Electroencephalographic correlates of cataplectic attacks in narcoleptic canines

Kushida, Clete A.; Baker, Theodore L.; Dement, William C.

doi:10.1016/0013-4694(85)91073-9

Cited by 44 publications

(26 citation statements)

References 13 publications

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“…After a 2-day vehicle run-in period, female dogs ( n = 8; Marshall Farms) were treated with MK-1064 (20 mg/kg) or vehicle in a 1-day vehicle x 2-day drug crossover design. Daytime FECTs324344 with simultaneous video and electrocorticography (ECoG), electromyography (EMG), and electrooculography (EOG) recordings were conducted 1 hour post-dose. Following release into the test room, dogs were remotely monitored while consuming 10 evenly spaced, approximately 1-inch2 balls of wet dog food (Pedigree ® chunk beef).…”

Section: Methodsmentioning

confidence: 99%

Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man

Gotter

Forman

Harrell

et al. 2016

Sci Rep

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Orexin neuropeptides regulate sleep/wake through orexin receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist. Preclinically, MK-1064 promotes sleep and increases both rapid eye movement (REM) and non-REM (NREM) sleep in rats at OX2R occupancies higher than the range observed for dual orexin receptor antagonists. Similar to dual antagonists, MK-1064 increases NREM and REM sleep in dogs without inducing cataplexy. Two Phase I studies in healthy human subjects evaluated safety, tolerability, pharmacokinetics and sleep-promoting effects of MK-1064, and demonstrated dose-dependent increases in subjective somnolence (via Karolinska Sleepiness Scale and Visual Analogue Scale measures) and sleep (via polysomnography), including increased REM and NREM sleep. Thus, selective OX2R antagonism is sufficient to promote REM and NREM sleep across species, similarly to that seen with dual orexin receptor antagonism.

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Section: Methodsmentioning

confidence: 99%

Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man

Gotter

Forman

Harrell

et al. 2016

Sci Rep

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“…A preliminary FECT study was necessary to confirm that classical conditioning of an acoustic stimulus with a salient food reward would not potentially confound a study of awakening from sleep, as strong emotional salience as seen with food anticipation is a primary trigger of cataplexy in orexin-deficient narcoleptic dogs (Babcock et al, 1976; Kushida et al, 1985; Nishino et al, 1997). …”

Section: Introductionmentioning

confidence: 99%

Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs

Tannenbaum

Stevens

Binns

et al. 2014

Front. Behav. Neurosci.

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The ability to awaken from sleep in response to important stimuli is a critical feature of normal sleep, as is maintaining sleep continuity in the presence of irrelevant background noise. Dual orexin receptor antagonists (DORAs) effectively promote sleep across species by targeting the evolutionarily conserved wake-promoting orexin signaling pathway. This study in dogs investigated whether DORA-induced sleep preserved the ability to awaken appropriately to salient acoustic stimuli but remain asleep when exposed to irrelevant stimuli. Sleep and wake in response to DORAs, vehicle, GABA-A receptor modulators (diazepam, eszopiclone and zolpidem) and antihistamine (diphenhydramine) administration were evaluated in telemetry-implanted adult dogs with continuous electrocorticogram, electromyogram (EMG), electrooculogram (EOG), and activity recordings. DORAs induced sleep, but GABA-A modulators and antihistamine induced paradoxical hyperarousal. Thus, salience gating studies were conducted during DORA-22 (0.3, 1, and 5 mg/kg; day and night) and vehicle nighttime sleep. The acoustic stimuli were either classically conditioned using food reward and positive attention (salient stimulus) or presented randomly (neutral stimulus). Once conditioned, the tones were presented at sleep times corresponding to maximal DORA-22 exposure. In response to the salient stimuli, dogs woke completely from vehicle and orexin-antagonized sleep across all sleep stages but rarely awoke to neutral stimuli. Notably, acute pharmacological antagonism of orexin receptors paired with emotionally salient anticipation produced wake, not cataplexy, in a species where genetic (chronic) loss of orexin receptor signaling leads to narcolepsy/cataplexy. DORA-induced sleep in the dog thereby retains the desired capacity to awaken to emotionally salient acoustic stimuli while preserving uninterrupted sleep in response to irrelevant stimuli.

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“…Theta rhythm, which accompanies exploratory behavior and REM sleep, is suppressed by MSDB lesions (Vanderwolf, 1969;Winson, 1976). Pronounced hippocampal theta occurs during cataplectic attacks in canine narcoleptics (Kushida et al, 1985). REM sleep deficits also occur in neurodegenerative disorders associated with a loss of basal forebrain cholinergic neurons, such as Lewy body dementia and Alzheimer's disease (Vitiello and Prinz, 1989;Montplaisir et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

Wu¹,

Záborszky²,

Hajszán³

et al. 2004

J. Neurosci.

131

101

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Hypothalamic fibers containing the wake-promoting peptides, hypocretins (Hcrts) or orexins, provide a dense innervation to the medial septum-diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics. The MSDB, via its cholinergic and GABAergic projections to the hippocampus, controls the hippocampal theta rhythm and associated learning and memory functions. Neurons of the MSDB express very high levels of the Hcrt receptor 2, which is mutated in canine narcoleptics. In the present study, we investigated the electrophysiological effects of Hcrt peptides on septohippocampal cholinergic neurons that were identified in living brain slices of the MSDB using a selective fluorescent marker. Hcrt activation of septohippocampal cholinergic neurons was reversible, reproducible, and concentration dependent and mediated via a direct postsynaptic mechanism. Both Hcrt1 and Hcrt2 activated septohippocampal cholinergic neurons with similar EC 50 values. The Hcrt effect was dependent on external Na ϩ , reduced by external Ba 2ϩ , and also reduced in recordings with CsCl-containing electrodes, suggesting a dual underlying ionic mechanism that involved inhibition of a K ϩ current, presumably an inward rectifier, and a Na ϩ -dependent component. The Na ϩ component was dependent on internal Ca 2ϩ , blocked by replacing external Na ϩ with Li ϩ , and also blocked by bath-applied Ni 2ϩ and KB-R7943, suggesting involvement of the Na ϩ -Ca 2ϩ exchanger. Using double-immunolabeling studies at light and ultrastructural levels, we also provide definitive evidence for a hypocretin innervation of cholinergic neurons. Thus Hcrt effects within the septum should increase hippocampal acetylcholine release and thereby promote hippocampal arousal.

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Electroencephalographic correlates of cataplectic attacks in narcoleptic canines

Cited by 44 publications

References 13 publications

Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man

Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man

Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

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