The Muscarinic Antagonists Scopolamine and Atropine are Competitive Antagonists at 5-HT3 Receptors
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Lochner, M., & Thompson, A. (2016). The Muscarinic Antagonists Scopolamine and Atropine are Competitive Antagonists at 5-HT3 Receptors. Neuropharmacology, 108 220-228. https://doi.org/10.1016/j.neuropharm.2016.04.027
Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 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_3A 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 [^3H]granisetron (Ki = 6.76 µM) and G-FL (Ki = 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 Ki of 7.94 µM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 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.
5-HT3, Cys-loop, binding site, ligand docking, scopolamine, muscarinic, antagonist, anxiety, cognition, memory, depression, hippocampus, amygdala
Our thanks are given to John Peters (University of Dundee) for the 5-HT3A subunit. ML thanks the Swiss National Science Foundation for financial support (SNSF- professorship PP00P2_123536 and PP00P2_146321). AJT thanks the British Heart Foundation for financial support (PG/13/39/30293).
British Heart Foundation (PG/13/39/30293)
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External DOI: https://doi.org/10.1016/j.neuropharm.2016.04.027
This record's URL: https://www.repository.cam.ac.uk/handle/1810/255834
Attribution-NonCommercial-NoDerivs 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by-nc-nd/2.0/uk/
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