Clozapine and haloperidol differentially alter the constitutive activity of central serotonin2C receptors in vivo

Sylvia Navailles, Philippe De Deurwaerdère, Umberto Spampinato
Biological Psychiatry. 2006-03-01; 59(6): 568-575
DOI: 10.1016/j.biopsych.2005.07.035

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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.


Auteurs Bordeaux Neurocampus