Toxicology, mode of action and target site-mediated resistance to insecticides acting on chloride channels.

1. The discovery that the avermectins and cyclodienes affected the chloride channels of excitable membranes generated intense research interest among academic and industrial scientists. 2. The results of biochemical and neurophysiological studies indicate that the gamma-aminobutyric acid (GABA)-gated chloride channel is an important, if not the primary site of action for these compounds. 3. The action of insecticides on the functional properties of the GABA receptor differs by structural class. The cyclodienes block the chloride ion channel and the avermectins activate it. 4. Blockage of the GABA-gated chloride channel by cyclodienes reduces neuronal inhibition, which leads to hyper-excitation of the central nervous system, convulsions, and death. For avermectins, activation of the channel suppresses neuronal activity, resulting in ataxia, paralysis and death. Although actions on the GABA-gated chloride channel can explain many of the effects of these compounds, there is evidence supporting the participation of other ligand- and voltage-gated chloride channels in the overall intoxication process. This consideration is especially true for the avermectins. 5. Several structural series of experimental insecticides have been synthesized which possess a blocking action on the GABA-gated chloride channel similar to that of the cyclodienes. 6. Resistance to cyclodienes usually occurs through an altered target site, and extends to all experimental compounds that block chloride channels. However, the resistance does not afford protection against the avermectins. 7. The continued search for new insecticides directed against chloride channels may lead to compounds with less environmental impact and greater selectivity than that of the cyclodienes. Given the pre-selection for resistance by the cyclodienes, new compounds with a similar mode of action must be used judiciously in order to suppress or delay the re-emergence of widespread resistance.