Efficacy and safety of glycine site agonists of the N-methyl-D-aspartate receptor in schizophrenia treatment

Abstract

Dopaminergic hyperactivity within frontostriatal brain systems is a key feature of schizophrenia, and an objective neural correlate of positive schizophrenia symptoms. N-methyl-d-aspartate (NMDA) receptors are known to play a prominent role in regulation of frontostriatal dopamine release. Furthermore, disturbances in glutamatergic function are increasingly being linked to pathophysiology of both positive and negative symptoms of schizophrenia. Prior studies have demonstrated that subchronic continuous administration of the NMDA antagonist phencyclidine (PCP) induces schizophrenia-like hyper-reactivity of frontostriatal dopamine release to amphetamine (AMPH) in rodents, and that effects were reversed by glycine and the prototypic glycine transport inhibitor (GTI) NFPS. The present study investigates effectiveness of the novel, high affinity and well tolerated GTIs, R231857, R231860 and Org29335, to reverse schizophrenia-like enhancement of AMPH-induced DA release, along with effects of the partial glycine-site agonist d-cycloserine. As previously, PCP had no significant effect on basal DA levels, but significantly enhanced AMPH-induced DA release in prefrontal cortex. All GTIs tested, as well as d-cycloserine, significantly reduced PCP-induced enhancement of DA release in prefrontal cortex. Neither PCP nor GTIs significantly affected striatal DA release. Overall, these findings suggest that treatments which target the glycine modulatory site of the NMDA receptor may significantly reverse NMDA receptor antagonist-induced dysregulation of frontal DA systems, consistent with potential beneficial effects on positive-, in addition to negative-, symptoms of schizophrenia.