Role of central alpha-1 adrenoceptors in canine narcolepsy.

Mignot, Emmanuel; Guilleminault, C.; Bowersox, S. Scott; Rappaport, Alain; Dement, William C.

doi:10.1172/jci113694

Cited by 50 publications

(29 citation statements)

References 22 publications

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“…The Food-Elicited Cataplexy Test (FECT), a standardized biological assay for quantifying the severity of cataplexy, was originally developed by Babcock et al (1976) and has been successfully used by several investigators to assess symptom severity in narcoleptic canines (Foutz et al, 1981;Mignot et al, 1988b, Nishino et al, 1989. Food, which is equivalent to an emotional stimulus in humans, precipitates multiple cataplectic attacks in these animals, sometimes resulting in full-blown REM-sleep periods.…”

Section: Methodsmentioning

confidence: 99%

Dopamine D2 mechanisms in canine narcolepsy

Nishino¹,

Arrigoni²,

Valtier³

et al. 1991

J. Neurosci.

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Narcolepsy is a sleep disorder characterized by abnormal manifestations of rapid-eye-movement (REM) sleep and excessive daytime sleepiness. Using a canine model of the disease, we found that central D, antagonists suppressed cataplexy, a form of REM-sleep atonia occurring in narcolepsy, whereas this symptom was aggravated by D, agonists. The effect on cataplexy was stereospecific for the S(-) enantiomer of sulpiride (a D, antagonist) and the I?(+) enantiomer of 3-PPP (a D, agonist). There was also a significant correlation between the in viva pharmacological potency and in vitro drug affinity for D, receptors (but not for D, and (Y* receptors) among the seven central D, antagonists tested. Selective D, compounds were also tested; however, the results were inconsistent because both antagonists and agonists generally suppressed cataplexy. Our current results demonstrate that central D,-type receptors are critically involved in the control of cataplexy and REM sleep. Furthermore, the finding that small doses of D, antagonists suppressed cataplexy and induced behavioral excitation, while small doses of D, agonists aggravated cataplexy and induced sedation, suggests that this effect is mediated presynaptically. However, considering the fact that selective dopamine reuptake inhibitors did not modify cataplexy and that our previous pharmacological results demonstrated a preferential involvement of the noradrenergic system in the control of cataplexy, we believe that the effect of D, compounds on cataplexy is mediated secondarily via the noradrenergic systems.Human narcolepsy is an incurable sleep disorder characterized by sleep-onset periods of rapid-eye-movement (REM) sleep, recurring bouts of flaccid muscular paralysis (cataplexy), which are often initiated by emotional stimuli, and excessive daytime sleepiness (Guilleminault, 1976). Canine narcolepsy is a spontaneous animal model ofthis condition that presents behavioral, pharmacological, and electrophysiological similarities to the human disorder (Baker and Dement, 1985; Mignot et al., 199 1). As with primary human narcolepsy, no morphological abnormalities in the CNS have been found in affected canines, and it is therefore suggested that subtle neurochemical dysfunctions are involved in the pathophysiology of this disorder (Baker et al., 1982;Baker and Dement, 1985). Received Nov. 19, 1990; revised Apr. 3, 1991; accepted Apr. 9, 1991. This work was supported by NIH Grant NS-23724 and by a grant from The Upjohn Company. We thank L. In the canine model, several neurochemical abnormalities have been found, including fluctuations in the levels of dopamine (DA) and norepinephrine (NE) and their metabolites in the cerebrospinal fluid (Faull et al., 1982) and localized brain regions (Mefford et al., 1983;Miller et al., 1990), and regional upregulations of adrenergic (Y,, q, and dopaminergic D, receptors in the narcoleptic canine CNS (Bowersox et al., 1987;Mignot et al., 1988a; Fruhstorfer et al., 1989). Furthermore, we have studied the effect on cataplexy of various ph...

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Section: Methodsmentioning

confidence: 99%

Dopamine D2 mechanisms in canine narcolepsy

Nishino¹,

Arrigoni²,

Valtier³

et al. 1991

J. Neurosci.

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“…However, this effect is not likely to be mediated by uptake inhibition, since Tuomisto reported that TRH has no effect on monoamine uptake (Tuomisto and Männistö 1973). In addition to the NE uptake mechanism, we previously demonstrated that presynaptic alpha-2 and postsynaptic alpha-1 receptors are also involved in the pharmacological control of cataplexy: alpha-2 stimulation (e.g., by BHT-9210), and alpha-1 blockade (e.g., by prazosin) significantly aggravate canine cataplexy (see Mignot et al 1988;Nishino et al 1994). Heal et al (1987) reported that both alpha-2 No fluctuations in serum T3 and free T4 levels were observed during the drug administration.…”

Section: Discussionmentioning

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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“…The FECT, a standardized biological assay for quantifying the severity of cataplexy, was originally developed by Babcock et al (4) and has been used successfully by several investigators (5)(6)(7)(8). Food precipitates multiple cataplectic attacks in these animals, sometimes blending into full-blown REM sleep.…”

Section: Methodsmentioning

confidence: 99%

“…Rectal temperature was measured at an ambient temperature of 22.2 ± 1.10C by using a glass thermometer inserted approximately 6 cm into the rectum. Blood pressure and heart rate were measured directly by an auscultatory method, which has been described elsewhere (8). Blood pressure was taken on a forelimb after detection of the humeral artery pulse.…”

Section: Methodsmentioning

confidence: 99%

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Prostaglandin E2 and its methyl ester reduce cataplexy in canine narcolepsy.

Nishino

Mignot

Fruhstorfer

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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The effects of intravenous administration of prostaglandins (PGs) were investigated in genetically narcoleptic Doberman pinschers. The treatment of narcoleptic dogs with PGE2 and PGE2 methyl ester, but not PGD2 and PGD2 methyl ester, induced a dose-dependent reduction of canine cataplexy, a dissociated manifestation of rapid-eye-movement sleep. The effect was specific and not associated with any change in other behavior. Furthermore, the effect was longlasting (up to 2 hr) and could not be explained by the acute cardiovascular changes seen after intravenous PG administration. PGE2 methyl ester, a lipophilic derivative of PGE2 with more central penetration than PGE2, was 4 times more potent than PGE2. These results indicate that PGE2 modifies cataplexy through a central effect and suggest that this prostaglandin may play a role in rapid-eye-movement sleep regulation.Narcolepsy is a disabling sleep disorder of unknown etiology characterized by excessive daytime sleepiness and cataplexy (attacks of flaccid muscle paralysis occurring at the onset of increased emotion) (1). Sleep-recording studies in narcoleptic patients show an abnormally rapid transition from wake to rapid-eye-movement (REM) sleep during the day and an extremely shortened REM latency at night (1). Since a state of muscular paralysis similar to cataplexy normally occurs during REM sleep, narcolepsy is considered a REM sleep disorder (1). Canine narcolepsy is a spontaneous animal model presenting striking similarities to human narcolepsy both in its behavioral manifestation (i.e., cataplexy and sleepiness) and response to therapeutic drugs (2-6).Studies on the regulation of narcolepsy-cataplexy and REM sleep have emphasized cholinergic and monoaminergic hypotheses (4-10). However, the recent discovery that human narcolepsy is strongly associated with human leukocyte antigens DR2, Dw2, and DQwl (11) has led several investigators to propose an autoimmune etiology for this disorder (12). Prostaglandins (PGs) are intimately involved in inflammation and the immune response (13). These mediators are natural constituents of the central nervous system (CNS) (14); metabolic pathways as well as specific receptors for PGs have been described in the brain (15-17). Furthermore, it has been demonstrated that CNS administration of PGD2 and PGE2, the two major prostaglandins in the mammalian CNS, respectively facilitates and inhibits sleep (18)(19)(20)(21)(22). As an alternative basis to the cholinergic and monoaminergic hypotheses, we explored the roles of PGD2 and PGE2 in canine narcolepsy. Recently, methyl ester derivatives of PGs with more CNS penetration have been described, and the peripheral administration of these compounds has been used to better define the CNS effects of PGs (23,24). In this study, we administered PGD2, PGE2 and their methyl esters, PGD2-Me and PGE2-Me, to narcoleptic dogs and found that intravenous administration of PGE2-Me induced a dose-dependent reduction of cataplexy in canine narcolepsy. MATERIALS AND METHODSAnimals. Six gene...

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Role of central alpha-1 adrenoceptors in canine narcolepsy.

Abstract: The role of central alpha-i adrenergic receptors

Cited by 50 publications

References 22 publications

Dopamine D2 mechanisms in canine narcolepsy

Dopamine D2 mechanisms in canine narcolepsy

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

Prostaglandin E2 and its methyl ester reduce cataplexy in canine narcolepsy.

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