N-Methyl-D-Aspartate Receptor-Coupled GlycineB Receptors in the Pathogenesis and Treatment of Schizophrenia: A Critical Review

M.   J.   Millan

Abstract

Glutamatergic pathways, metabotropic receptors, and ionotropic α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors are all implicated in the etiology and management of schizophrenia. As concerns NMDA receptors, open channel blockers (OCBs) such as phencyclidine (PCP) elicit psychotic symptoms in human subjects. This observation underpins biochemical studies indicating that a deficit in activity at NMDA receptors may be associated with psychotic states. Inasmuch as agonists at the NMDA recognition site are excitotoxic, drugs acting via the co-agonist, glycineB (GLYB) site are more promising clinical candidates as antipsychotic agents. Glycine (GLY) itself, a further endogenous agonist, D-Serine, and inhibitors of GLY reuptake are active in certain experimental models predictive of antipsychotic properties. Further, in controlled clinical trials, GLY and D-Serine enhance the ability of conventional neuroleptics such as haloperidol to impro ve cognitive and negative symptoms. Their actions are mimicked by the partial agonist, D-cycloserine (DCS). However, these agents exert little effect alone and may interfere with therapeutic actions of the atypical antipsychotic, clozapine. An important issue in the interpretation of drug actions at GLYB sites is their degree of occupation by endogenous GLY and D-Serine - although they are unlikely to be saturated. Further, distinct ”subtypes“ of GLYB site-bearing NMDA receptor may fulfill differential roles in psychotic states Finally, blockade of certain populations of NMDA receptor may be of use in the management of schizophrenia. This article reviews the complex role of GLYB sites / NMDA receptors and their endogenous ligands in the pathogenesis and treatment of psychotic states.

Keywords: schizophrenia, antipsychotic, glycine receptors, nmda receptors, d-cycloserine, d-serine, phencyclidine, ketamine, dizocilpine, glutamate, milacemide