title: Neonicotinoid insecticides display partial and super agonist actions on native insect nicotinic acetylcholine receptors.
abstract: Nicotinic acetylcholine receptors (nAChRs) are present in high density in insect nervous tissue and are targeted by neonicotinoid insecticides. Improved understanding of the actions of these insecticides will assist in the development of new compounds. Here, we have used whole-cell patch-clamp recording of cholinergic neurons cultured from the central nervous system of 3rd instar Drosophila larvae to examine the actions of acetylcholine (ACh) and nicotine, as well as the neonicotinoids imidacloprid, clothianidin and P-CH-clothianidin on native nAChRs of these neurons. Dose-response data yield an EC(50) value for ACh of 19 microm. Both nicotine and imidacloprid act as low efficacy agonists at native nAChRs, evoking maximal current amplitudes 10-14% of those observed for ACh. Conversely, clothianidin and P-CH-clothianidin evoke maximal current amplitudes up to 56% greater than those evoked by 100 microm ACh in the same neurons. This is the first demonstration of 'super' agonist actions of an insecticide on native insect nAChRs. Cell-attached recordings indicate that super agonism results from more frequent openings at the largest (63.5 pS) conductance state observed.
authors.affiliation: Department of Physiology, Anatomy and Genetics, MRC Functional Genetics Unit, Le Gros Clark Building, University of Oxford, South Parks Road, Oxford, UK.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Brown
authors.forename: Makoto
authors.initials: M
authors.lastname: Ihara
authors.forename: Steven D
authors.initials: SD
authors.lastname: Buckingham
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Matsuda
authors.forename: David B
authors.initials: DB
authors.lastname: Sattelle
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology*; D007814:Larva / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D015394:Molecular Structure; D000073943:Neonicotinoids; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D009574:Nitro Compounds; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles
chemical_list: D006146:Guanidines; D007093:Imidazoles; D007306:Insecticides; D000073943:Neonicotinoids; D018722:Nicotinic Agonists; D009574:Nitro Compounds; D011978:Receptors, Nicotinic; D013844:Thiazoles; C480342:clothianidin; C082359:imidacloprid; D009538:Nicotine; D000109:Acetylcholine