Putative selective 5-HT-2 antagonists block serotonin 5-HT-1c receptors in the choroid plexus

The binding of [3H]mianserin to rat choroid plexus was characterized and compared with two other radioligands that label the 5-HT (serotonin)-1c receptor ([3H]mesulergine and [125I] lysergic acid diethylamide). [3H]Mianserin binding to a crude membrane preparation of choroid plexus from rat brain was rapid, saturable and of high affinity (Kd = 1 nM). The density of sites labeled by [3H]mianserin and [3H]mesulergine was equal. Furthermore, an excellent correlation was found between the potencies of drugs in competing for [3H]mianserin binding and for [125]lysergic acid diethylamide binding. Based on these data, it was concluded that [3H]mianserin labels the 5-HT-1c binding site. Using this ligand, the binding of the putative selective 5-HT-2 antagonist ritanserin to the 5-HT-1c site was evaluated. Ritanserin was a potent inhibitor of [3H]mianserin binding with a Ki value of 0.2 nM. Functional studies of 5-HT-stimulated phosphoinositide hydrolysis, the transmembrane signaling pathway for the 5-HT-1c receptor, showed that ritanserin blocks the effect of 5-HT and that it functions as a competitive antagonist of the 5-HT-1c receptor in intact choroid plexus. The potencies of ritanserin and several other drugs, including other 5-HT-2 antagonists, at the 5-HT-1c binding site correlated with their potencies at blocking 5-HT-stimulated phosphoinositide hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)