Linking phencyclidine intoxication to the tryptophan-kynurenine pathway

Therapeutic implications for schizophrenia

Research output: Contribution to journalReview article

Abstract

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.

Original languageEnglish
Pages (from-to)1-6
Number of pages6
JournalNeurochemistry International
Volume125
DOIs
Publication statusPublished - 01-05-2019

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Kynurenine
Phencyclidine
Tryptophan
Schizophrenia
N-Methyl-D-Aspartate Receptors
Kynurenic Acid
Therapeutics
Dissociative Anesthetics
Hallucinogens
Excitatory Amino Acid Antagonists
Ketamine
Prefrontal Cortex
Synaptic Transmission
Neurotransmitter Agents
Cerebrospinal Fluid
Rodentia
Healthy Volunteers

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

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title = "Linking phencyclidine intoxication to the tryptophan-kynurenine pathway: Therapeutic implications for schizophrenia",
abstract = "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.",
author = "Hidetsugu Fujigaki and Akihiro Mouri and Yasuko Yamamoto and Toshitaka Nabeshima and Kuniaki Saito",
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T2 - Therapeutic implications for schizophrenia

AU - Fujigaki, Hidetsugu

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AU - Yamamoto, Yasuko

AU - Nabeshima, Toshitaka

AU - Saito, Kuniaki

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AB - 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.

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