Drosophila Cocaine Avoidance is Mediated by Peripheral Bitter Gustatory Neurons

Genetic variation contributes to heterogeneity in the prevalence of complex disorders such as addiction. The genetic risk for developing a substance use disorder can vary between drugs. The estimated heritability rate of cocaine addiction is 72%, higher than any other drug. Despite recognition of this significant genetic component, little is known about the specific genes and mechanisms that lead to the development of cocaine addiction. Drosophila is an effective model organism for identifying the genes that underlie complex behaviors, including addiction. While Drosophila exposed to cocaine display features of intoxication similar to those observed in mammals, there is currently no model of cocaine self-administration in flies. Because cocaine is a natural insecticide, we wondered if Drosophila might naively avoid it through bitter chemosensory detection. To answer this question, we performed cocaine consumption and preference assays comparing wild-type flies and bitter-taste mutants. Our results demonstrate that Drosophila detect and avoid cocaine through bitter sensing gustatory neurons, and that this process requires gustatory receptor 66a (Gr66a). Additionally, we identify a peripheral mechanism of avoidance through cocaine detection with Drosophila legs. Our findings reveal that preingestive mechanisms of toxin detection play a significant role in Drosophila cocaine avoidance and provide evidence that disrupting gustatory perception of cocaine is essential for self-administration and, therefore, developing a model of self-administration in Drosophila.