Clozapine and haloperidol differentially alter the constitutive activity of central serotonin2C receptors in vivo.
BACKGROUND
Central serotonin2C (5-HT2C) receptors are known to play a role in the mechanism of action of the antipsychotic drugs (APDs) clozapine and haloperidol. However, evidence for the involvement of the constitutive activity of 5-HT2C receptors in the dopamine (DA)ergic effects of APDs is lacking in vivo.


METHODS
Using in vivo microdialysis in halothane-anesthetized rats, we assessed the ability of selective 5-HT2C compounds to modulate the release of DA induced by haloperidol and clozapine in the nucleus accumbens and striatum.


RESULTS
Both APDs induced a dose-dependent increase in accumbal and striatal DA extracellular levels. The effect of .01 mg/kg haloperidol was potentiated by the 5-HT2C inverse agonist SB 206553 (5 mg/kg) but unaltered by the 5-HT2C antagonists SB 243213 and SB 242084 (1 mg/kg). Conversely, the effect of 1 mg/kg clozapine, a dose able to reverse the decrease in DA outflow induced by the 5-HT2C agonist Ro 60-0175 (3 mg/kg), was unaffected by SB 206553 but blocked by SB 243213 (1 mg/kg) and SB 242084 (.3 and 1 mg/kg).


CONCLUSIONS
These results show that clozapine and haloperidol differentially alter the constitutive activity of 5-HT2C receptors and suggest that clozapine behaves as a 5-HT2C inverse agonist in vivo.
Navailles
Sylvia
S
Unité Mixte de Recherche-Centre National de la Recherche Scientifique, Bordeaux Cedex, France.
De Deurwaerdère
Philippe
P
Spampinato
Umberto
U
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009415:Nerve Net / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D014150:Antipsychotic Agents; D005021:Ethylamines; D007211:Indoles; D011725:Pyridines; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C094868:SB 206553; D003024:Clozapine; D006220:Haloperidol; C406343:SB 243213; D004298:Dopamine