Molecular Physiology and Toxicology Laboratory, Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
School of Neuroscience, Fralin Life Science Institute, Virginia Polytechnic Institute and State University, Virginia Tech Center for Drug Discovery, Center for Emerging Zoonotic and Arthropod-borne Diseases, and Molecular and Cellular Biology Program, Blacksburg, VA, USA.
Pest Manag Sci. 2022 Nov;78(11):4599-4607. doi: 10.1002/ps.7079. Epub 2022 Aug 4.
Pest management requires continual identification of new physiological targets and strategies to control pests affecting agriculture and public/animal health. We propose the muscarinic system as a target for agrochemicals because of its physiological importance. Unlike the muscarinic system, gamma-amino butyric acid (GABA) receptors are an established insecticide target. Here, we investigated target-site synergism using small molecule probes (agonist and antagonist) against the muscarinic system and their ability to enhance the toxicity of GABAergic insecticides in Drosophila melanogaster (Meigen).
Oral delivery of pilocarpine (muscarinic agonist) enhanced the toxicity of dieldrin, fipronil, and lindane, resulting in synergist ratios (SRs) between 4-32-fold (orally delivered) or between 2-67-fold when insecticides were topically applied. The synergism between pilocarpine and the GABA-insecticides was greater than the synergism observed with atropine (muscarinic antagonist), and was greater, or comparable, to the synergism observed with the metabolic inhibitor piperonyl butoxide. In addition to lethality, pilocarpine increased the knockdown of lindane. The mechanism of synergism was also investigated in the central nervous system using extracellular electrophysiology, where pilocarpine (3 μmo/L) lowered the half-maximal inhibitory concentration (IC ) of lindane from 1.3 (0.86-1.98) μmol/L to 0.17 (0.14-0.21) μmol/L and fipronil's IC from 2.2 (1.54-3.29) μmol/L to 0.56 (0.40-0.77) μmol/L.
Convergence of the cellular function between the muscarinic and GABAergic systems enhanced the insecticidal activity of GABA receptor blocking insecticides through the modulation of the central nervous system (CNS). The future impact of the findings could be the reduction of the active ingredient needed in a formulation with the development of muscarinic synergists. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
害虫管理需要不断识别新的生理靶标和策略，以控制影响农业和公共/动物健康的害虫。我们提出毒蕈碱系统作为农用化学品的靶标，因为它具有重要的生理学意义。与毒蕈碱系统不同，γ-氨基丁酸（GABA）受体是一种已确立的杀虫剂靶标。在这里，我们使用针对毒蕈碱系统的小分子探针（激动剂和拮抗剂）研究了靶标协同作用，以及它们在黑腹果蝇（Drosophila melanogaster）（Meigen）中增强 GABA 能杀虫剂毒性的能力。
口服给予毛果芸香碱（毒蕈碱激动剂）增强了狄氏剂、氟虫腈和林丹的毒性，导致协同比（SR）在 4-32 倍（口服）或 2-67 倍之间，当杀虫剂局部应用时。毛果芸香碱与 GABA 杀虫剂之间的协同作用大于与阿托品（毒蕈碱拮抗剂）观察到的协同作用，并且与代谢抑制剂胡椒基丁醚观察到的协同作用相当或更大。除了致死率外，毛果芸香碱还增加了林丹的击倒。还使用细胞外电生理学在中枢神经系统中研究了协同作用的机制，其中毛果芸香碱（3 μmo/L）将林丹的半最大抑制浓度（IC ）从 1.3（0.86-1.98）μmol/L 降低到 0.17（0.14-0.21）μmol/L，将氟虫腈的 IC 从 2.2（1.54-3.29）μmol/L 降低到 0.56（0.40-0.77）μmol/L。
毒蕈碱和 GABA 能系统的细胞功能趋同通过调节中枢神经系统（CNS）增强了 GABA 受体阻断杀虫剂的杀虫活性。未来的研究结果可能是减少制剂中有效成分的用量，并开发毒蕈碱增效剂。© 2022 作者。害虫管理科学由 John Wiley & Sons Ltd 代表化学工业协会出版。
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