Drosophila Model of Cocaine Use Disorder

Cocaine use disorder (CUD) is a major public health challenge. While the primary mechanism of action of cocaine has been well characterized, and family studies have identified a strong genetic component, the specific genetic factors that influence susceptibility to development of CUD remain poorly understood. Genetic studies of cocaine use disorder are difficult in humans, but can be readily performed in Drosophila, where environment, genetic background, and cocaine exposure can be controlled. Drosophila exhibit behavioral and transcriptomic responses to cocaine, which binds to the dopamine transporter in fruit flies as it does in humans. Here, we use Drosophila to investigate the cell-specific transcriptomic response to cocaine across the whole brain, identifying sexually-dimorphic networks of cocaine-responding genes. These networks implicate cell types often ignored in studies of CUD. Then, we present the Microplate Feeder Assay for high-throughput quantification of consumption behaviors in Drosophila. This assay allowed for a large-scale screen of genetic variation in cocaine consumption traits using the Drosophila Genetic Reference Panel, which identified and validated multiple novel genes for association with cocaine preference behavior. Specifically, we identified candidate genes CG8837, Shaw, and nAChRalpha6, all of which have human orthologs not previously associated with CUD. Finally, we demonstrate the utility of Drosophila for cross-species preclinical drug discovery to identify potential treatments for CUD. Together, these studies utilize Drosophila as a model to investigate the genetics of CUD, from the single-cell level to pharmaceutical testing.