Dexmedetomidine-Induced Sedation Does Not Mimic the Neurobehavioral Phenotypes of Sleep in Sprague Dawley Rat

Garrity, Abigail G.; Botta, Simhadri; Lazar, Stephanie B.; Swor, Erin; Vanini, Giancarlo; Baghdoyan, Helen A.; Lydic, Ralph

doi:10.5665/sleep.4328

Cited by 38 publications

(34 citation statements)

References 76 publications

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“…This is because maintaining a patient in a non-REM II state may not confer benefits that are specific to non-REM III and REM sleep stages. A recent laboratory investigation has confirmed previous observations in humans that dexmedetomidine eliminated REM sleep in rats, and that it may not fully compensate for sleep need [ 58 ]. We suggest a principled approach where the administration of dexmedetomidine in critically ill patients may involve different daytime and nighttime sedation drug regimens, and drug delivery systems with electroencephalogram feedback control to more precisely target brain-state goals of care.…”

Section: Discussionsupporting

confidence: 59%

Spatiotemporal Dynamics of Dexmedetomidine-Induced Electroencephalogram Oscillations

et al. 2016

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An improved understanding of the neural correlates of altered arousal states is fundamental for precise brain state targeting in clinical settings. More specifically, electroencephalogram recordings are now increasingly being used to relate drug-specific oscillatory dynamics to clinically desired altered arousal states. Dexmedetomidine is an anesthetic adjunct typically administered in operating rooms and intensive care units to produce and maintain a sedative brain state. However, a high-density electroencephalogram characterization of the neural correlates of the dexmedetomidine-induced altered arousal state has not been previously accomplished. Therefore, we administered dexmedetomidine (1mcg/kg bolus over 10 minutes, followed by 0.7mcg/kg/hr over 50 minutes) and recorded high-density electroencephalogram signals in healthy volunteers, 18–36 years old (n = 8). We analyzed the data with multitaper spectral and global coherence methods. We found that dexmedetomidine was associated with increased slow-delta oscillations across the entire scalp, increased theta oscillations in occipital regions, increased spindle oscillations in frontal regions, and decreased beta oscillations across the entire scalp. The theta and spindle oscillations were globally coherent. During recovery from this state, these electroencephalogram signatures reverted towards baseline signatures. We report that dexmedetomidine-induced electroencephalogram signatures more closely approximate the human sleep onset process than previously appreciated. We suggest that these signatures may be targeted by real time visualization of the electroencephalogram or spectrogram in clinical settings. Additionally, these signatures may aid the development of control systems for principled neurophysiological based brain-state targeting.

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Section: Discussionsupporting

confidence: 59%

Spatiotemporal Dynamics of Dexmedetomidine-Induced Electroencephalogram Oscillations

et al. 2016

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“…Similarly, systemic DEX induces excitation in the preoptic hypothalamic area, as seen by cFOS expression (Nelson et al, 2003 ; Zhang et al, 2015 ). One study, on the other hand, did not find cFOS was induced in the POA following DEX-induced sedation (Garrity et al, 2015 ).…”

Section: The Hypothalamic Preoptic Area and α2 Adrenergic Agonist Indmentioning

confidence: 99%

Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems

Franks

Wisden

2018

Front. Neural Circuits

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Sedatives target just a handful of receptors and ion channels. But we have no satisfying explanation for how activating these receptors produces sedation. In particular, do sedatives act at restricted brain locations and circuitries or more widely? Two prominent sedative drugs in clinical use are zolpidem, a GABAA receptor positive allosteric modulator, and dexmedetomidine (DEX), a selective α2 adrenergic receptor agonist. By targeting hypothalamic neuromodulatory systems both drugs induce a sleep-like state, but in different ways: zolpidem primarily reduces the latency to NREM sleep, and is a controlled substance taken by many people to help them sleep; DEX produces prominent slow wave activity in the electroencephalogram (EEG) resembling stage 2 NREM sleep, but with complications of hypothermia and lowered blood pressure—it is used for long term sedation in hospital intensive care units—under DEX-induced sedation patients are arousable and responsive, and this drug reduces the risk of delirium. DEX, and another α2 adrenergic agonist xylazine, are also widely used in veterinary clinics to sedate animals. Here we review how these two different classes of sedatives, zolpidem and dexmedetomideine, can selectively interact with some nodal points of the circuitry that promote wakefulness allowing the transition to NREM sleep. Zolpidem enhances GABAergic transmission onto histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) to hasten the transition to NREM sleep, and DEX interacts with neurons in the preoptic hypothalamic area that induce sleep and body cooling. This knowledge may aid the design of more precise acting sedatives, and at the same time, reveal more about the natural sleep-wake circuitry.

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“…Until now, the sedative and hypnotic effects of orally delivered dexmedetomidine remain unclear and the impacts of dexmedetomidine on sleep structure are not yet fully understood. Moreover, dexmedetomidine can still induce hypnotic effect in mice unable to synthesize NA (Gilsbach et al, 2009; Hu et al, 2012; Sanders and Maze, 2012; Garrity et al, 2015) or with selective knockdown of alpha-2A adrenergic receptors in the LC (Zhang et al, 2015), suggesting that dexmedetomidine-induced hypnosis may depend on other brain areas in addition to the LC.…”

Section: Introductionmentioning

confidence: 99%

Oral Delivered Dexmedetomidine Promotes and Consolidates Non-rapid Eye Movement Sleep via Sleep–Wake Regulation Systems in Mice

Feng

Dong

et al. 2018

Front. Pharmacol.

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Dexmedetomidine, a highly selective α2-adrenergic agonist, is widely used in clinical anesthesia and ICU sedation. Recent studies have found that dexmedetomidine-induced sedation resembles the recovery sleep that follows sleep deprivation, but whether orally delivered dexmedetomidine can be a candidate for the treatment of insomnia remains unclear. In this study, we estimated the sedative effects of orally delivered dexmedetomidine by spontaneous locomotor activity (LMA), and then evaluated the hypnotic effects of dexmedetomidine on sleep–wake profiles during the dark and light phase using electroencephalography/electromyogram (EEG/EMG), respectively. Using c-Fos staining, we explored the effects of dexmedetomidine on the cerebral cortex and the sub-cortical sleep–wake regulation systems. The results showed that orally delivered dexmedetomidine at 2 h into the dark cycle reduced LMA and wakefulness in a dose-dependent manner, which was consistent with the increase in non-rapid eye movement sleep (NREM sleep). However, dexmedetomidine also induced a rebound in LMA, wake and rapid eye movement sleep (REM sleep) in the later stage. In addition, orally delivered dexmedetomidine 100 μg/kg at 2 h into the light cycle shortened the latency to NREM sleep and increased the duration of NREM sleep for 6 h, while decreased REM sleep for 6 h. Sleep architecture analysis showed that dexmedetomidine stabilized the sleep structure during the light phase by decreasing sleep–wake transition and increasing long-term NREM sleep (durations of 1024–2024 s and >2024 s) while reducing short-term wakefulness (duration of 4–16 s). Unlike the classic hypnotic diazepam, dexmedetomidine also increased the delta power in the EEG spectra of NREM sleep, especially at the frequency of 1.75–3.25 Hz, while ranges of 0.5–1.0 Hz were decreased. Immunohistochemical analysis showed that orally delivered dexmedetomidine 100 μg/kg at 2 h into the dark cycle decreased c-Fos expression in the cerebral cortex and sub-cortical arousal systems, while it increased c-Fos expression in the neurons of the ventrolateral preoptic nucleus. These results indicate that orally delivered dexmedetomidine can induce sedative and hypnotic effects by exciting the sleep-promoting nucleus and inhibiting the wake-promoting areas.

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Dexmedetomidine-Induced Sedation Does Not Mimic the Neurobehavioral Phenotypes of Sleep in Sprague Dawley Rat

Cited by 38 publications

References 76 publications

Spatiotemporal Dynamics of Dexmedetomidine-Induced Electroencephalogram Oscillations

Spatiotemporal Dynamics of Dexmedetomidine-Induced Electroencephalogram Oscillations

Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems

Oral Delivered Dexmedetomidine Promotes and Consolidates Non-rapid Eye Movement Sleep via Sleep–Wake Regulation Systems in Mice

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