J. Hietala et al., Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist butnot antagonist binding to 5-HT2c receptors after chronic treatment, PSYCHOPHAR, 157(2), 2001, pp. 180-187
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.