Is narcolepsy a REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans

Nishino, Seiji; Riehl, Joyce; Hong, James Won‐Ki; Kwan, Marilyn L.; Reid, Malcolm S.; Mignot, Emmanuel

doi:10.1016/s0168-0102(00)00195-4

Cited by 83 publications

(51 citation statements)

References 27 publications

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“…9 in addition, orexins probably stabilize wake and sleep; narcoleptic people, dogs, and mice lacking orexins have great difficulty remaining awake for long periods and also experience fragmented sleep. [10][11][12][13] in earlier work, we found that the fragmented wakefulness of orexin deficiency is not a consequence of abnormal sleep homeostasis, poor circadian control, or defective fundamental arousal systems. 10 however, conventional sleep scoring in 10-to 30-second epochs reveals little about the process of transitioning between states as cortical activity and behavior can change quite rapidly.…”

mentioning

confidence: 97%

Abnormal Sleep/Wake Dynamics in Orexin Knockout Mice

Behn

Klerman

Mochizuki

et al. 2010

Sleep

110

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Over 20 years agO, BrOughtOn and cOlleagues hypOthesized that narcOlepsy is Best cOnsidered a disease Of state BOundary cOntrOl. 1 they argued that sleepiness, cataplexy, hallucinations, and many other symptoms could be viewed as a breakdown of "whatever neurochemical 'glues' or integrative neurophysiological mechanisms exist for sleep and wake state continuity." 1 This hypothesis is compelling, but it has been difficult to examine using conventional sleep scoring methods.More recently, our understanding of narcolepsy has been greatly advanced by the discovery that narcolepsy with cataplexy is caused by a loss of functional signaling by the orexin (hypocretin) neuropeptides. 2-5 the neurons producing orexins are active during wakefulness, 6-8 and direct activation of these neurons can awaken mice from sleep. 9 in addition, orexins probably stabilize wake and sleep; narcoleptic people, dogs, and mice lacking orexins have great difficulty remaining awake for long periods and also experience fragmented sleep. [10][11][12][13] in earlier work, we found that the fragmented wakefulness of orexin deficiency is not a consequence of abnormal sleep homeostasis, poor circadian control, or defective fundamental arousal systems. 10 however, conventional sleep scoring in 10-to 30-second epochs reveals little about the process of transitioning between states as cortical activity and behavior can change quite rapidly. Furthermore, conventional scoring simply identifies discrete states, so it can overlook important variations within states, such as the distinctions between light and deep nreM sleep or between drowsy wake and high levels of arousal. Therefore, to determine how orexin deficiency causes behavioral state instability we developed a state space analysis technique to examine the dynamics of sleep/wake behavior in orexin knockout (OXKO) mice, a model of narcolepsy.The previous application of state space techniques to sleep recordings used local field potential data, but the variability in these signals prevented comparisons between animals. [14][15][16] We adapted these techniques for analysis of EEG recordings in mice and developed metrics for inter-animal comparisons. State space techniques have high temporal resolution and analyze behavior as a continuum, rather than in discrete states, thus facilitating higher dimensional examination of state transitions. this approach enabled us to determine whether the state instability in this mouse model of narcolepsy reflects abnormal sleep/wake states, faster movements between states, or abnormal transition processes. METHODS AnimalsFounder OXKO mice were on a C57BL/6J-129/SvEV background (t. sakurai, Kanazawa university), and their offspring were backcrossed with C57BL/6J mice for 8 generations. We recorded sleep/wake behavior in 7 male OXKO mice and 6 wild type (Wt) littermates, all 5-6 months old and weighing 30-35 g. all experiments were approved by the institutional animal Study Objectives: Narcolepsy with cataplexy is caused by a loss of orexin (hypocretin) signaling, bu...

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mentioning

confidence: 97%

Abnormal Sleep/Wake Dynamics in Orexin Knockout Mice

Behn

Klerman

Mochizuki

et al. 2010

Sleep

110

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“…Amphetamines and modafinil are thought to increase wakefulness by increases dopamine levels and often used in treatment of narcolepsy and cataplexy [43,44].…”

Section: Section 163-monoaminergic Mechanisms In Cataplexymentioning

confidence: 99%

“…REM sleep follows an ultradian rhythm, whereas cataplexy does not. Also REM sleep is regulated homeostatically, whereas cataplexy is triggered [43].…”

Section: Section 17 -Rem Sleep and Cataplexy -Shared Mechanism?mentioning

confidence: 99%

Pharmacogenetic inhibition of the subcoeruleus region influences rem sleep and cataplexy in narcoleptic mice

2013

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Introduction: Cataplexy -the sudden involuntary loss of skeletal muscle tone -is a defining feature of narcolepsy. The current study aimed to determine if cataplexy is influenced by direct manipulation of REM sleep circuitry. We did this by pharmacogenetically inhibiting the REM sleep centre, subcoeruleus (Sub-C). Methods:Inhibitory DREADD (hM4D-Gi) was bilaterally targeted to the Sub-C in hypocretin knockout mice (n=7). Intraperitoneal administration of clozapine-n-oxide was used to inhibit Sub-C cells expressing hM4D-Gi. Electrophysiological and behavioural criteria were used to characterize cataplexy and REM sleep.Results: Sub-C inhibition increased REM sleep and cataplexy amounts (p<0.05). Sub-C inhibition increased time spent in cataplexy amounts by increasing the number of cataplexy attacks (p<0.05). This intervention triggered increases in basal muscle tone during REM sleep, but had negligible effects on muscle tone during cataplexy (p>0.05).ii Conclusion: Pharmacogenetic manipulation of the Sub-C suggest that REM sleep and cataplexy are mediate by similar neural mechanism.iii

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“…Like humans, narcoleptic canines exhibit short sleep latency, fragmented sleep patterns, and cataplexy (Kaitin et al 1986;Nishino et al 1998c;Riehl et al 1998). Narcolepsy in Doberman pinschers and Labrador retrievers is caused by mutations in the gene encoding a receptor ( Hcrtr-2 ) for a novel neuropeptide, the hypocretins (orex- Received July 27, 1999; revised November 10, 1999; accepted December 23, 1999.…”

Section: The Effects On Cataplexy and Daytime Sleep Of Acute And Chromentioning

confidence: 99%

Chronic Oral Administration of CG-3703, a Thyrotropin Releasing Hormone Analog, Increases Wake and Decreases Cataplexy in Canine Narcolepsy

Riehl

Honda

Kwan

et al. 2000

Neuropsychopharmacology

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The effects on cataplexy and daytime sleep of acute and chronic oral administration of CG-3703, a potent TRH analog were assessed in canine narcolepsy. CG-3703 was found to be orally active and to reduce cataplexy (0.25 to 16 mg/kg) and sleep (8 and 16 mg/kg) in a dose-dependent manner. Two-week oral administration of Human narcolepsy is a chronic life-long disorder characterized by excessive daytime somnolence (EDS), abnormal manifestations of rapid eye movement (REM) sleep (hypnagogic hallucinations and sleep paralysis), and cataplexy (Aldrich 1992;Guilleminault 1994;. Cataplexy is a sudden loss of muscle tone in response to emotionally-exciting stimuli. It is akin to the muscle atonia that occurs during physiological REM sleep, but it occurs inappropriately during wakefulness (Aldrich 1992;Guilleminault 1994;. The current treatments for narcolepsy require the use of central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep (Guilleminault 1994;Mitler et al. 1990;Thorpy and Goswami 1990). These treatments, however, are often unsatisfactory due to incomplete therapeutic efficacy, the occurrence of various side effects, and the rapid development of drug tolerance (Guilleminault 1994;Mitler et al. 1990;Thorpy and Goswami 1990). It is therefore necessary to explore more efficacious compounds with different pharmacological profiles for possible use in narcolepsy treatment.Canine narcolepsy is a naturally-occurring animal model of the human disorder. Like humans, narcoleptic canines exhibit short sleep latency, fragmented sleep patterns, and cataplexy (Kaitin et al. 1986;Nishino et al. 1998c;Riehl et al. 1998). Narcolepsy in Doberman pinschers and Labrador retrievers is caused by mutations in the gene encoding a receptor ( Hcrtr-2 ) for a novel neuropeptide, the hypocretins (orex- Received July 27, 1999; revised November 10, 1999; accepted December 23, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 1 CG-3703, a TRH Analog, in Narcoleptic Dogs 35 ins) (Lin et al. 1999). Human and canine narcolepsy share similar pharmacological characteristics (see for a review). This model is thus an invaluable resource for the study of the pathophysiology and treatment of narcolepsy. To this end, the canine model has been used in numerous pharmacological experiments to dissect the mode of action of various compounds on their effects on wakefulness and cataplexy, and to screen new compounds for use as possible treatments for narcolepsy (see for a review).Thyrotropin releasing hormone (TRH) is a tripeptidic hormone (L-pyroglutamyl-L-histidyl-L-prolineamide) originally extracted from the hypothalamus (Boler et al. 1969). It is now known to be distributed widely in the CNS, with receptors reported to exist in structures such as the pituitary, cortex, brainstem, thalamus, hippocampus, amygdala, and spinal cord (see Griffiths and Bennett 1987;Jackson 1982;Metcalf 1982;Sharif 1985;and Winokur et al. 1989 for reviews). Besides its role in stimulating the release of thyroid stimul...

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Is narcolepsy a REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans

Cited by 83 publications

References 27 publications

Abnormal Sleep/Wake Dynamics in Orexin Knockout Mice

Abnormal Sleep/Wake Dynamics in Orexin Knockout Mice

Pharmacogenetic inhibition of the subcoeruleus region influences rem sleep and cataplexy in narcoleptic mice

Chronic Oral Administration of CG-3703, a Thyrotropin Releasing Hormone Analog, Increases Wake and Decreases Cataplexy in Canine Narcolepsy

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