Linking phencyclidine intoxication to the tryptophan-kynurenine pathway: Therapeutic implications for schizophrenia.

Phencyclidine (PCP) and related NMDA receptor antagonists induce schizophrenia-like symptoms in humans and rodents by blocking neurotransmission at NMDA receptors. The endogenous NMDA receptor antagonist kynurenic acid (KYNA), a product of the tryptophan-kynurenine pathway, is elevated in the prefrontal cortex and cerebrospinal fluid of schizophrenia patients. KYNA elevation affects neurotransmitter release similarly to PCP, suggesting a molecular basis for its role in schizophrenia. This review examines the relationship between PCP and kynurenine pathway metabolites, highlighting how both exogenous and endogenous NMDA receptor antagonists contribute to schizophrenia pathogenesis and discussing dysfunctional glutamatergic signaling as a potential therapeutic target.

Study at a glance

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.