Effects of Clozapine on N-Methyl-D-Aspartate Glutamate Receptor-Related Amino Acids in the Rat Medial Prefrontal Cortex

Abstract

Clozapine is an atypical antipsychotic drug used for schizophrenia with treatment-refractory symptoms to other antipsychotics. Since a body of evidence indicates the involvement of the dysfunction of the N-methyl-D-aspartate type glutamate receptor (NMDAR) in the pathophysiology of antipsychotic-resistant and responsive symptoms of schizophrenia, we have evaluated the exact mechanisms underlying the superior clinical efficacy of clozapine by studying its effects on the extracellular signaling of NMDAR-related amino acids in the rat medial prefrontal cortex of freely moving rats using an in vivo dialysis technique. Intra-peritoneal injection of clozapine (5, 10 and 20 mg/kg) failed to affect the prefrontal extracellular levels of D-serine, a coagonist for the NMDAR acting at the glycine site, and its precursor, L-serine, from 20 to 160-min post-injection The cortical extracellular concentrations of glycine, another NMDAR coagonist, and L-arginine, a nitric oxide/NMDAR pathway-associated factor, were significantly reduced by 10 mg/kg of clozapine. Clozapine administration (20 mg/kg) elevated the prefrontal extracellular levels of L-glutamate (P < 0.027 by pairwise comparison with saline-injected controls), which was not statistically significant after multiple comparisons. The present findings support the view that clozapine could influence the NMDAR function, at least in part, through modulation of the prefrontal extracellular concentrations of glycine, L-arginine and/or L-glutamate.