Adaptive changes in the 5-HT2 binding site after chronic administration of agonists and antagonists

This study confirms and extends an earlier report that acute administration of the serotonin (5-HT) antagonist, mianserin, caused a marked decrease in the density of 5-HT2 binding sites in brain of the rat (Blackshear and Sanders-Bush, 1982). Using [3H]ketanserin, a selective ligand for the 5-HT2 site, the present study further investigated the mechanism of this effect. The effects of mianserin in vivo and in vitro were compared with those of trifluoromethylphenylpiperazine (TFPP), a directly acting 5-HT agonist. While TFPP, unlike mianserin, was not active in single doses, it caused a 58% decrease in the density of 5-HT2 sites after repeated doses. The adaptive change induced by chronic treatment with TFPP was qualitatively and quantitatively similar to that caused by chronic administration of mianserin. Furthermore, mianserin and TFPP had similar effects in vitro; preincubation of membranes from brain induced a concentration-dependent increase in the Kd value with no change in the Bmax value. Similar adaptive changes in 5-HT2 sites after administration of mianserin, a presumed 5-HT antagonist, and after TFPP, a presumed 5-HT agonist, suggests that adaptive mechanisms in the serotonergic system are different from those in other aminergic systems or that the drugs used to characterize 5-HT receptor systems need to be re-evaluated.