Tricyclic Antidepressants suppress sleep in Caenorhabditis elegans

Abstract Study objectives Sleepiness and fatigue are common symptoms during illness and may persist after the resolution of illness. To gain insight into the neurochemistry of sickness-induced sleep and to discover therapeutic candidates, we performed a high throughput chemical screen using the animal model Caenorhabditis elegans. Methods Worms were irradiated with ultraviolet light to induce sickness and then transferred to wells of a 96-well plate each containing a different bioactive chemical dissolved in an aqueous solution. The fraction of quiescent animals was assessed via stereomicroscopic observation. We performed 12 vehicle-only controls for each 96-well plate and considered sleep-inhibiting chemicals as those with a fraction quiescent at least 3 standard deviations less than controls. We followed up the screen with dedicated mechanistic studies of the drug amitriptyline. Results Among 3,683 bioactive chemicals screened, 42 strongly reduced sleep behavior. We retested 26 and replicated 23 chemicals as sleep-disrupting. Among replicated compounds were amitriptyline (AMI) and other tricyclic anti-depressants (TCAs). AMI acts downstream of or in parallel to activation of sleep-promoting neurons. In addition to suppressing sleep in sickness (SIS), AMI also suppressed sleep in health and reduces survival. We tested and rejected the hypothesis that AMI acts by increasing monoaminergic tone, providing evidence that TCAs act via a novel mechanism to block sleep. Conclusions This is the first high-throughput screen for chemicals modulating SIS. Elucidating the mechanism by which AMI and other chemicals regulate sleep will lead to new biological insights regarding the mechanisms of sleep.