A Fly’s Eye View of Natural and Drug Reward

Eve G. Lowenstein, Norma A. Velazquez-Ulloa

Animals encounter multiple stimuli each day. Some of these stimuli are innately appetitive or aversive, while others are assigned valence based on experience. Drugs like ethanol can elicit aversion in the short term and attraction in the long term. The reward system encodes the predictive value for different stimuli, mediating anticipation for attractive or punishing stimuli and driving animal behavior to approach or avoid conditioned stimuli. The neurochemistry and neurocircuitry of the reward system is partly evolutionarily conserved. In both vertebrates and invertebrates, including Drosophila melanogaster, dopamine is at the center of a network of neurotransmitters and neuromodulators acting in concert to encode rewards. Behavioral assays in D. melanogaster have become increasingly sophisticated, allowing more direct comparison with mammalian research. Moreover, recent evidence has established the functional modularity of the reward neural circuits in Drosophila. This functional modularity resembles the organization of reward circuits in mammals. The powerful genetic and molecular tools for D. melanogaster allow characterization and manipulation at the single-cell level. These tools are being used to construct a detailed map of the neural circuits mediating specific rewarding stimuli and have allowed for the identification of multiple genes and molecular pathways that mediate the effects of reinforcing stimuli, including their rewarding effects. This report provides an overview of the research on natural and drug reward in D. melanogaster, including natural rewards such as sugar and other food nutrients, and drug rewards including ethanol, cocaine, amphetamine, methamphetamine, and nicotine. We focused mainly on the known genetic and neural mechanisms underlying appetitive reward for sugar and reward for ethanol. We also include genes, molecular pathways, and neural circuits that have been identified using assays that test the palatability of the rewarding stimulus, the preference for the rewarding stimulus, or other effects of the stimulus that indicate how it can modify behavior. Commonalities between mechanisms of natural and drug reward are highlighted and future directions are presented, putting forward questions best suited for research using D. melanogaster as a model organism.