Effect of suvorexant on event-related oscillations and EEG sleep in rats exposed to chronic intermittent ethanol vapor and protracted withdrawal

SLEEPJ, 2019, 1–14 doi: 10.1093/sleep/zsz020 Advance Access Publication Date: 31 January 2019 Original Article Original Article and EEG sleep in rats exposed to chronic intermittent ethanol vapor and protracted withdrawal Manuel Sanchez-Alavez, Jessica Benedict, Derek N. Wills and Cindy L. Ehlers*, Department of Neurosciences, The Scripps Research Institute, La Jolla, CA *Corresponding author. Cindy L. Ehlers, Department of Neurosciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Email: . Abstract Study Objectives: Insomnia is a prominent complaint in patients with alcohol use disorders (AUD). However, despite the importance of sleep in the maintenance of sobriety, treatment options for sleep disturbance associated with a history of AUD are currently limited. Recent clinical trials have demonstrated that suvorexant, a dual Hct/OX receptor antagonist, normalizes sleep in patients with primary insomnia; yet, its potential for the treatment of sleep pathology associated with AUD has not been investigated in either preclinical or clinical studies. Methods: This study employed a model whereby ethanol vapor exposure or control conditions were administered for 8 weeks to adult rats. Waking event-related oscillations (EROs) and EEG sleep were evaluated at baseline before exposure and again following 24 hr of withdrawal from the exposure. Subsequently, the ability of vehicle (VEH) and two doses (10, 30 mg/kg IP) of suvorexant to modify EROs, sleep, and the sleep EEG was investigated. Results: After 24 hr following EtOH withdrawal, the ethanol-treated group had increases in waking ERO θ and β activity, more fragmented sleep (shorter duration and increased frequency of slow wave (SW) and rapid eye movement [REM] sleep episodes), and increased θ and β power in REM and SW sleep. Suvorexant induced a dose-dependent decrease in the latency to REM and SW sleep onsets but also produced REM and SW sleep fragmentation and increased β energy in waking EROs when compared with VEH. Conclusions: Taken together, these studies suggest that suvorexant has overall sleep-promoting effects, but it may exacerbate some aspects of sleep and EEG pathology. Statement of Significance Insomnia is one of the problems that is associated with alcohol use disorder. However, the mechanisms underlying alcohol-associated sleep disturbances and potential targets for therapy remain under-investigated. Recent clinical trials have demonstrated that the dual Hypocretin/Orexin receptor antagonist suvorexant may have therapeutic value in the treatment of primary insomnia; yet, the use of this class of drugs in the treatment of alcohol-associated sleep disturbances has not been studied in an animal model. We examined the role of suvorexant on alcohol-associated insomnia in rats. We found that suvorexant promotes sleep, however, increased rapid eye movement, and slow-wave sleep fragmentation. Future studies are needed to explore the role of hypocretin/orexin-receptor 1 or receptor 2 on alcoholassociated sleep pathology. Key words: alcohol; EEG; event-related oscillations; suvorexant; slow-wave sleep Submitted: 21 September, 2018; Revised: 7 December, 2018 © Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail . 1 Effect of suvorexant on event-related oscillations 2 | SLEEPJ, 2019, Vol. 42, No. 4 Introduction Insomnia is a prominent complaint of patients with alcohol use disorder (AUD). AUD-induced insomnia can also fail to resolve over the course of recovery, is a leading cause of patients’ relapse to drinking [1], and may have psychosocial and psychiatric consequences [2]. It has been reported that after acute withdrawal, chronic alcohol users may complain of light, fragmented sleep and demonstrate a deficit in slow-wave sleep (SWS) that can persist for months [3, 4]. Insomnia is one of the eight core criteria in the diagnosis of alcohol withdrawal syndrome [5] and refers to nonrestorative or poor-quality sleep as reported by the patient [6, 7] that occurs even in the absence of mood disorders [8]. There are a number of studies that have demonstrated that alcohol relapse is more likely among persons with persistent sleep disturbances who are recovering from an AUD [9]. A number of sleep measures have been employed in these studies, and decreased sleep efficiency, decreased total sleep time, increased rapid eye movement (REM) sleep, increased sleep pressure, and decreased SWS have all been found to be good predictors of alcohol relapse [1]. Foster and colleagues [10], using the Nottingham Health Profile Questionnaire (NHP), found that sleep latency was the most significant predictor of relapse. Additional studies that used spectral power analysis of the sleep electroencephalogram found enhancement in the β2 band (24–32 Hz) during REM sleep in those patients with AUDs who relapsed when compared with either alcohol abstainers or controls, suggesting that sleep may be lighter in AUD [11]. Other studies have shown that REM measures may be particularly good markers of relapse to AUD in nondepressed inpatients with primary alcoholism [12]. Furthermore, patients who reported using alcohol to help them fall asleep have also been found to be more vulnerable to relapse to AUD [13, 14]. Despite the importance of sleep in the maintenance of sobriety, treatment options for sleep disturbance in patients recovering from AUD are currently limited [6, 15]. This is especially problematic since some drugs, in particular hypnotics, may not be suitable for the treatment of sleep disturbance associated with AUD because of their addiction liability and potential interactions with alcohol [16]. FDA-approved pharmacological treatments for primary insomnia include benzodiazepines and nonbenzodiazepine hypnotics, tricyclic antidepressants, off-label use of drugs such as other antidepressants, antihistamines, herbal preparations, and antipsychotics and more recently therapeutic drugs that target orexin/hypocretin receptors [17–19]. Although evidence of sleep improvement is presented for individual drugs for insomnia [18, 20, 21], no evidence-based clinical practice guidelines have been published to date by the American Academy of Sleep Medicine (AASM) to draw conclusions regarding the overall efficacy of pharmacotherapy in the insomnia population [18]. It has been suggested that insomnia disorder and AUD might be best thought of as comorbid disorders, each of which requires its own treatment rather than categorizing insomnia as a symptom of a primary illness [5, 6, 15]. The development of animal models of alcohol-induced insomnia [22–24] allows for the experimental control necessary to study the effects of ethanol, independent of many factors that confound human studies, such as psychiatric comorbidity and other substance use. Recent literature supports a prominent role for the hypoth (...truncated)