MIANSERIN-INDUCED DOWN-REGULATION OF HUMAN 5-HYDROXYTRYPTAMINE(2A) AND 5-HYDROXYTRYPTAMINE(2C) RECEPTORS STABLY EXPRESSED IN THE HUMAN NEUROBLASTOMA CELL-LINE SH-SY5Y

We have assessed the ability of the serotonergic antagonist mianserin to modulate the number and functional activity of human 5-hydroxytrypt amine(2A) (5-HT2A) and 5-HT2C receptors stably expressed in the human neuroblastoma cell line SH-SY5Y. Incubation of cells expressing the 5- HT2A receptor with mianserin (100 nM) for 24 h caused a significant de crease (48%) in the binding capacity of [H-3]ketanserin. This receptor down-regulation was associated with a corresponding decrease in the m aximal production of inositol phosphates induced by 5-HT but not by ca rbachol. Exposure of cells expressing the 5-HT2C receptor to mianserin (100 nM) for 72 h but not for 24 h similarly resulted in a significan t reduction (44%) in [H-3]mesulergine binding. Corresponding analysis of inositol phosphate production by 5-HT at the 5-HT2C receptor after incubation with mianserin showed no change in maximal response after 2 4 h. No change in the binding capacity of either radioligand was seen after incubation with mianserin for 1 h. A decrease in the binding aff inity of both radioligands was also observed after mianserin treatment , but this decrease was similar after 1 h of incubation to that seen a fter 24 or 72 h, and was probably due to the retention of mianserin wi thin the tissue. We conclude that antagonist down-regulation is eviden t at human 5-HT2A and 5-HT2C receptors stably expressed in a human neu roblastoma cell line and is probably mediated by a direct action of mi anserin at the receptor.