Bitter Sensing Protects<i>Drosophila</i>from Developing Experience-Dependent Cocaine Consumption Preference

Cocaine is an addictive psychostimulant, and the risk of developing cocaine use disorder (CUD) is highly heritable. Little is known about the specific genes and mechanisms that lead to the development of CUD, and there are currently no FDA-approved pharmacotherapies that can treat it. <i>Drosophila</i> has proven an effective model organism to identify genes and mechanisms underlying addiction, especially alcohol use disorder. While flies exposed to cocaine display features of acute intoxication like those observed in mammals, including hyperactivity and reduced sleep, to date, there is no model of preferential cocaine self-administration in flies. Here, we assayed cocaine consumption in <i>Drosophila</i> males, as well as preference in a two-choice paradigm. We also investigated mechanisms involved in cocaine taste sensing using genetic and imaging tools. We show that cocaine is innately aversive to flies and that this avoidance depends on bitter sensing. Gustatory sensory neurons expressing the Gr66a bitter receptor are activated upon exposure to cocaine. Silencing of these bitter-sensing neurons or mutation of <i>Gr66a</i> reduces cocaine avoidance. In a longitudinal choice assay, these flies develop preference for cocaine-containing solutions within 12-18 h, whereas control flies do not. Our findings show that bitter sensation protects flies from developing cocaine self-administration preference. Conversely, silencing bitter perception enables us to use <i>Drosophila</i> as a model for experience-dependent cocaine self-administration preference. This opens the door to testing human variants associated with CUD for their causative role in cocaine self-administration in this highly tractable model organism.