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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