The NMDA receptor hypofunction model of psychosis.

NMDA glutamate receptor antagonists like PCP, ketamine, and CGS-19755 cause cognitive and behavioral changes in humans and histopathological and neurochemical changes in rodents. These effects appear to be dose-dependent manifestations of a disinhibition process where NMDA antagonists reduce GABAergic inhibition, leading to excessive release of acetylcholine and glutamate. Low doses can produce memory dysfunction without psychosis, while more severe NMDA receptor hypofunction (NRHypo) can mimic psychotic schizophrenic exacerbation. Sustained severe NRHypo in adult brains is associated with neurotoxicity. This paper reviews these effects, their likely mechanism, and the possible role of NRHypo in idiopathic psychotic disorders.

Study at a glance

Abstract

Antagonists of the NMDA glutamate receptor, including phencyclidine (PCP), ketamine, and CGS-19755, produce cognitive and behavioral changes in humans. In rodents these agents produce a myriad of histopathological and neurochemical changes. Several lines of evidence suggest that a large number of these drug-induced effects are dose-dependent manifestations of the same general disinhibition process in which NMDA antagonists abolish GABAergic inhibition, resulting in the simultaneous excessive release of acetylcholine and glutamate. Progressive increases in the severity of NMDA receptor hypofunction (NRHypo) within the brain produce an increasing range of effects on brain function. Underexcitation of NMDA receptors, induced by even relatively low doses of NMDA antagonist drugs, can produce specific forms of memory dysfunction without clinically evident psychosis. More severe NRHypo can produce a clinical syndrome very similar to a psychotic schizophrenic exacerbation. Finally, sustained and severe NRHypo in the adult brain is associated with a form of neurotoxicity with well-characterized neuropathological features. In this paper several of these effects of NMDA antagonists and a likely mechanism responsible for producing them will be reviewed. In addition the possible role of NRHypo in the pathophysiology of idiopathic psychotic disorders will be considered.