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Since a body of evidence indicates the involvement of the dysfunction of the N\u2010methyl\u2010D\u2010aspartate type glutamate receptor (NMDAR) in the pathophysiology of antipsychotic\u2010resistant 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\u2010related amino acids in the rat medial prefrontal cortex of freely moving rats using an in vivo dialysis technique. Intra\u2010peritoneal injection of clozapine (5, 10 and 20\u2009mg\/kg) failed to affect the prefrontal extracellular levels of D\u2010serine, a coagonist for the NMDAR acting at the glycine site, and its precursor, L\u2010serine, from 20 to 160\u2010min post\u2010injection The cortical extracellular concentrations of glycine, another NMDAR coagonist, and L\u2010arginine, a nitric oxide\/NMDAR pathway\u2010associated factor, were significantly reduced by 10\u2009mg\/kg of clozapine. Clozapine administration (20\u2009mg\/kg) elevated the prefrontal extracellular levels of L\u2010glutamate (P\u2009&lt;\u20090.027 by pairwise comparison with saline\u2010injected 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\u2010arginine and\/or L\u2010glutamate.<\/jats:p>","DOI":"10.1002\/cbic.202500209","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T11:29:48Z","timestamp":1747826988000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effects of Clozapine on N\u2010Methyl\u2010D\u2010Aspartate Glutamate Receptor\u2010Related Amino Acids in the Rat Medial Prefrontal Cortex"],"prefix":"10.1002","volume":"26","author":[{"given":"Masakazu","family":"Umino","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Medicine, and Pharmacological Research Center Showa University 1\u20105\u20108, Hatanodai, Shinagawa\u2010ku Tokyo 142\u20108555 Japan"},{"name":"Psychiatry and Behavioral Sciences 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