Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine

Int J Neuropsychopharmacol. 2006 Oct;9(5):565-73. doi: 10.1017/S1461145705005900. Epub 2005 Aug 15.


N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine can evoke psychotic symptoms in normal individuals and schizophrenic patients. Here, we have examined the effects of PCP (5 mg/kg) and ketamine (25 mg/kg) on the efflux of serotonin (5-HT) in the medial prefrontal cortex (mPFC) and their possible blockade by the antipsychotics, clozapine, olanzapine and haloperidol, as well as ritanserin (5-HT2A/2C receptor antagonist) and prazosin (alpha1-adrenoceptor antagonist). The systemic administration, but not the local perfusion, of the two NMDA receptor antagonists markedly increased the efflux of 5-HT in the mPFC. The atypical antipsychotics clozapine (1 mg/kg) and olanzapine (1 mg/kg), and prazosin (0.3 mg/kg), but not the classical antipsychotic haloperidol (1 mg/kg), reversed the PCP- and ketamine-induced increase in 5-HT efflux. Ritanserin (5 mg/kg) was able to reverse only the effect of PCP. These findings indicate that an increased serotonergic transmission in the mPFC is a functional consequence of NMDA receptor hypofunction and this effect is blocked by atypical antipsychotic drugs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Antipsychotic Agents / pharmacology*
  • Benzodiazepines / pharmacology
  • Brain Chemistry / drug effects*
  • Clozapine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Haloperidol / pharmacology
  • Ketamine / pharmacology
  • Male
  • Microdialysis / methods
  • Olanzapine
  • Phencyclidine / pharmacology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Rats
  • Rats, Wistar
  • Serotonin / metabolism*
  • Time Factors


  • Antipsychotic Agents
  • Excitatory Amino Acid Antagonists
  • Benzodiazepines
  • Serotonin
  • Ketamine
  • Phencyclidine
  • Clozapine
  • Haloperidol
  • Olanzapine