Linking phencyclidine intoxication to the tryptophan-kynurenine pathway: Therapeutic implications for schizophrenia
Linking phencyclidine intoxication to the tryptophan-kynurenine pathway: Therapeutic implications for schizophrenia
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DOI：
10.1016/j.neuint.2019.02.001
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发表时间：
2019-05-01
影响因子：
4.2
通讯作者：
Saito, Kuniaki
中科院分区：
文献类型：
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作者：
Fujigaki, Hidetsugu;Mouri, Akihiro;Saito, Kuniaki
苯环己哌啶（PCP）是一种分离性麻醉剂，可诱导啮齿动物出现精神病症状和神经认知缺陷，与精神分裂症患者相似。五氯苯酚在健康人类受试者中的施用诱导精神分裂症样症状，例如阳性和阴性症状，以及一系列认知缺陷。据报道，PCP、氯胺酮和相关药物（如N-甲基-D-天冬氨酸型（NMDA）谷氨酸受体拮抗剂）通过阻断NMDA受体的神经传递诱导行为效应。此外，NMDA受体拮抗剂再现精神分裂症症状的特定方面。基于PCP作用的神经化学模型已经很好地建立起来，越来越多的人关注作为精神分裂症症状和认知功能障碍基础的多巴胺能功能障碍。另一方面，内源性NMDA受体拮抗剂犬尿氨酸（KYNA）是犬尿氨酸途径（KP）代谢产物，参与精神分裂症的发病机制。精神分裂症患者的前额皮质和脑脊液中KYNA浓度升高。KYNA升高以类似于拟精神病药物（如PCP）的方式影响神经递质释放，强调了其参与精神分裂症病理生理学的分子基础。本文综述了外源性和内源性NMDA受体拮抗剂参与精神分裂症发病机制的基础上，PCP和KP代谢产物之间的关系，并讨论了我们目前对精神分裂症潜在治疗靶点的功能障碍性谷氨酸能信号转导机制的理解。
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.