N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

• Published in: Psychopharmacology 2005-04, Vol.179 (1), p.30-53
• Main Author: Millan, Mark J
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Glycine - pharmacology; Humans; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - physiology; Schizophrenia - drug therapy; Schizophrenia - etiology; Schizophrenia - metabolism; Serine - pharmacology
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-005-2199-1

Activation of "co-agonist" N-methyl-D-aspartate (NMDA) and Glycine(B) sites is mandatory for the operation of NMDA receptors, which play an important role in the control of mood, cognition and motor function. This article outlines the complex regulation of activity at Glycine(B)/NMDA receptors by multiple classes of endogenous ligand. It also summarizes the evidence that a hypoactivity of Glycine(B)/NMDA receptors contributes to the pathogenesis of psychotic states, and that drugs which enhance activity at these sites may possess antipsychotic properties. Polymorphisms in several genes known to interact with NMDA receptors are related to an altered risk for schizophrenia, and psychotic patients display changes in levels of mRNA encoding NMDA receptors, including the NR1 subunit on which Glycine(B) sites are located. Schizophrenia is also associated with an overall decrease in activity of endogenous agonists at Glycine(B)/NMDA sites, whereas levels of endogenous antagonists are elevated. NMDA receptor "open channel blockers," such as phencyclidine, are psychotomimetic in man and in rodents, and antipsychotic agents attenuate certain of their effects. Moreover, mice with genetically invalidated Glycine(B)/NMDA receptors reveal similar changes in behaviour. Finally, in initial clinical studies, Glycine(B) agonists and inhibitors of glycine reuptake have been found to potentiate the ability of "conventional" antipsychotics to improve negative and, albeit modestly, cognitive and positive symptoms. In contrast, therapeutic effects of clozapine are not reinforced, likely since clozapine itself enhances activity at NMDA receptors. Reduced activity at NMDA receptors is implicated in the aetiology of schizophrenia. Correspondingly, drugs that (directly or indirectly) increase activity at Glycine(B) sites may be of use as adjuncts to other classes of antipsychotic agent. However, there is an urgent need for broader clinical evaluation of this possibility, and, to date, there is no evidence that stimulation of Glycine(B) sites alone improves psychotic states.