The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT(3) receptors

Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT(3) receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT(3) receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT(3)A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT(3) receptor-responses were reversibly inhibited by scopolamine with an IC(50) of 2.09 μM. Competitive antagonism was shown by Schild plot (pA(2) = 5.02) and by competition with the 5-HT(3) receptor antagonists [(3)H]granisetron (K(i) = 6.76 μM) and G-FL (K(i) = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC(50) of 1.74 μM, and competed with G-FL with a K(i) of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (K(i) = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC(50) values found here. It is therefore possible that 5-HT(3) receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects.