The proposed research will test the hypothesis that pyrethroid insecticides exert their neurotoxic action by binding to an unique and as-yet-uncharacterized stereospecific receptor site associated with nerve membrane sodium channels. Two complementary approaches will be used: a stereospecific receptor binding assay using optically pure pyrethroid radiligands; and an assay of pyrethroid stimulation of veratridinedependent radiosodium flux through nerve synaptosomal sodium channels. Data will be obtained from these two approaches using a series of pyrethroids exemplifying critical structure-activity relationships in synaptosomal preparations from mouse brain and cockroach nerve cord. Comparison of these data with in vivo measurements of intrinsic toxicity in both mice and cockroaches will (1) allow critical evaluation of the stereospecific binding site as a toxicologically significant pyrethroid receptor, (2) determine the relationship between stereospecific binding and pyrethroid-dependent potentiation of sodium channel activation, and (3) define intrinsic differences in the pyrethroid receptor of target and non-target species. Subsequent studies will explore the binding and pharmacological effects of pyrethroids on purified and reconstituted sodium channel preparations from mouse brain. Results of these studies will contribute to the resolution of the current controversy over the mode of action of these important insecticides. They will also provide experimental systems appropriate for identifying specific antidotes for pyrethroid intoxication in mammals and for developing intrinsically selective new insecticides by exploiting receptor differences between mammals and insects.

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National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Study Section (TOX)
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Cornell University
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Rubin, J G; Soderlund, D M (1993) Binding of [3H]batrachotoxinin A-20-alpha-benzoate and [3H]saxitoxin to receptor sites associated with sodium channels in trout brain synaptoneurosomes. Comp Biochem Physiol C 105:231-8
Bloomquist, J R; Grubs, R E; Soderlund, D M et al. (1991) Prolonged exposure to GABA activates GABA-gated chloride channels in the presence of channel-blocking convulsants. Comp Biochem Physiol C 99:397-402
Payne, G T; Soderlund, D M (1991) Activation of gamma-aminobutyric acid insensitive chloride channels in mouse brain synaptic vesicles by avermectin B1a. J Biochem Toxicol 6:283-92
Ottea, J A; Payne, G T; Bloomquist, J R et al. (1989) Activation of sodium channels and inhibition of [3H]batrachotoxinin A-20-alpha-benzoate binding by an N-alkylamide neurotoxin. Mol Pharmacol 36:280-4
Soderlund, D M; Bloomquist, J R (1989) Neurotoxic actions of pyrethroid insecticides. Annu Rev Entomol 34:77-96
Soderlund, D M; Grubs, R E; Adams, P M (1989) Binding of [3H]batrachotoxinin A-20-alpha-benzoate to a high affinity site associated with house fly head membranes. Comp Biochem Physiol C 94:255-60
Bloomquist, J R; Soderlund, D M (1988) Pyrethroid insecticides and DDT modify alkaloid-dependent sodium channel activation and its enhancement by sea anemone toxin. Mol Pharmacol 33:543-50
Stuart, A M; Bloomquist, J R; Soderlund, D M (1987) Pharmacological characterization of the voltage-dependent sodium channels of rainbow trout brain synaptosomes. Brain Res 437:77-82
Soderlund, D M; Adams, P M; Bloomquist, J R (1987) Differences in the action of avermectin B1a on the GABAA receptor complex of mouse and rat. Biochem Biophys Res Commun 146:692-8
Bloomquist, J R; Adams, P M; Soderlund, D M (1986) Inhibition of gamma-aminobutyric acid-stimulated chloride flux in mouse brain vesicles by polychlorocycloalkane and pyrethroid insecticides. Neurotoxicology 7:11-20

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