Small-molecule screen in adult Drosophila identifies VMAT as a regulator of sleep

Sleep is an important physiological state, but its function and regulation remain elusive. In Drosophila melanogaster, a useful model organism for studying sleep, forward genetic screens have identified important sleep-modulating genes and pathways; however, the results of such screens may be limited by developmental abnormalities or lethality associated with mutation of certain genes. To circumvent these limitations, we used a small-molecule screen to identify sleep-modulating genes and pathways. We administered 1280 pharmacologically active small molecules to adult flies and monitored their sleep. We found that administration of reserpine, a small-molecule inhibitor of the vesicular monoamine transporter (VMAT) that repackages monoamines into presynaptic vesicles, resulted in an increase in sleep. Supporting the idea that VMAT is the sleep-relevant target of reserpine, we found that VMAT-null mutants have an increased sleep phenotype, as well as an increased arousal threshold and resistance to the effects of reserpine. However, although the VMAT mutants are consistently resistant to reserpine, other aspects of their sleep phenotype are dependent on genetic background. These findings indicate that small-molecule screens can be used effectively to identify sleep-modulating genes whose phenotypes may be suppressed in traditional genetic screens. Mutations affecting single monoamine pathways did not affect reserpine sensitivity, suggesting that effects of VMAT/reserpine on sleep are mediated by multiple monoamines. Overall, we identify VMAT as an important regulator of sleep in Drosophila and demonstrate that small-molecule screens provide an effective approach to identify genes and pathways that impact adult Drosophila behavior.