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 chl oride channels of excitable membranes generated intense research inter est among academic and industrial scientists. 2, The results of bioche mical and neurophysiological studies indicate that the gamma-aminobuty ric acid (GABA)-gated chloride channel is an important, if not the pri mary site of action for these compounds. 3. The action of insecticides on the functional properties of the GABA receptor differs by structur al class. The cyclodienes block the chloride ion channel and the averm ectins activate it. 4. Blockage of the GABA-gated chloride channel by cyclodienes reduces neuronal inhibition, which leads to hyper-excitati on of the central nervous system, convulsions, and death. For avermect ins, activation of the channel suppresses neuronal activity, resulting in ataxia, paralysis and death. Although actions on the GABA-gated ch loride channel can explain many of the effects of these compounds, the re is evidence supporting the participation of other ligand- and volta ge-gated chloride channels in the overall intoxication process. This c onsideration is especially true for the avermectins. 5. Several struct ural series of experimental insecticides have been synthesized which p ossess 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 compou nds that block chloride channels. However, the resistance does not aff ord protection against the avermectins. 7. The continued search for ne w insecticides directed against chloride channels may lead to compound s with less environmental impact and greater selectivity than that of the cyclodienes. Given the pre-selection for resistance by the cyclodi enes, new compounds with a similar mode of action must be used judicio usly in order to suppress or delay the re-emergence of widespread resi stance.