Schizophrenia NMDA receptor

SSR-504734 is a potent, selective, and reversible inhibitor (IC50 = 18 nM) that is competitive with glycine [47,51]. The inhibitor rapidly and reversibly blocked the uptake of [14C]glycine in mouse cortical homogenates, which was sustained for up to 7 h. Complete cessation of blockade and return to glycine basal levels occurred prior to 24 h, which is in stark contrast to NFPS (>24 h). SSR-504734 potentiated a nearly twofold increase of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices and produced an increase in contralateral rotations in mice when microinjected into the striatum. Microdialysis experiments indicated that the inhibitor induced a rapid and sustained increase in extracellular glycine levels in the PFC of freely moving rats [51]. The compound also demonstrated efficacy in a variety of psychosis models [51-53]. SSR-504734 was reportedly in clinical trials for schizophrenia but discontinued after Phase I (data not disclosed) [54]. 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia 880... 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

NMDA receptors are anchored in the postsynaptic density (PSD95, 95 kDa), a complex with which over 80 proteins have been associated (see Ch. 15). Postmortem studies have examined the expression of the subunits of the NMDA receptors as well as components of the PSD [29]. In one study in the thalamus, the NR1 and NR2B subunits were decreased in schizophrenia and PSD95, SAP102 (Synapse Associated Protein kDa 102) and NF-L (Neurofilament-Light), components of the PSD, were also significantly reduced with the latter reduction also found in bipolar disorder. Similarly, other studies have shown... 

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. 

Phencyclidine (PCP) psychosis faithfully masquerades as schizophrenia, though some say it resembles mania. PCP is discovered to block NMDA subtypes of glutamate receptors. Glycine and cycloserine, which stimulate NMDA receptors, are antipsychotic. 

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-... 

Neurochemical imaging and MRS techniques have obvious, although longterm studies of neurochemistry in vivo have yet to be applied to schizophrenia. One correlate of the neurodegenerative process proposed in the NMDA receptor hypofunction hypothesis is demonstrated in the relationship between anterior cingulate NAA deficits and disease duration (Ende et al., 2000). A... 

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). 

Recent studies have identified abnormalities associated with schizophrenia that interfere with the activation of the glycine modulatory site of the NMDA receptor (Coyle and Tsai 2004). Further, the use of NMDA receptor glycine site agonists such as glycine, o-serine or o-cycloserine in clinical trials has demonstrated some efficacy in ameliorating the negative symptoms and cognitive disabihties in schizophrenics (Coyle and Tsai 2004). 

Abnormalities of the glutamate system have also been documented in neuropsychiatric disorders. For example, compounds such as PCP and ketamine, which block the NMDA receptor, can induce psychotic symptoms. By contrast, compounds such as d-cycloserine or glycine, which increase NMDA receptor function via the glycine binding site, can decrease psychotic and/or negative symptoms in schizophrenia (Farber et ah, 1999 Goff et ah, 1999, Fleresco-Levy et ah, 1999). 

Farber, N.B., Wozniak, D.E, Price, M.T., Labruyere, J., Huss, J., St. Peter, H., and Olney, J.W. (1995) Age-specific neurotoxicity in the rat associated with NMDA receptor blockade potential relevance to schizophrenia Biol Psychiatry 38 788-796. 

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). 

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