Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine.
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.
Amargós-Bosch
Mercè
M
Department of Neurochemistry, Institut d'Investigacions Biomèdiques de Barcelona, CSIC (IDIBAPS), 08036 Barcelona, Spain.
López-Gil
Xavier
X
Artigas
Francesc
F
Adell
Albert
A
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D017551:Microdialysis / Q000379:methods; D000077152:Olanzapine; D010622:Phencyclidine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D001569:Benzodiazepines; D012701:Serotonin; D007649:Ketamine; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol; D000077152:Olanzapine