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Br J Pharmacol. 2012 Mar;165(5):1543-55. doi: 10.1111/j.1476-5381.2011.01638.x.

Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes.

Author information

1
Department of Psychiatry, Division of Neuroscience, Graduate School of Medicine, Brain Science and Animal Model Research Center, Mie University, 2-174 Edobashi, Tsu, Mie, Japan.

Abstract

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.

PMID:
21880034
PMCID:
PMC3372736
DOI:
10.1111/j.1476-5381.2011.01638.x
[Indexed for MEDLINE]
Free PMC Article

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