Br J Pharmacol. 2025 Nov 28. doi: 10.1111/bph.70262. Online ahead of print.
ABSTRACT
BACKGROUND AND PURPOSE: d-cycloserine, N-methyl-d-aspartate/glutamate (NMDA) receptor co-agonist (GluN2A/GluN2B partial and GluN2C super-agonist), improves negative symptom of schizophrenia with narrow therapeutic window, but the mechanisms remains unclear.
EXPERIMENTAL APPROACH: Effects of chronic d-cycloserine administration (2-5 mg·kg-1) on sucrose preference of adult male rats were determined. Dose/concentration-dependent effects of acute/chronic administrations of d-cycloserine (25-300 μM and 2-25 mg·kg-1) on expression of GluN2 subunits and associated transmission of l-glutamate/d-serine/GABA were determined using microdialysis in adult male rats, primary cultured astrocytes (male/female neonatal rats) and capillary immunoblotting.
KEY RESULTS: d-cycloserine dose-dependently increased release of astroglial l-glutamate/d-serine and neuronal GABA in the thalamus and medial prefrontal cortex (mPFC) (d-serine > GABA > l-glutamate), according to intrinsic activities (GluN2C > GluN2A [but unaffected GluN2B]). Chronic d-cycloserine dose-dependently down-regulated GluN2C > GluN2B > GluN2A (according to affinity) and attenuated d-cycloserine-induced astroglial release of l-glutamate/d-serine, dose dependently (GluN2C > GluN2A). Chronic exposure (25 μM) d-cycloserine down-regulated GluN2C but increased GluN2C-related astroglial l-glutamate/d-serine release. Chronic exposure to >60μM d-cycloserine diminished GluN2C-related astroglial release but activated GluN2A-related release. Chronic administration of 2 but not 5-mg·kg-1 d-cycloserine restored MK-801-induced decrease sucrose preference.
CONCLUSION AND IMPLICATIONS: Chronic d-cycloserine (25 μM and 2 mg·kg-1) down-regulated GluN2C without affecting GluN2A/GluN2B but increased GluN2-related astroglial l-glutamate/d-serine release. Higher d-cycloserine dose (>60 μM; >5 mg·kg-1) inactivated GluN2C, but increased GluN2A related astroglial release. These results indicate that dose-dependent activation and inactivation of GluN2C by d-cycloserine is possibly involved in its efficacy on negative symptom of schizophrenia, but with a narrow therapeutic window.
PMID:41314791 | DOI:10.1111/bph.70262
