title: Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors: 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.
authors: Shunske
authors: S
authors: Tanahashi
authors: Satoshi
authors: S
authors: Yamamura
authors: Masanori
authors: M
authors: Nakagawa
authors: Eishi
authors: E
authors: Motomura
authors: Motohiro
authors: M
authors: Okada
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002951:Citrates / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D013744:Tetanus Toxin / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D002951:Citrates; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D013744:Tetanus Toxin; C007744:fluorocitrate; D018698:Glutamic Acid; D013779:Tetrodotoxin; D012694:Serine; D003024:Clozapine; D006220:Haloperidol