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ARS Home » Southeast Area » Gainesville, Florida » Center for Medical, Agricultural and Veterinary Entomology » Mosquito and Fly Research » Research » Publications at this Location » Publication #384318
Research Project: Integrated Pest Management of Mosquitoes and Biting Flies

Location: Mosquito and Fly Research

Title: Mechanism of toxicity for the sesquiterpene, nootkatone

Author
item SWALE, DANIEL - Louisiana State University
item Norris, Edmund
item CHEN, RUI - Louisana State University
item GELDENHUYS, WERNER - West Virginia University
item BLOOMQUIST, JEFFREY - University Of Florida

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 4/26/2021
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: Nootkatone is a sesquiterpene with known acaricidal and repellent properties, resulted in registration by the EPA in 2020 for use as an insecticide or insect repellent. Previous efforts have failed to determine the mechanism of toxicity for nootkatone and thus, we aimed to provide evidence suggesting the likely molecular target driving nootkatone toxicity. Molecular overlays between nootkatone and picrotoxinin, a known GABA antagonist, indicated the two molecules have strong structural overlay and share electrostatic coverage. Considering the structural similarities, we employed toxicological and electrophysiological methods to determine if the putative mode of toxicity is through GABA-gated chloride channels. Topical application of nootkatone to susceptible (CSOR) strain of Drosophila melanogaster yielded an LD50 of 45 (16-110) µg/mg, which was 10.7-fold more toxic when compared to the dieldrin resistant (RDL1675) strain. Further, significant differences in nerve firing after application of nootkatone between the RDL1675 and CSOR strain were observed. Two minutes after application of 100 µM nootkatone, nerve firing of 78 ± 17% of baseline firing in the CSOR strain was significantly different from 24 ± 11% of baseline firing in the RDL1675 strain (p = 0.035). For CSOR, 100 µM nootkatone significantly reversed GABA-mediated block, yet no significant reversal was observed in the RDL1675 strain. Patch clamp recordings on D. melanogaster central neurons mirrored extracellular recordings where nootkatone inhibited chloride current by 62% ' 14% at 100 µM, whereas chloride current was inhibited approximately 3-fold less at 100 µM in RDL1675. Taken together, these data suggest nootkatone toxicity in D. melanogaster is mediated through GABA receptor antagonism.