dysfunctional glutamatergic signaling as potential therapeutic targets for schizophrenia.

中文翻译：

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将苯环利定中毒与色氨酸-犬尿氨酸途径相关联：对精神分裂症的治疗意义。

苯环利定（PCP）是一种解离性麻醉药，可在啮齿动物中诱发精神病性症状和神经认知缺陷，类似于在精神分裂症患者中观察到的情况。在健康人类受试者中施用五氯苯酚会诱发精神分裂症样症状，例如阳性和阴性症状，以及一系列认知缺陷。据报道，五氯苯酚，氯胺酮和相关药物，例如N-甲基-D-天冬氨酸型（NMDA）谷氨酸受体拮抗剂，可通过阻断NMDA受体的神经传递来诱导行为效应。此外，NMDA受体拮抗剂可再现精神分裂症症状的特定方面。建立了基于五氯苯酚作用的神经化学模型，越来越重视作为精神分裂症症状和认知功能障碍的基础的谷氨酸能功能障碍。另一方面，内源性NMDA受体拮抗剂运动尿酸（KYNA）是色氨酸-犬尿氨酸途径（KP）代谢的产物，与精神分裂症的发病有关。精神分裂症患者的前额叶皮层和脑脊液中的KYNA浓度升高。KYNA升高以与拟精神病药物（如PCP）类似的方式影响神经递质的释放，强调了其参与精神分裂症病理生理的分子基础。这篇综述将基于外源性和内源性NMDA受体拮抗剂均参与精神分裂症发病机理的证据，突出PCP和KP代谢物之间的关系，并讨论我们目前对功能障碍的谷氨酸能信号传导作为精神​​分裂症潜在治疗靶点的潜在机制的理解。