Clozapine, but not haloperidol, enhances glial d‐serine and L‐glutamate release in rat frontal cortex and primary cultured astrocytes

BACKGROUND AND PURPOSE Deficient transmission at the glutamate NMDA receptor is considered a key component of the pathophysiology of schizophrenia. However, the effects of antipsychotic drugs on the release of the endogenous NMDA receptor partial agonist, d‐serine, remain to be clarified. EXPERIMENTAL APPROACH We determined the interaction between antipsychotic drugs (clozapine and haloperidol) and transmission‐modulating toxins (tetanus toxin, fluorocitrate, tetrodotoxin) on the release of L‐glutamate and d‐serine in the medial prefrontal cortex (mPFC) of freely moving rats, using microdialysis, and primary cultures of astrocytes using extreme high‐pressure liquid chromatography. KEY RESULTS Release of L‐glutamate and d‐serine in the mPFC and in cultured astrocytes was inhibited by tetanus toxin (a synaptobrevin inhibitor) and fluorocitrate (a glial toxin), whereas tetrodotoxin (a voltage‐sensitive Na+ blocker) inhibited depolarization‐induced L‐glutamate release in the mPFC without affecting that of d‐serine. Clozapine (1 and 5 mg·kg−1), but not haloperidol (0.5 and 1 mg·kg−1), dose‐dependently increased L‐glutamate and d‐serine release from both astrocytes and mPFC. Clozapine‐induced release of L‐glutamate and d‐serine was also reduced by tetanus toxin and fluorocitrate. Tetrodotoxin reduced clozapine‐induced mPFC L‐glutamate release but not that of d‐serine. Clozapine‐induced L‐glutamate release preceded clozapine‐induced d‐serine release. MK‐801 (a NMDA receptor antagonist) inhibited the delayed clozapine‐induced L‐glutamate release without affecting that of d‐serine. CONCLUSIONS AND IMPLICATIONS Clozapine predominantly activated glial exocytosis of d‐serine, and this clozapine‐induced d‐serine release subsequently enhances neuronal L‐glutamate release via NMDA receptor activation. The enhanced d‐serine associated glial transmission seems a novel mechanism of action of clozapine but not haloperidol.