title: Competitive potentiation of acetylcholine effects on neuronal nicotinic receptors by acetylcholinesterase-inhibiting drugs.
abstract: The effects of the acetylcholinesterase inhibitors physostigmine and tacrine on alpha4beta2 and alpha4beta4 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 microM: physostigmine on alpha4beta4 nicotinic receptors and amounts to 70% at 1 microM: ACh. The mechanism underlying the effects of physostigmine on alpha4beta4 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 (125)I-epibatidine from its recognition sites on alpha4beta4 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 alpha4-containing nicotinic ACh receptors.
authors.affiliation: Research Institute of Toxicology, Utrecht University, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Zwart
authors.forename: R G
authors.initials: RG
authors.lastname: van Kleef
authors.forename: C
authors.initials: C
authors.lastname: Gotti
authors.forename: C J
authors.initials: CJ
authors.lastname: Smulders
authors.forename: H P
authors.initials: HP
authors.lastname: Vijverberg
mesh_terms: D000109:Acetylcholine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017136:Ion Transport / Q000187:drug effects; D008024:Ligands; D008959:Models, Neurological; D018722:Nicotinic Agonists / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010830:Physostigmine / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013619:Tacrine / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002800:Cholinesterase Inhibitors; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D013619:Tacrine; D010830:Physostigmine; C082748:epibatidine; D000109:Acetylcholine