NMDA receptor antagonists schizophrenia

Krystal, J. H., D Souza, D. C., Mathalon, D. et al. NMDA receptor antagonist effects, cortical glutamatergic function and schizophrenia toward a paradigm shift in medication development. Psychopharmacology 169 215-233, 2003. 

Several lines of evidence have implicated NMDA receptor hypofunction in the pathophysiology of schizophrenia. The administration of certain, but not all, uncompetitive NMDA receptor antagonists exacerbates psychotic symptoms in schizophrenics and mimics schizophrenia in non-psychotic subjects (Coyle et al. 2003 Konradi and Heckers 2003). 

Glutamate was initially implicated in schizophrenia by studies of the behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., PCP, ketamine), which produce psychotic symptoms and cognitive dysfunction in healthy subjects and exacerbate psychotic, negative, and cognitive symptoms in patients with schizophrenia. Studies show that acute administration of NMDA antagonists causes NMDA receptor dysfunction, resulting in decreased inhibition of subcortical dopamine neurons and consequent increased mesolimbic dopamine release. Chronic administration produces decreased release, or hypoactivity, of dopamine in the prefrontal cortex (Davis and Lieberman, 2000). 

Glutamate Decreased presynaptic markers Decreased HC AMPA and kainate receptor expression Minor changes in FC NMDA R sub-units Altered glutamate fibres in cingulate cortex NMDA receptor antagonists produce schizophrenia-like psychosis Roles of NMDA receptors in development and neurotoxicity Partial NMDA receptor agonists have some therapeutic benefits... 

NMDA receptor antagonists induce schizophrenia-like deficits in early sensory information processing, such as abnormal mismatch negativity, abnormal visual Pl-evoked potentials and deficits in continuous performance tasks (Javitt et al., 2008). 

One of the most popular hypotheses to explain schizophrenia, the glutamate hypothesis of schizophrenia, is based on the observation of psychotomimetic effects of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), dizocilpine (MK-801), and ketamine. Like amphetamine, NMDA antagonists produce a psychosis-like state when administered to healthy individuals. Further... 

This hypothesis is further supported by the similarities between the behavioral effects caused by the administration of N-methyl-o-aspartate (NMDA) receptor antagonists to human subjects and the clinical symptoms of schizophrenia. Moreover, clinical trials in which NMDA receptor activity was enhanced by agents acting at the glycine modulatory site have demonstrated decreases in negative symptoms and variable improvements in cognitive function. There are also data from postmortem studies suggesting alterations in... 

Glutamate systems have long been implicated in the pathophysiology of schizophrenia. Strong if circumstantial evidence comes from the psychosis associated with phencyclidine (PGP) administration PGP blocks of the ion channel the glutamate/NMDA receptor. Psychosis due to PGP and other noncompetitive NMDA antagonists includes the development of negative as well as positive symptoms and therefore is considered a better model of schizophre-... 

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