Millions of Americans abuse illicit drugs, including the stimulant cocaine. The annual economic burden thiscreates is in the hundreds of billions of dollars. There is a substantial genetic contribution to the developmentof substance abuse disorders (SUD), but many molecular pathways remain to be elucidated. The vinegar fly,Drosophila melanogaster, has been a genetic model organism for more than a hundred years. Major strideshave been made in the last 10 years studying the behavioral responses to alcohol in flies, both incharacterizing novel conserved genes and pathways, but also in the development of new assays that resembleaddiction more closely. The goal of this proposal is to engineer Drosophila flies to self-administer cocaine. Thiscompound normally acts as an aversive antiherbivore chemical, and we hypothesize that this is becausecocaine amplifies dopaminergic signaling, which in flies is mainly, but not exclusively, aversive. First, we willdetermine whether flies self-administer cocaine. We will establish dose response curves, and test the effects ofcocaine pre-exposure on cocaine preference/aversion. We will also test the impact of dopamine signaling oncocaine consumption. Second, we will engineer flies that contain cocaine-sensitive dopamine transporters onlyin these dopamine neurons required for the development of self-administration. In the other, aversivedopamine neurons, these engineered flies will contain a cocaine-insensitive dopamine transporter. Theproposed experiments will yield a novel cocaine self-administration assay in a model organism that hashistorically demonstrated great economy of scale and success in elucidating the molecular mechanisms ofnumerous basic physiological, and behavioral processes.
????????????????????????????????????????????????????????????????Cocaine abuse disorders are a chronic human condition with a substantial genetic contribution where initialconsumption leads to long lasting behavioral changes; including compulsive consumption despite adverseconsequences. The proposed studies will provide a novel cocaine self-administration assay in a high-throughput model organism; Drosophila; resembling abuse much more closely than previous assays in thisspecies. This paves the way for future abuse gene identification and molecular characterization; a prerequisitefor the smart design of therapeutic interventions.
|Kaun, Karla R; Rothenfluh, Adrian (2017) Dopaminergic rules of engagement for memory in Drosophila. Curr Opin Neurobiol 43:56-62|
|Narayanan, Anjana S; Rothenfluh, Adrian (2016) I Believe I Can Fly!: Use of Drosophila as a Model Organism in Neuropsychopharmacology Research. Neuropsychopharmacology 41:1439-46|