Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers

Mignot, Emmanuel; Renaud, Alain; Nishino, Seiji; Arrigoni, Janis; Guilleminault, Christian; Dement, William C.

doi:10.1007/bf02244337

Cited by 109 publications

(33 citation statements)

References 49 publications

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“…Posthoc tests revealed a significant reduction in cataplexy during week 1 and week 2 compared to the baseline. tors potently reduce cataplexy, while selective 5HT and DA uptake inhibitors have little or no effect (Mignot et al 1993;Nishino et al 1993a). In contrast, the DA uptake mechanism is found to be important for the control of EEG arousal; selective DA uptake inhibitors and modafinil potently induce EEG arousal, and their in vivo potency on EEG arousal correlates well with their in vitro binding affinity to the dopamine transporter (Nishino et al 1998a).…”

Section: Discussionmentioning

confidence: 41%

Sulpiride, a D2/D3 Blocker, Reduces Cataplexy but not REM Sleep in Canine Narcolepsy

Okura

Riehl

Mignot

et al. 2000

Neuropsychopharmacology

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Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness (EDS), fragmented nighttime sleep, cataplexy, hypnagogic hallucinations, and sleep paralysis (Aldrich 1992). EDS and cataplexy, "a sudden and bilateral loss of postural muscle tone in association with intense emotion" ICSD (International classification of sleep disorders ) (Diagnostic Classification Steering Committee, Thorpy MJ, Chairman 1990), are the most disabling symptoms of narcolepsy. EDS is usually treated using amphetamine-like stimulants (Aldrich 1992;Nishino and Mignot 1997). Although stimulants reduce daytime sleepiness, they have little effect on cataplexy, and thus additional anticataplectic medications are often needed in the treatment of narcolepsy. Tricyclic antidepressants have been the most commonly used anticataplectic agents since the 1960s (Akimoto et al. 1960;Aldrich 1992;Nishino and Mignot 1997). However, tricyclics have a variety of pharmacological effects, such as anticholinergic and antihistaminergic effects and/or alpha-1 adrenergic antagonism (Baldessarini 1983). Some of these effects are responsible for a variety of side effects during chronic treatment (dry mouth, tachycardia, weight gain, sexual dysfunction, sedation, and orthostatic hypotension) (Guilleminault 1994;Thorpy and Goswami 1990). Tricyclics also significantly affect nocturnal sleep by suppressing REM sleep, increasing muscle tone and inducing nocturnal movements (Guilleminault 1994). The long-term impact of chronically disturbing sleep in narcoleptic patients due to these compounds is unknown.Canine narcolepsy is a naturally occurring animal model which presents behavioral, pharmacological and electrophysiological similarities to the human disorder Sulpiride, aD2/D3 Blocker, in Narcoleptic Dogs 529 (Baker and Dement 1985;Kaitin et al. 1986;Nishino and Mignot 1997). Narcoleptic dogs manifest a short sleep latency, fragmented sleep patterns, and cataplexy (Kaitin et al. 1986;Nishino et al. 1999). It was recently discovered that mutations in the gene encoding a receptor for hypocretins (also called orexins) induces genetic narcolepsy in Dobermans and Labradors (Lin et al. 1999). Subsequently, it was also found that cerebrospinal fluid hypocretin-1 levels are low in human narcoleptic subjects, indicating that a deficit in hypocretin neurotransmission is also involved in human narcolepsy (Nishino et al. 2000b). Thus, the use of the canine model to uncover the pathophysiology of narcolepsy and to develop new treatments for human narcolepsy is further warranted. Previous pharmacological studies in canine narcolepsy have demonstrated that decreased monoaminergic transmission is one of the most important factors in the pathophysiology of narcolepsy (Mignot et al. 1989;Nishino et al. 1990;Nishino and Mignot 1997;Reid et al. 1998). Inactivation of catecholaminergic transmission aggravates cataplexy and/or induces sleep in these animals [see (Nishino and Mignot 1997)]. We further identified several catecholaminergic receptor subtypes specifically i...

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Section: Discussionmentioning

confidence: 41%

Sulpiride, a D2/D3 Blocker, Reduces Cataplexy but not REM Sleep in Canine Narcolepsy

Okura

Riehl

Mignot

et al. 2000

Neuropsychopharmacology

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“…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). As serotonin reuptake inhibitors also reduce REM sleep, this may suggest a preferential adrenergic control of REM atonia by the adrenergic system.…”

Section: Pharmacological Studies In Canine Narcolepsymentioning

confidence: 88%

“…fluoxetine). Adrenergic reuptake inhibition has been shown to be most effective in reducing cataplexy in animal models (Mignot et al 1993a) but few antidepressants are targeting the adrenergic transporter site to date. Clinical experience using reuptake blockers of this system such as reboxetine suggest very positive anticataplectic effects but experience with these newer drugs is more limited.…”

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confidence: 99%

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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“…Both the adrenergic and cholinergic systems are critically involved in the control of cataplexy (Mignot et al, 1989(Mignot et al, , 1993Nishino et al, 1990Nishino et al, , 1993aNishino et al, ,b, 1995Reid et al, 1994a,b), whereas dopaminergic systems are important in the regulation of alertness (Nishino et al, 1996(Nishino et al, , 1997. Large numbers of experiments suggest that TRH has modulatory effects on these neurotransmitters.…”

Section: Discussionmentioning

confidence: 44%

Effects of Thyrotropin-Releasing Hormone and Its Analogs on Daytime Sleepiness and Cataplexy in Canine Narcolepsy

et al. 1997

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The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 g/kg, i.v.) and TA0910 (100 and 400 g/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 g/kg, i.v.) had no significant effect. TRH (25-1600 g/kg, i.v.) and all three TRH analogs, CG3703 (6.25-400 g/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 g/kg, i.v.), and TA0910 (25-1600 g/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T 3 and T 4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.

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Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers

Cited by 109 publications

References 49 publications

Sulpiride, a D2/D3 Blocker, Reduces Cataplexy but not REM Sleep in Canine Narcolepsy

Sulpiride, a D2/D3 Blocker, Reduces Cataplexy but not REM Sleep in Canine Narcolepsy

A Commentary on the Neurobiology of the Hypocretin/Orexin System

Effects of Thyrotropin-Releasing Hormone and Its Analogs on Daytime Sleepiness and Cataplexy in Canine Narcolepsy

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