ANTAGONIST-MEDIATED DOWN-REGULATION OF 5-HYDROXYTRYPTAMINE TYPE-2 RECEPTOR GENE-EXPRESSION - MODULATION OF TRANSCRIPTION

Prolonged exposure to an agonist results in a progressive loss of most G protein-coupled receptors, whereas exposure to an antagonist causes increased receptor response. The 5-hydroxy-tryptamine (5-HT)(2) recep tor is down-regulated by agonists but, paradoxically, antagonists can also elicit a decrease in receptor density. Here we show that long ter m treatment with serotonin or mianserin, an antagonist and antidepress ant, results in reduced levels of both the 5-HT2 receptor and its RNA. Antagonist-induced down-regulation requires the presence of the 5-HT2 receptor, it occurs at the level of transcription, and it is mediated by a drug response sequence in the 5' flanking region of the 5-HT2 re ceptor gene. The effect of mianserin might result, at least in part, f rom its ability to modulate transcription.