Effects of clozapine on N-methyl-D-aspartate glutamate receptor-related amino acids in the rat medial prefrontal cortex

Chembiochem. 2025 May 21:e202500209. doi: 10.1002/cbic.202500209. Online ahead of print.

ABSTRACT

Clozapine is an excellent antipsychotic that has been widely used to treat conventional antipsychotic-refractory schizophrenia. 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 explored the exact mechanisms underlying the superior clinical efficacy of clozapine by studying the effects of clozapine on brain extracellular signaling of NMDAR-related amino acids in the rat medial prefrontal cortex using an in vivo dialysis technique by a quantitative HPLC detection method. 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 10mg/kg of clozapine. Clozapine administration (20 mg/kg) nominally elevated the prefrontal extracellular levels of L-glutamate, which was not statistically significant after multiple comparisons. The present findings are consistent with the view that clozapine could influence the NMDAR function, at least in part, through modulation of the prefrontal cortical extracellular levels of glycine, L-arginine and glutamate.

PMID:40397451 | DOI:10.1002/cbic.202500209