Selective down-regulation of the agonist-dependent high affinity state of rat cortical 5-HT2 receptors following chronic treatment with amperozide.

Amperozide, a putative antipsychotic drug, is a selective serotonin 5-HT2 receptor antagonist with moderate affinity for the rat brain dopamine D2 receptor. The aim of the present study was to investigate the regulation of 3H-ketanserin binding of the rat cerebral cortex 5-HT2 receptor following chronic amperozide treatment. Amperozide (5 mg/kg/day p.o. for three weeks) significantly reduced the number of 5-HT2 receptors in rat cerebral cortex (172.9 +/- 8.3 vs 128.4 +/- 4.8 fmol/mg protein; p < 0.001, n = 5-6). There was no change of Kd of 3H-ketanserin. The agonist serotonin (5-HT) recognized two sites of 3H-ketanserin binding in membranes from both saline- and amperozide-treated rats as analysed by non-linear regression using LIGAND. The concentration of high affinity sites was reduced by 51% (53.1 +/- 2.9 vs 25.7 +/- 3.7 fmol/mg protein; p < 0.01, n = 3) while the amount of the low affinity sites remained unchanged. Serotonin displacement of 3H-ketanserin binding was sensitive to regulation by GTP. The present data indicated that GTP regulation was partially lost following chronic amperozide treatment. Displacement of the antagonists methysergide and amperozide were not affected by GTP. In conclusion, the down-regulation of the 5-HT2 receptors appears mainly due to a decrease of the serotonin-recognized high affinity state, and the loss of GTP sensitivity may indicate a decreased ability to form the high affinity state of the receptor. Such a molecular regulation might underlie an altered 5-HT responsiveness and thus be of therapeutic value.