PSPH-D-18-00526: Effect of a dual orexin receptor antagonist (DORA-12) on sleep and event-related oscillations in rats exposed to ethanol vapor during adolescence

Rationale Sleep difficulties are one of the problems associated with adolescent binge drinking. However, the mechanisms underlying adolescent alcohol-associated sleep disturbances and potential targets for therapy remain under investigated. Orexin receptor antagonists may have therapeutic value in the treatment of insomnia, yet the use of this class of drugs in the treatment of sleep disturbances following adolescent alcohol exposure has not been studied. Objectives This study employed a model whereby ethanol vapor exposure occurred for 5 weeks during adolescence (AIE), and waking event-related oscillations (EROs) and EEG sleep were subsequently evaluated in young adult rats. The ability of two doses (10, 30 mg/kg PO) of a dual orexin receptor antagonist (DORA-12) to modify sleep, EEG, and EROs was investigated in AIE rats and controls. Results Adolescent vapor exposure was found to produce a fragmentation of sleep, in young adults, that was partially ameliorated by DORA-12. DORA-12 also produced increases in delta and theta power in waking EROs recorded before sleep, and deeper sleep as indexed by increases in delta and theta power in the sleep EEG in both ethanol and control rats. Rats given DORA-12 also fell asleep faster than vehicle-treated rats as measured by a dose-dependent reduction in the latency to both the first slow wave and REM sleep episodes. Conclusions This study showed that DORA-12 can affect the sleep disturbance that is associated with a history of adolescent ethanol exposure and also has several other sleep-promoting effects that are equivalent in both ethanol and control rats.