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Competitive Potentiation of Acetylcholine Effects on Neuronal Nicotinic Receptors by Acetylcholinesterase‐Inhibiting Drugs

Abstract: The effects of the acetylcholinesterase inhibitors physostigmine and tacrine on α4β2 and α4β4 subtypes of neuronal nicotinic acetylcholine (ACh) receptors, expressed in Xenopus laevis oocytes, have been investigated. In voltage‐clamp experiments low concentrations of physostigmine and tacrine potentiate ion currents induced by low concentrations of ACh, whereas at high concentrations they inhibit ACh‐induced ion currents. These dual effects result in bell‐shaped concentration—effect curves. Physostigmine and tacrine, by themselves, do not act as nicotinic receptor againsts. The larger potentiation is observed with 10 μM physostigmine on α4β4 nicotinic receptors and amounts to 70% at 1 μM ACh. The mechanism underlying the effects of physostigmine on α4β4 ACh receptors has been investigated in detail. Potentiation of ACh‐induced ion current by low concentrations of physostigmine is surmounted at elevated concentrations of ACh, indicating that this is a competitive effect. Conversely, inhibition of ACh‐induced ion current by high concentrations of physostigmine is not surmounted at high concentrations of ACh, and this effect appears mainly due to noncompetitive, voltage‐dependent ion channel block. Radioligand binding experiments demonstrating displacement of the nicotinic receptor agonist 125I‐epibatidine from its recognition sites on α4β4 ACh receptors by physostigmine confirm that physostigmine is a competitive ligand at these receptors. A two‐site equilibrium receptor occupation model, combined with noncompetitive ion channel block, accounts for the dual effects of physostigmine and tacrine on ACh‐induced ion currents. It is concluded that these acetylcholinesterase‐inhibiting drugs interact with the ACh recognition sites and are coagonists of ACh on α4‐containing nicotinic ACh receptors.