PSPH-D-18-00526: Effect of a dual orexin receptor antagonist (DORA-12) on sleep and event-related oscillations in rats e
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ORIGINAL INVESTIGATION
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 Cindy L. Ehlers 1
&
Jessica Benedict 1 & Derek Wills 1 & Manuel Sanchez-Alavez 1
Received: 26 December 2018 / Revised: 12 September 2019 / Accepted: 30 September 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract 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. Keywords Adolescence . Alcohol . Sleep . EROs . DORA
Introduction Disturbance in sleep regulation is one of the health risks associated with adolescent alcohol and drug use. Adolescence is a time when both drug and alcohol-seeking behaviors and disturbances in sleep emerge; and adolescents may be particularly vulnerable to sleep disturbance associated with substance use (Bartel et al. 2015; Hasler and Clark 2013; Hasler et al. 2014a; Hasler et al. 2013; Hasler et al. 2014b, 2015). Recently, animal models of alcohol-induced insomnia have been developed that allow for study of the effects of ethanol
* Cindy L. Ehlers [email protected] 1
Department of Neurosciences, The Scripps Research Institute, 10550 North Torrey Pines Road, SR307C, La Jolla, CA 92037, USA
on sleep independent of factors that may confound human studies, such as premorbid conditions and other substance use. Investigations conducted in our laboratory as well as others, in rodents, have shown that chronic ethanol exposure can produc
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