Pharmacological Aspects of Human and Canine Narcolepsy

Nishino, Seiji; Mignot, Emmanuel

doi:10.1016/s0301-0082(96)00070-6

Cited by 429 publications

(308 citation statements)

References 288 publications

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“…As serotonin reuptake inhibitors also reduce REM sleep, this may suggest a preferential adrenergic control of REM atonia by the adrenergic system. Surprisingly, we also found that D2/D3 dopaminergic drugs have important effects on cataplexy, an effect that contrast with the lack of effect of dopaminergic reuptake blockers on this symptom (Nishino and Mignot 1997). Local perfusion studies have shown this effect to be mediated by dopaminergic autoreceptors, with stimulation and blockade exacerbating and reducing the symptoms respectively (Nishino and Mignot 1997).…”

Section: Pharmacological Studies In Canine Narcolepsymentioning

confidence: 77%

“…Current treatments are purely symptomatic and partially effective (Nishino and Mignot 1997;Overeem et al 2001).…”

Section: Treatment Of Human Narcolepsymentioning

confidence: 99%

“…Surprisingly, we also found that D2/D3 dopaminergic drugs have important effects on cataplexy, an effect that contrast with the lack of effect of dopaminergic reuptake blockers on this symptom (Nishino and Mignot 1997). Local perfusion studies have shown this effect to be mediated by dopaminergic autoreceptors, with stimulation and blockade exacerbating and reducing the symptoms respectively (Nishino and Mignot 1997).Fewer pharmacological studies have been performed to evaluate drug effects on daytime sleepiness. A number of studies have shown that amphetamine-like stimulants and modafinil produces wakefulness by presynaptically enhancing dopaminergic transmission, either via dopamine reuptake inhibition and/or by enhancing dopamine release (Nishino et al 1998;Wisor et al 2001).…”

mentioning

confidence: 91%

“…Disturbed nocturnal sleep can be treated using benzodiazepine hypnotic but this treatment does not alleviate daytime sleepiness. A novel compound, Gammahydroxybutyrate (GHB), is now in clinical trial for the treatment of narcolepsy (Nishino and Mignot 1997;Bernasconi et al 1999). This hypnotic, a former anesthetic agent, is unique as it consolidate nocturnal sleep by increasing deep slow wave sleep and to a less extent REM sleep.…”

mentioning

confidence: 99%

“…Twenty-four sleep recordings have indicated that narcoleptic animals, whether ligand or receptor deficient, have disrupted sleep patterns. MSLT-like procedures have also been adapted to the canine species and have shown reduced sleep latency and REM latency in narcoleptic canines (Nishino and Mignot 1997).The effect of more than 200 pharmacological agents have been examined over three decades in these animals (Baker and Dement 1985;Nishino and Mignot 1997). Most of the studies have focused on cataplexy.…”

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confidence: 99%

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A Commentary on the Neurobiology of the Hypocretin/Orexin System

Mignot¹

2001

Neuropsychopharmacology

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Rarely in the history of medicine has scientific discovery moved so quickly from the report of a neurotransmitter system to a disease pathophysiology (Mignot 2001). In 1998, two groups independently identified the same neuropeptide system and called the molecules "hypocretins" and "orexins" respectively (de Lecea et al. 1998;Sakurai et al. 1998). One of the most striking findings of these initial studies was the discrete localization of hypocretin-containing cells within a very discrete region of the lateral hypothalamus. This led one group to call this peptide system "hypocretin", a term derived from hypo thalamus and se cretin (a weak-and contested-homology with secretin was noted by these authors). The established role of the perifornical region in the regulation of appetite, together with the observation that intracerebroventricular injections of the peptides induced food intake in rats, led the other group to coin the term "orexin" (orexis ϭ appetite) for this system.The discovery in 1999 that canine narcolepsy was caused by mutations in the Hypocretin receptor 2 (Hcrtr2) gene is shifting the research emphasis from appetite control to sleep regulation (Lin et al. 1999). This finding was followed by the observation that hypocretin knockout mice have sleep and behavioral abnormalities reminiscent of narcolepsy (Chemelli et al. 1999). Other studies have indicated dense projections to all monoaminergic cell groups and wake-promoting effects of hypocretins when administered centrally (Hagan et al. 1999). More recently, clinical studies have shown that most patients with narcolepsy have undetectable hypocretins in the CSF and a striking decrease in hypocretin immunoreactivity and transcript levels in the perifornical hypothalamus Thannickal et al. 2000). The most fre- quent cause of human narcolepsy is now known to be hypocretin deficiency, most probably as the result of an autoimmune attack against hypocretin-containing cells. In this commentary, I will briefly review the current knowledge regarding this system, speculate on its possible function in sleep regulation and discuss the potential importance of this system for neuropsychiatry. HYPOCRETIN/OREXINS: NEURONATOMY AND RECEPTOR SYSTEMSThe description of this system has been the object of multiple recent reviews ( Kilduff and Peyron 2000;Sutcliffe and de Lecea 2000;Hungs and Mignot 2001;Overeem et al. 2001;Willie et al. 2001) and will only be briefly outlined. Two biologically active peptides encoded by a single two-exon precursor gene, the preprohypocretin (Hcrt) locus, have been described. The precursor gene contains a signal peptide sequence, followed by a first active peptide, hypocretin-1 (or orexin-A), a second active peptide, hypocretin-2 (or orexin-B) and a C-terminal section of unknown biological activity. Endopeptidic cleavage occurs at typical dibasic residue sequences located between the hypocretin peptides and at the C-terminal of the hypocretin-2 sequence. The hypocretin-1 and hypocretin-2 regions but not the C-terminal region of the precursor ...

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Section: Pharmacological Studies In Canine Narcolepsymentioning

confidence: 77%

“…Current treatments are purely symptomatic and partially effective (Nishino and Mignot 1997;Overeem et al 2001).…”

Section: Treatment Of Human Narcolepsymentioning

confidence: 99%

mentioning

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Commentary on the Neurobiology of the Hypocretin/Orexin System

Mignot¹

2001

Neuropsychopharmacology

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The Role of Cerebrospinal Fluid Hypocretin Measurement in the Diagnosis of Narcolepsy and Other Hypersomnias

Mignot¹,

Lammers²,

Ripley³

et al. 2002

Arch Neurol

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1,033

582

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Dog EEG for Wake‐Promotion Studies

Parmentier¹,

Bricout²,

Brousseau³

et al. 2006

CP Pharmacology

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Described in this unit is a protocol for investigating the wake-promoting activity of new chemical entities (NCEs) in dog. The experimental approach is based on scoring of sleep/wake stages in animals implanted with a telemetry device for recording EMG and cortical EEG signals. A major advantage of this procedure is that it is conducted in nontethered animals, limiting possible bias and complications encountered with conventional recording systems. In this procedure, polygraphic recording is conducted using four implanted beagles. Results of studies with modafinil, a wake-promoting agent, are described to demonstrate the utility of this test procedure.

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Pharmacological Aspects of Human and Canine Narcolepsy

Cited by 429 publications

References 288 publications

A Commentary on the Neurobiology of the Hypocretin/Orexin System

A Commentary on the Neurobiology of the Hypocretin/Orexin System

The Role of Cerebrospinal Fluid Hypocretin Measurement in the Diagnosis of Narcolepsy and Other Hypersomnias

Dog EEG for Wake‐Promotion Studies

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