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

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Abstract

Rationale

Activation of “co-agonist” N-methyl-d-aspartate (NMDA) and GlycineB sites is mandatory for the operation of NMDA receptors, which play an important role in the control of mood, cognition and motor function.

Objectives

This article outlines the complex regulation of activity at GlycineB/NMDA receptors by multiple classes of endogenous ligand. It also summarizes the evidence that a hypoactivity of GlycineB/NMDA receptors contributes to the pathogenesis of psychotic states, and that drugs which enhance activity at these sites may possess antipsychotic properties.

Results

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 GlycineB sites are located. Schizophrenia is also associated with an overall decrease in activity of endogenous agonists at GlycineB/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 GlycineB/NMDA receptors reveal similar changes in behaviour. Finally, in initial clinical studies, GlycineB 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.

Conclusions

Reduced activity at NMDA receptors is implicated in the aetiology of schizophrenia. Correspondingly, drugs that (directly or indirectly) increase activity at GlycineB 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 GlycineB sites alone improves psychotic states.

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Abbreviations

AMPA:

dl-α-NH2-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid

d-AAO:

d-amino acid oxidase

DCS:

d-Cycloserine

EAAT:

excitatory amino acid transporter

GCP:

glutamate carboxypeptidase

GlyT:

glycine transporter

GRI:

glycine reuptake inhibitor

NAAG:

N-acetyl-aspartate-glutamate

NMDA:

N-methyl-d-aspartate

mGluR:

metabotropic

OCB:

open channel blocker

PCP:

phencyclidine

SNAT:

small neutral amino acid transporter

vGluT:

vesicular glutamate transporter

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Acknowledgements

M. Soubeyran is thanked for secretarial assistance, J.-P. Mothet for helpful comments on the manuscript, B. Di Cara for graphics and A. Cordi for assistance with chemical structures.

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  1. Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde, 78290, Croissy/Seine, Paris, France

    Mark J. Millan

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Millan, M.J. N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology 179, 30–53 (2005). https://doi.org/10.1007/s00213-005-2199-1

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