The Effects of Acute Trazodone Administration on Sleep in Mice

Study ObjectivesTrazodone is an antidepressant with robust hypnotic effects, frequently prescribed off-label to treat insomnia. Trazodone has gained recent attention in the context of neurodegenerative diseases because sleep has been proposed as a novel target for disease-modifying therapeutics. Preclinical research in rodents examining the effects of trazodone on sleep is limited, so here we aimed to develop a translationally-focused protocol to study the sleep-promoting effects of trazodone in mice. MethodsWe investigated the effects of voluntary oral trazodone administration at doses of 0 mg/kg, 10 mg/kg, 40 mg/kg, and 60 mg/kg on sleep in C57BL/6J mice (n = 15; females = 6; age 10-13 months). Mice were dosed with trazodone for 6 consecutive nights, while being recorded with intracranially implanted 2-channel electroencephalogram (EEG) and electromyography (EMG). EEG/EMG recordings were analyzed for time spent in each vigilance state and power spectra. ResultsA single dose of trazodone, administered prior to the onset of the 12-h rest phase, dose-dependently increased non-rapid eye movement (NREM) sleep and delta power during NREM sleep, at the expense of rapid eye movement (REM) sleep. These effects on sleep persisted after six consecutive days of dosing, albeit to a lesser extent. ConclusionWe have validated a novel voluntary oral administration protocol for trazodone use in mice and have shown that trazodone effectively promotes NREM in mice. Our novel protocol will be useful for future research investigating the effects of trazodone on sleep in mouse models of disease. Statement of significanceTrazodone is an antidepressant known to increase slow wave sleep in humans. Slow wave sleep promotion is being explored as a disease-modifying therapeutic target for neurodegenerative diseases, such as Alzheimers disease. We have developed a novel translationally-focused protocol for administering trazodone to mice, which overcomes some of the challenges of using trazodone for preclinical sleep research. Using our protocol we have demonstrated for the first time that trazodone dose-dependently increases the amount of NREM sleep and delta power in mice, recapitulating the enhancement of slow wave sleep in humans treated with trazodone.