Development of Cataplexy in Genetically Narcoleptic Dobermans

Riehl, Joyce; Nishino, Seiji; Cederberg, Rachel A.; Dement, William C.; Mignot, Emmanuel

doi:10.1006/exnr.1998.6847

Cited by 51 publications

(31 citation statements)

References 26 publications

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“…As displayed in Figure 4 E, muscle tone, when compared with either normal wakefulness or NREM sleep, was markedly reduced and became essentially absent during REM sleep, REM sleep after an abnormal transition, and these episodes of behavioral collapse with wakefulness-like EEG. In contrast to human and canine cataplectic events, however, which are often triggered by emotional stimuli (Aldrich, 1992;Riehl et al, 1998), we could not reliably elicit behavioral arrests in the orexin/ataxin-3 transgenic rats using external emotive stimuli.…”

Section: Behavioral Analysiscontrasting

confidence: 65%

Expression of a Poly-Glutamine-Ataxin-3 Transgene in Orexin Neurons Induces Narcolepsy–Cataplexy in the Rat

Beuckmann¹,

Sinton²,

Williams³

et al. 2004

J. Neurosci.

175

101

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The sleep disorder narcolepsy has been linked to loss of hypothalamic neurons producing the orexin (hypocretin) neuropeptides. Here, we report the generation of transgenic rats expressing a human ataxin-3 fragment with an elongated polyglutamyl stretch under control of the human prepro-orexin promoter (orexin/ataxin-3 rats). At 17 weeks of age, the transgenic rats exhibited postnatal loss of orexinpositive neurons in the lateral hypothalamus, and orexin-containing projections were essentially undetectable. The loss of orexin production resulted in the expression of a phenotype with fragmented vigilance states, a decreased latency to rapid eye movement (REM) sleep and increased REM sleep time during the dark active phase. Wakefulness time was also reduced during the dark phase, and this effect was concentrated at the photoperiod boundaries. Direct transitions from wakefulness to REM sleep, a defining characteristic of narcolepsy, occurred frequently. Brief episodes of muscle atonia and postural collapse resembling cataplexy were also noted while rats maintained the electroencephalographic characteristics of wakefulness. These findings indicate that the orexin/ataxin-3 transgenic rat could provide a useful model of human narcolepsy.

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Section: Behavioral Analysiscontrasting

confidence: 65%

Expression of a Poly-Glutamine-Ataxin-3 Transgene in Orexin Neurons Induces Narcolepsy–Cataplexy in the Rat

Beuckmann¹,

Sinton²,

Williams³

et al. 2004

J. Neurosci.

175

101

View full text Add to dashboard Cite

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“…However, it is equally likely that genetic and environmental factors unrelated to the mutation but differing in Labradors and Dobermans breeds may contribute to the difference in symptom severity. Females of both breeds are typically more affected than males (Riehl et al 1998).…”

Section: Unanswered Questions Symptom Variabilitymentioning

confidence: 99%

“…There is also a marked developmental component to the variability (Baker and Dement 1985;Riehl et al 1998). At birth and during the early stages of weaning, most puppies show no symptoms.…”

Section: Unanswered Questions Symptom Variabilitymentioning

confidence: 99%

A Brief History of Hypocretin/Orexin and Narcolepsy

Siegel¹,

Moore

Thannickal³

et al. 2001

Neuropsychopharmacology

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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%

“…The effect of CG-3703 (Grünenthal GmBH, Stolberg, Germany) on cataplexy was assessed in each dog using the Food Elicited Cataplexy Test (FECT) (Baker and Dement 1985;Riehl et al 1998). In this assay, 12 scoops of canned dog food (1 cm 3 ) are arrayed in sequence on the floor.…”

Section: Cataplexy Testingmentioning

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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Development of Cataplexy in Genetically Narcoleptic Dobermans

Cited by 51 publications

References 26 publications

Expression of a Poly-Glutamine-Ataxin-3 Transgene in Orexin Neurons Induces Narcolepsy–Cataplexy in the Rat

Expression of a Poly-Glutamine-Ataxin-3 Transgene in Orexin Neurons Induces Narcolepsy–Cataplexy in the Rat

A Brief History of Hypocretin/Orexin and Narcolepsy

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

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