Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist butnot antagonist binding to 5-HT2c receptors after chronic treatment

Rationale: Sertindole is a novel antipsychotic drug with high affinity for dopamine D-2, alpha-1-adrenoceptors and serotonin 5-HT2A and 5-HT2c recepto rs. The 5-HT2c 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-HT2C receptor using rat choroid plexus as a physiolog ical receptor source. Results: Sertindole had nanomolar affinity for the 5- HT2c receptor in vitro. Sertindole antagonised 5-HT-stimulated phosphoinosi tide (PI) hydrolysis and, like clozapine, also inhibited basal PI hydrolysi s suggesting that sertindole is a 5-HT2c receptor inverse agonist. The effe ct of repeated sertindole dosing on 5-HT2C receptors was studied in rats tr eated for 21 days with sertindole (20, 300 and 1250 mug/kg/day). Clozapine (25 mg/kg/day) was used as a comparison drug. 5-HT2C receptor binding in th e choroid plexus was measured with antagonist and agonist ligands ([H-3]mes ulergine and [I-125]DOI) using quantitative autoradiography 8 days after wi thdrawal. Clozapine decreased 5-HT2C receptor antagonist and agonist bindin g sites equally by 36% and 32%, respectively. Sertindole did not induce sig nificant changes in the total number of 5-HT2C receptors, but the highest d ose of sertindole lowered the affinity of [H-3]mesulergine for 5-HT2C recep tors. This was most likely due to residual sertindole levels in the brain w hich, was supported by direct concentration measurements. In contrast, sert indole induced a highly significant and dose-related decrease in 5-HT2C ago nist binding (up to 77%). Neither drug affected striatal D-2 receptor bindi ng. Conclusions: Sertindole, like clozapine, was found to be a serotonin 5- HT2c receptor inverse agonist. The preferential downregulation of 5-HT2C re ceptor agonist (G-protein-coupled) sites by chronic administration seemed t o differentiate sertindole from clozapine at these dose regimens. The 5-HT2 c receptor downregulation during repeated dosing may contribute to therapeu tic efficacy and/or side effects of sertindole treatment.