Competitive antagonism by recognised 5-HT2 receptor antagonists at 5-HT1C receptors in pig choroid plexus

Abstract

The effects of several antagonists, known to interact with 5-HT2 receptors (ritanserin, LY 53857, ICI 169,369, methysergide, mesulergine and ketanserin), were tested against 5-HT-stimulated production of inositol phosphate in pig choroid plexus, a 5-HT1C receptor model. These antagonists produced dextral shifts of the concentration response curve to 5-HT in a parallel manner, without depressing significantly the maximal response. The following pA2 values (in parentheses) were obtained: mesulergine (8.88), methysergide (8.85), LY 53857 (8.69), ritanserin (8.69), ICI 169,369 (7.86), and ketanserin (6.57). These pA2 values were in good agreement with the pKD values determined in radioligand binding studies performed in pig choroid plexus with [3H]mesulergine. The present data demonstrate that several drugs described as 5-HT2 receptor selective antagonists (e.g. ritanserin, LY 53857 and ICI 169,369) are also potent, competitive and surmountable antagonists at 5-HT1C receptors. Thus, the results provide further evidence for the pharmacological similarity of 5-HT1C and 5-HT2 receptors. However, in contrast to the situation described with methysergide, ritanserin and LY 53857 in several 5-HT2 receptor models, none of these antagonists acted in a non-competitive or unsurmountable fashion at 5-HT1C receptors. These results suggest, but do not firmly rule out, that at least in the presence of the drugs tested in the present study, 5-HT1C receptors in the choroid plexus do not undergo an allosteric modulation; these findings are apparently in contrast to a model proposed previously for 5-HT2 receptors (Kaumann and Frenken 1985, Naunyn-Schmiedeberg's Arch Pharmacol 328:295-300).