Insecticides play a pivotal role in the control of insect pests affecting public/animal health and agriculture with a continued need to find new insecticidal chemistry working at underutilized molecular targets. Physiological synergism, which uses small molecules modulating different physiological pathways, could enhance pest management and possibly delay the development of resistance, decrease the amount of active ingredient, and potentially break resistance. G-protein-coupled receptors (GPCRs) are an underutilized insecticide/synergist target, where these proteins and signal transduction pathways likely enhance the toxicity of established insecticide classes. Muscarinic acetylcholine receptors (mAChRs) are involved in a variety of physiological processes, but mAChRs have never been fully developed as a target for arthropod management. Agonism of muscarinic receptors with pilocarpine (muscarinic probe) at a less lethal concentration, significantly enhanced the toxicity (lethality and knockdown) of several insecticides that block gamma-amino butyric acid (GABA) chloride channels (lindane, dieldrin, and fipronil) with synergistic ratios of 4–32-fold and 4–67-fold when the insecticides were orally or topically delivered, respectively. Blocking muscarinic receptors with atropine did not result in synergism, and with fipronil, resulted in an antagonistic toxic effect. Toxicity bioassays correlated with the mixture effect on the central nervous system (CNS) firing rate, which was measured using extracellular electrophysiology. A target-site mutation in the GABA-gated chloride ionophore (Rdl) is one mechanism for the loss of efficacy of dieldrin, lindane and fipronil in the field, with an established Drosophila melanogaster strain originally collected in Maryland (MD-RR). This stable mutation (Rdl) is maintained by the MD-RR strain outside of selective pressure. While the Rdl mutation does not affect orthosteric binding of the endogenous ligand, a change in gating kinetics has been reported. We postulate that the biophysical change associated with the mutated channel results in compensation by the CNS affecting the cholinergic system where pilocarpine’s excitatory effect on the CNS firing rate is curtailed along with the overexpression of acetylcholinesterase in the resistant strain. Collectively, this compensatory mechanism affects the target-site synergism in the resistant strain but could likely have a greater impact on resistant management programs.

Insect muscarinic acetylcholine receptors: A target for physiological synergists and the greater effect of the Rdl mutation on the cholinergic system

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ACS Fall 2022

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