The avermectins are a group of pesticides whose main mode of action is to block synaptic transmission between neurons or between neurons and muscle cells. A number of closely related genes encoding avermectin-binding proteins have been cloned from a variety of invertebrates, including Drosophila melanogaster. Here we present the results of our study on the responses to avermectins of the D. melanogaster ort (ora transientless; 3-66.4) mutants. Mutations in this gene are known to affect synaptic transmission in the visual system. By the use of bioassays that we developed, three ort mutations were examined for resistance to two avermectins: ivermectin and abamectin. The results demonstrated an increased susceptibility to both toxins in all the mutant strains analyzed. compared to the wild-type flies. The levels of the susceptibility were allele specific in either the homo- or the hemizygous state of the mutations and in interstrain hybrids between different art mutants. These observations allowed us to eliminate the genetic background of the mutants as a possible reason for their changed resistance. At the third instar larval stage, all the mutants were also more susceptible than the wild type, though a specific response to ivermectin was only shown by one mutant and there were no mutant-specific larval responses to abamectin. Double ort heterozygotes displayed a level of susceptibility inherited from the more resistant parent. No increased susceptibility of the ort mutants was found to treatment with dieldrin, which specifically blocks gamma-aminobutyric acid receptors. Together, these data provide evidence that ort is implicated in the genetic determination of avermectin sensitivity and provide the first example of mutations establishing hypersensitivity to these insecticides in Drosophila. (C) 2002 Elsevier Science (USA).