Chronic clozapine treatment decreases 5-hydroxytryptamine1C receptor density in the rat choroid plexus: comparison with haloperidol.
We studied the effects of chronic treatment (14 days) with clozapine (10 and 25 mg/kg/day s.c.) and haloperidol (0.5 mg/kg/day s.c.) on 5-hydroxytryptamine (5-HT)1C receptor characteristics in the rat choroid plexus. In addition, we measured the effects of these treatments on dopamine D2 receptor characteristics in the rat striatum and determined the brain clozapine concentrations. Finally, the functional role of clozapine at the 5-HT1C receptors was evaluated by using phosphoinositide hydrolysis assay. Chronic administration of clozapine decreased, in a dose-related manner, 5-HT1C receptor density in the choroid plexus (by 49 and 70% with 10- and 25-mg/kg/day dose regimens of clozapine, respectively). The affinity of 5-HT1C receptors was not significantly affected, although there was a tendency toward a higher 5-HT1C receptor KD value in the group of rats treated with the 25-mg/kg/day dose regimen of clozapine. However, no detectable levels of residual clozapine were found in the cortices of rats treated with either clozapine dose regimen. Clozapine did not affect striatal D2 receptor characteristics. In turn, haloperidol, in a dose of 0.5 mg/kg/day that caused dopamine D2 receptor upregulation in the striatum, had no effects on 5-HT1C receptor characteristics in the choroid plexus. Phosphoinositide hydrolysis assays showed that clozapine is a 5-HT1C receptor antagonist. In conclusion, an atypical antipsychotic, clozapine, induced a marked downregulation of 5-HT1C receptors after chronic treatment, whereas a classical antipsychotic, haloperidol, did not. Therefore, we suggest that the decrease in the 5-HT1C receptor density after chronic clozapine treatment may contribute to some of its atypical properties.
Department of Pharmacology, University of Turku, Finland.
M
M
Kuoppamäki
T
T
Seppälä
E
E
Syvälahti
J
J
Hietala
D000818:Animals; D002831:Choroid Plexus / Q000187:drug effects* / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D015536:Down-Regulation; D006220:Haloperidol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000187:drug effects; D011985:Receptors, Serotonin / Q000032:analysis / Q000187:drug effects* / Q000502:physiology
D010716:Phosphatidylinositols; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D003024:Clozapine; D006220:Haloperidol