Heterozygosity at the canarc-1 locus can confer susceptibility for narcolepsy: induction of cataplexy in heterozygous asymptomatic dogs after administration of a combination of drugs acting on monoaminergic and cholinergic systems

Mignot, Emmanuel; Nishino, Seiji; Sharp, LH; Arrigoni, Janis; Siegel, J. M.; Reid, Derryck T.; Dm, Edgar; Ciaranello, Roland D.; Wc, Dement

doi:10.1523/jneurosci.13-03-01057.1993

Cited by 62 publications

(28 citation statements)

References 22 publications

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“…In the dogs, symptom onset occurs relatively early in life, at 1-4 months of age (Mignot et al, 1993), consistent with the observed neuronal degeneration. Human narcolepsy has been seen in children as young as 3 years (Yoss and Daly, 1960;Billiard, 1985;Kotagal et al, 1990;Challamel et al, 1994) but typically starts in the second or third decade (Aldrich, 1990).…”

Section: Discussionsupporting

confidence: 80%

Neuronal Degeneration in Canine Narcolepsy

et al. 1999

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Narcolepsy is a lifelong illness characterized by persistent sleepiness, hypnagogic hallucinations, and episodes of motor paralysis called cataplexy. We have tested the hypothesis that a transient neurodegenerative process is linked to symptom onset. Using the amino-cupric silver stain on brain sections from canine narcoleptics, we found elevated levels of axonal degeneration in the amygdala, basal forebrain (including the nucleus of the diagonal band, substantia innominata, and preoptic region), entopeduncular nucleus, and medial septal region. Reactive neuronal somata, an indicator of neuronal pathology, were found in the ventral amygdala. Axonal degeneration was maximal at 2-4 months of age. The number of reactive cells was maximal at 1 month of age. These degenerative changes precede or coincide with symptom onset. The forebrain degeneration that we have observed can explain the major symptoms of narcolepsy.Key words: narcolepsy; REM sleep; amygdala; basal forebrain; canine; amino-cupric silver; degeneration; cataplexy Narcolepsy, which occurs at a rate of 0.2-1.6 per thousand (Aldrich, 1990;Hublin et al., 1994), was first recognized 118 years ago by Gélineau (Passouant, 1976). Its symptoms include excessive daytime sleepiness, hypnagogic hallucinations (dream-like mentation in waking), REM sleep at sleep onset, cataplexy (a loss of muscle tone in waking, usually triggered by sudden, strong emotions), and sleep paralysis (an inability to move at sleep onset or awakening) . Narcolepsy has been reported in horses, cattle, and dogs (Mitler et al., 1976; Strain et al., 1984). C anine narcoleptics have been intensively studied. Like human narcoleptics, they are excessively sleepy and have cataplexy. Symptoms in canine and human narcoleptics display a similar response to pharmacological agents Nishino and Mignot, 1997). The cause of narcolepsy is unknown.Narcolepsy is not a progressive disease, in that once symptoms have become f ully established, in both human and canine narcoleptics, they do not become worse (or markedly better) with age. This suggests that narcolepsy may be caused by a transient degenerative process. E xaminations of postmortem tissue in human narcoleptics have not produced consistent evidence for degenerative changes. However, symptom onset is typically 50 or more years before autopsy, a sufficient interval for the removal of any debris resulting from degeneration at the time of disease onset. The age of onset of canine narcolepsy is between 1 and 4 months. In the current study, we have used the amino-cupric stain (de Olmos et al., 1994), an extremely sensitive indicator of degenerating neurons and axons (Switzer, 1991;Fix et al., 1996), to test the hypothesis that narcolepsy onset is linked to neuronal degeneration. MATERIALS AND METHODSEighteen Doberman pinscher dogs, nine narcoleptic and nine age-and breed-matched controls (four male narcoleptics and seven male controls), from six narcoleptic and five normal litters ranging from 1 to 8 months of age were used (Table 1). Control and narcole...

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Section: Discussionsupporting

confidence: 80%

Neuronal Degeneration in Canine Narcolepsy

et al. 1999

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“…Of note however, this pattern of activity is most striking for serotoninergic, adrenergic and histaminergic tone; dopaminergic neuronal activity does not change very significantly across the sleep cycle. Consistent with this model, drugs that either activate cholinergic tone or decrease monoaminergic activity increase cataplexy while anticholinergic and monoaminergic enhancers reduce the symptoms (Baker and Dement 1985;Mignot et al 1993b;Nishino and Mignot 1997). As mentioned above, however, adrenergic uptake inhibition is more effective than serotonin or dopamine reuptake inhibition in reducing cataplexy (Mignot et al 1993a).…”

Section: Pharmacological Studies In Canine Narcolepsymentioning

confidence: 86%

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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“…Canine narcolepsy was first reported in the 1970's, and since then dogs have been extensively used for exploring the underlying mechanisms of the disease [3]. A colony of Doberman pinschers with a heritable form of narcolepsy due to a mutation in a single major gene was established at Stanford Sleep Research Center in 1976 [4]. The genetic transmission of the mutation, also known as canarc-1 , is autosomal recessive.…”

Section: Introductionmentioning

confidence: 99%

Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain

et al. 2007

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Background: Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the hypocretin signals.

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Heterozygosity at the canarc-1 locus can confer susceptibility for narcolepsy: induction of cataplexy in heterozygous asymptomatic dogs after administration of a combination of drugs acting on monoaminergic and cholinergic systems

Cited by 62 publications

References 22 publications

Neuronal Degeneration in Canine Narcolepsy

Neuronal Degeneration in Canine Narcolepsy

A Commentary on the Neurobiology of the Hypocretin/Orexin System

Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain

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