Aripiprazole advances delayed sleep-wake rhythm in methamphetamine-treated mice

Circadian rhythm sleep-wake disorders (CRSWD) are characterized by misalignment between the sleep-wake rhythm and the environmental day-night cycle, leading to disturbances in daily life. Melatonin and light therapy targeting circadian rhythms are generally used, but with limited efficacy. Recent studies have revealed that one-third or more of CRSWD patients with abnormal sleep-wake rhythm have normal melatonin rhythm, indicating the possible involvement of internal desynchronization, where circadian rhythm and sleep-wake rhythm dissociate. Aripiprazole (APZ) is a dopamine D2/D3 receptor partial agonist and has recently been shown effective to CRSWD. In this study, we explored the potential of APZ in treating mouse model of CRSWD. We use male C57/Black6 mice and first demonstrated APZ administered to the mice with normal sleep-wake rhythm increased sleep during the rest period and also increased wakefulness during the next active period. We next found APZ administered to the chronic methamphetamine (MAP)-treated mice with CRSWD like sleep phenotype synchronized their sleep-wake rhythm to the light-dark cycle. This entrainment was also accompanied by changes in sleep architecture. These findings brought insights into the mechanism how APZ acts on patients with CRSWD, especially with internal desynchronization.