부산대학교 도서관

Rationale: Sertindole is a novel antipsychotic drug with high affinity for dopamine D[sub 2] , alpha-1-adrenoceptors and serotonin 5-HT[sub 2A] and 5-HT[sub 2c] receptors. The 5-HT[sub 2c] receptor component of sertindole may be clinically relevant as this receptor subtype is implicated in regulation of anxiety, cognition/memory and brain plasticity. Objective: To characterise the interaction of sertindole with the 5-HT[sub 2C] receptor using rat choroid plexus as a physiological receptor source. Results: Sertindole had nanomolar affinity for the 5-HT[sub 2c] receptor in vitro. Sertindole antagonised 5-HT-stimulated phosphoinositide (PI) hydrolysis and, like clozapine, also inhibited basal PI hydrolysis suggesting that sertindole is a 5-HT[sub 2C] receptor inverse agonist. The effect of repeated sertindole dosing on 5-HT[sub 2C] receptors was studied in rats treated for 21 days with sertindole (20, 300 and 1250 µg/kg/day). Clozapine (25 mg/kg/day) was used as a comparison drug. 5-HT[sub 2C] receptor binding in the choroid plexus was measured with antagonist and agonist ligands ([[sup 3] H]mesulergine and [[sup 125] I]DOI) using quantitative autoradiography 8 days after withdrawal. Clozapine decreased 5-HT[sub 2C] receptor antagonist and agonist binding sites equally by 36% and 32%, respectively. Sertindole did not induce significant changes in the total number of 5-HT[sub 2C] receptors, but the highest dose of sertindole lowered the affinity of [[sup 3] H]mesulergine for 5-HT[sub 2C] receptors. This was most likely due to residual sertindole levels in the brain which was supported by direct concentration measurements. In contrast, sertindole induced a highly significant and dose-related decrease in 5-HT[sub 2C] agonist binding (up to 77%). Neither drug affected striatal D[sub 2] receptor binding. Conclusions: Sertindole, like clozapine, was found to be a serotonin 5-HT[sub 2C] receptor inverse agonist. The preferential downregulation of 5-... [ABSTRACT FROM AUTHOR]