Almorexant Promotes Sleep and Exacerbates Cataplexy in a Murine Model of Narcolepsy

Black, Sarah Wurts; Morairty, Stephen R.; Fisher, Simon P.; Chen, Tsui-Ming; Warrier, Deepti R; Kilduff, Thomas S.

doi:10.5665/sleep.2442

Cited by 60 publications

(51 citation statements)

References 46 publications

(74 reference statements)

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“…Mice were surgically implanted with transmitters for EEG, EMG, T b and locomotor activity recording as described (41, 42). Physiological and video-recorded behavioral data were simultaneously acquired with DataQuest Art 4.2 (Data Sciences Inc., St. Paul, MN).…”

Section: Methodsmentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics

Black

Schwartz

Chen

et al. 2017

Biological Psychiatry

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BACKGROUND Narcolepsy, a disorder of Rapid Eye Movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. Since partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy. METHODS In the first experiment, male homozygous B6-Taar1tm1(NLSLacZ)Blt (Taar1 KO) and wildtype mice were surgically implanted to record EEG, EMG, locomotor activity (LMA) and body temperature (Tb) and the efficacy of the TAAR1 agonist, RO5256390, on sleep/wake and physiological parameters was determined. In the second experiment, the effects of the TAAR1 full agonist RO5256390 and partial agonist RO5263397 on sleep/wake, LMA, Tb and cataplexy were assessed in two mouse narcolepsy models. RESULTS RO5256390 profoundly reduced REM sleep in wildtype mice; these effects were eliminated in Taar1 KO mice. The TAAR1 partial agonist RO5263397 also promoted wakefulness and suppressed NREM sleep. Both compounds reduced Tb in the two narcolepsy models at the highest doses tested. Both TAAR1 compounds also mitigated cataplexy, the pathognomonic symptom of this disorder, in the mouse narcolepsy models. The therapeutic benefit was mediated through a reduction in the number of cataplexy episodes and time spent in cataplexy. CONCLUSIONS These results suggest TAAR1 agonism as a new therapeutic pathway for the treatment of this orphan disease. The common underlying mechanism may be the suppression of REM sleep.

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Section: Methodsmentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics

Black

Schwartz

Chen

et al. 2017

Biological Psychiatry

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“…However, cataplexy and other symptoms of narcolepsy in which orexin neurons are functionally absent had been noted as a potential concern in clinical development of ORAs. 130,133 This is because it was thought that antagonism of the orexinergic system would produce narcolepsy-like or cataplexy-like symptoms. Such effects were not observed in a pivotal phase 3 trial of suvorexant.…”

Section: New and Emerging Drugsmentioning

confidence: 97%

Integrating Modern Concepts of Insomnia and its Contemporary Treatment into Primary Care

Doghramji

2014

Postgraduate Medicine

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Insomnia affects one-third of the adult population. Ten percent of adults surveyed in America consider it a serious problem. Chronic insomnia is associated with poor quality of life and the potential for various psychiatric and medical conditions, notably depression and cardiovascular disease. Since most patients with insomnia are unlikely to disclose obvious sleeping difficulties, the first step in diagnosing and managing patients is having a high index of suspicion in patients with specific complaints, comorbidities, and risk factors. This is followed by a complete evaluation of the patient's medical and physical history to determine if the insomnia is primary or comorbid with another disease. The management of insomnia should consider the extent of impairment associated with the disorder, as well as duration, causes, and comorbidities. In some cases, referral to a specialist is warranted. Recently, there have been new definitions of insomnia proposed; elucidation of the role of orexin-mediated hyperarousal brain neural pathway in the sleep-wake cycle; and new drugs available that target this system. Thus, a review and update for today's primary care physician is warranted.

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“…Rats were recorded by telemetry (10,38,39); mice were recorded either by telemetry (40) or by tethered (10,21) procedures. State determinations and data analysis were conducted as described in these publications.…”

Section: Methodsmentioning

confidence: 99%

A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity

Morairty

Dittrich

Pasumarthi

et al. 2013

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

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125

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Although the neural circuitry underlying homeostatic sleep regulation is little understood, cortical neurons immunoreactive for neuronal nitric oxide synthase (nNOS) and the neurokinin-1 receptor (NK1) have been proposed to be involved in this physiological process. By systematically manipulating the durations of sleep deprivation and subsequent recovery sleep, we show that activation of cortical nNOS/NK1 neurons is directly related to non-rapid eye movement (NREM) sleep time, NREM bout duration, and EEG δ power during NREM sleep, an index of preexisting homeostatic sleep drive. Conversely, nNOS knockout mice show reduced NREM sleep time, shorter NREM bouts, and decreased power in the low δ range during NREM sleep, despite constitutively elevated sleep drive. Cortical NK1 neurons are still activated in response to sleep deprivation in these mice but, in the absence of nNOS, they are unable to up-regulate NREM δ power appropriately. These findings support the hypothesis that cortical nNOS/NK1 neurons translate homeostatic sleep drive into up-regulation of NREM δ power through an NO-dependent mechanism.T he electrical activity of the cerebral cortex has been used to distinguish sleep vs. wakefulness since the earliest EEG studies of sleep (1). Several neural circuits have been implicated in the synchronization and desynchronization of cortical activity that distinguish non-rapid eye movement sleep (NREM) from wakefulness and rapid eye movement sleep (REM). Input from the basal forebrain (BF), likely from both cholinergic and noncholinergic neurons, is critical for the desynchronized EEG characteristic of wakefulness and REM (2, 3). Synchronization of the EEG during NREM depends on thalamic as well as intrinsic cortical oscillators (4).The firing rate of cortical neurons has generally been reported to be reduced during NREM relative to wakefulness and REM (5, 6). A few studies have reported cortical neurons with the opposite pattern. For example, 4 of 177 neurons in the monkey orbitofrontal cortex increased their firing rates during NREM (7). In the cat parietal cortex, 25% of neurons discharged in phase with NREM slow waves during up states but ceased firing during quiet wakefulness (8).Using Fos immunohistochemistry as a marker of cellular activity, we described a population of cortical GABAergic interneurons that are activated during sleep in three species (9, 10). These neurons express neuronal nitric oxide synthase (nNOS) and thus likely release nitric oxide (NO) as well as GABA (11). The percentage of activated cortical nNOS neurons was proportional to NREM δ energy (NRDE), the product of NREM time and NREM EEG δ power. Because NREM time and δ power increase in response to prolonged wakefulness through a regulated process referred to as sleep homeostasis, NRDE is an electrophysiological marker of homeostatic sleep "drive." Consequently, activation of cortical nNOS neurons during sleep seems to be related to the sleep need that accrues during wakefulness.Cortical nNOS neurons receive cholinergic (12), monoamin...

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Almorexant Promotes Sleep and Exacerbates Cataplexy in a Murine Model of Narcolepsy

Abstract: Black SW; Morairty SR; Fisher SP; Chen TM; Warrier DR; Kilduff TS. Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. SLEEP 2013;36(3):325-336.

Cited by 60 publications

References 46 publications

Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics

Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics

Integrating Modern Concepts of Insomnia and its Contemporary Treatment into Primary Care

A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity

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