Modafinil maintains waking in the fruit fly Drosophila melanogaster

Fruit flies exhibit a sleep-like rest state that shares behavioral characteristics with mammalian sleep, including a homeostatic increase in rest after deprivation by mechanical methods. We tested the effect of modafinil, a novel wake-promoting agent, to discover whether its effect is conserved. Flies fed various concentrations of modafinil were compared to groups of control flies fed diluent only. Flies were also tested for a homeostatic response to the modafinil-related rest deprivation by examining rest and activity during recovery after 48H modafinil administration, compared to rest deprivation alone and to both treatments combined. The duration and consolidation of rest, and the duration, intensity, and circadian rhythms of activity were measured. Modafinil significantly and dose-dependently decreased rest when fed at concentrations from 2.5 mg/ml to 0.3125 mg/ml. Activity intensity was not increased, and circadian timing was unchanged, although the 2.5 mg/ml dose blunted the amplitude of overt circadian locomotor rhythms. Compared to controls, the duration of rest bouts was decreased in flies fed 2.5 mg/ml, and waking was frequently interrupted by 5-min periods of immobility. A rest rebound (significant increase in rest) followed withdrawal of either 2.5mg/ml or 0.625mg/ml modafinil after 48H. When directly compared to 6H total rest deprivation, the increase after withdrawal was briefer, reminiscent of the attenuated rest rebound seen in mammals, including humans, after modafinil. However, modafinil withdrawal combined with 6H total rest deprivation significantly enhanced the rebound, suggesting that a rest debt is accumulating during modafinil. We conclude that modafinil affects states of arousal in Drosophila in the same direction as it does in mammals. This discovery provides a tool for searching for conserved molecular mechanisms by which modafinil regulates rest and waking.