Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition

Uslaner, Jason M.; Tye, Spencer J.; Eddins, Donnie; Wang, Xiaohai; Fox, Steven V.; Savitz, Alan T.; Binns, Jacquelyn; Cannon, Christopher E.; Garson, Susan L.; Yao, Lihang; Hodgson, Robert A.; Stevens, Joanne; Bowlby, Mark R.; Tannenbaum, Pamela L.; Brunner, John; McDonald, Terrence; Gotter, Anthony L.; Kuduk, Scott D.; Coleman, Paul J.; Winrow, Christopher J.; Renger, John J.

doi:10.1126/scitranslmed.3005213

Cited by 85 publications

(94 citation statements)

References 69 publications

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“…ALM and other HcrtR antagonists effectively induce sleep (Brisbare-Roch et al, 2007;Cox et al, 2010) but cause less impairment in memory tasks (Dietrich and Jenck, 2010;Morairty et al, 2014) or motor function in rodents (Ramirez et al, 2013;Steiner et al, 2011), dogs (Tannenbaum et al, 2014), and non-human primates (Uslaner et al, 2013) than do traditional hypnotics. Although some degree of impairment may occur at high doses in humans (Hoever et al, 2010(Hoever et al, , 2012Jacobson et al, 2014), HcrtR antagonists are expected to exhibit a favorable safety profile compared with ZOL and other hypnotics, though years of post-market surveillance will be needed to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…Because HcrtR antagonists may act via disfacilitation rather than generalized inhibition, they are predicted to cause less functional impairment than BzRAs (Morairty et al, 2014;Steiner et al, 2011), a hypothesis that has been supported by recent behavioral studies (Morairty et al, 2014;Tannenbaum et al, 2014;Uslaner et al, 2013).…”

Section: Introductionmentioning

confidence: 93%

“…Benzodiazepine receptor agonist (BzRA) hypnotics such as zolpidem (ZOL) that are currently used to treat insomnia modulate the GABA A receptor and induce sleep through a general inhibition of neural activity. Although BzRAs are effective for the induction of sleep, they can have detrimental effects on cognitive performance (Huang et al, 2010;Uslaner et al, 2013;Wesensten et al, 1996), resulting in the need for hypnotics with an improved cognitive profile. Because of the involvement of the Hcrt system in sleep and arousal, Hcrt receptor (HcrtR) antagonists have been extensively investigated for the treatment of insomnia (Brisbare-Roch et al, 2007;Dugovic et al, 2009;Morairty et al, 2014;Roecker and Coleman, 2008;Uslaner et al, 2013;Winrow et al, 2011) and are thought to promote sleep through selective disfacilitation of wake-promoting systems.…”

Section: Introductionmentioning

confidence: 99%

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The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

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The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wakepromoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH-or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos + cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH-and ALMtreated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL-but not in VEH-or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

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“…Because orexins have been implicated in the maintenance of wakefulness, many groups are trying to develop nonpeptidic orexin receptor antagonists aiming at new medication for insomnia. Recently, suvorexant, a dual orexin receptor antagonist, was clinically approved in Japan and the United States (4,5).…”

mentioning

confidence: 99%

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

Irukayama-Tomobe

Ogawa

Tominaga

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

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Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexindeficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists. neuropeptides produced by neurons exclusively localized to the lateral hypothalamus that act on two G protein-coupled receptors termed OX1R and OX2R (1). Orexin-producing neurons send axons diffusely through the central nervous system, with especially dense innervations to several nuclei involved in sleep/wakefulness regulation (2, 3). Because orexins have been implicated in the maintenance of wakefulness, many groups are trying to develop nonpeptidic orexin receptor antagonists aiming at new medication for insomnia. Recently, suvorexant, a dual orexin receptor antagonist, was clinically approved in Japan and the United States (4, 5).A crucial role of the orexin system in the regulation of sleep/ wakefulness was initially uncovered by the discovery that OX2R-deficient dogs (6) and prepro-orexin knockout (Hcrt −/− , abbreviated as OXKO) mice (2) exhibited symptoms resembling human narcolepsy-cataplexy. According to the clinical definition by the International Classification of Sleep Disorders-Third Edition, two types of narcoleptic disorders are categorized (7). Narcolepsy type 1 is characterized by the existence of cataplexy and low levels of orexin-A in cerebrospinal fluid (CSF) (8-10). However, patients with narcolepsy type 2 show no cataplexy and normal orexin-A levels in CSF. Narcolepsy-cataplexy, or narcolepsy type 1 (11), is characterized by a marked instability of sleep/ wake state transitions, resulting in nonrapid eye movement (NREM) sleep-related symptoms (e.g., excessive daytime sleepiness, "sleep attacks," and fragmented nighttime sleep), and rapid eye movement (REM) sleep-related symptoms (e.g., cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations). In polysomnography, narcolepsy-cataplexy patients show markedly reduced daytime sleep latency, and sleep-onset REM periods (SOREMs). Currently available treatments for narcolepsyca...

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“…Presently, nonbenzodiazepine, positive allosteric modulators of the GABA A receptor such as zolpidem (ZOL) are the most widely prescribed hypnotic medications. Although known to induce sleep, these compounds have been shown to significantly impair psychomotor and memory functions in rodents (Huang et al, 2010;Uslaner et al, 2013;Zanin et al, 2013), non-human primates (Makaron et al, 2013;Soto et al, 2013;Uslaner et al, 2013) and humans (Balkin et al, 1992;Wesensten et al, 1996Wesensten et al, , 2005Mattila et al, 1998;Mintzer and Griffiths, 1999;Verster et al, 2002;Storm et al, 2007;Otmani et al, 2008;Gunja, 2013). Such impairment can be particularly troubling when there is an urgent need for highly functional performance in the presence of drug such as with first responders, military personnel, and caregivers.…”

Section: Introductionmentioning

confidence: 99%

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

Kilduff¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)September 2014 (From -To) REPORT TYPE Annual DATES COVERED P ERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SRI InternationalMenlo Park, CA 94025-3493 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENT SUPPLEMENTARY NOTES ABSTRACTDuring Year 5, we continued tests of the hypothesis that disfacilitation of wake-promoting systems by the hypocretin (Hcrt) receptor antagonist almorexant (ALM) results in less functional impairment than the inhibition of neural activity produced by the benzodiazepine receptor agonist zolpidem (ZOL). One paper was published (Morairty et al. 2014), another has been accepted for publication (Dittrich et al., in press) and a third is in resubmission (Vazquez-DeRose et al., submitted). Data collection for Aims 2c and 3b.2 have been completed and data analysis ongoing; manuscripts will be written and submitted during Year 6. Data collection and analysis of Aim 3a is nearing completion; an abstract summarizing this work has been submitted for presentation at the 2014 Society for Neuroscience meeting. Data collection for Aims 3b.3, 4c and 6a have been initiated. The overall results obtained to date are consistent with the hypothesis that the hypocretin/orexin antagonist ALM produces less functional impairment than the benzodiazepine receptor agonist zolpidem (ZOL) because ZOL causes a general inhibition of neural activity whereas ALM specifically disfacilitates wake-promoting systems. SUBJECT TERMSSleep, performance, drug, neurotransmitter, hypocretin, orexin, benzodiazepine, zolpidem, neurochemistry, microdialysis INTRODUCTIONAlmorexant (ALM) is a hypocretin/orexin (Hcrt) receptor antagonist with a novel mechanism of action that has shown promise as an effective hypnotic. Preclinical data demonstrate that animals treated with ALM are easily aroused from sleep and are free of ataxia and other behavioral impairments. If this observation is confirmed in humans, it would have enormous implications for the management of disturbed sleep in both military a...

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Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition

Cited by 85 publications

References 69 publications

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

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