Desmethyl Metabolites of Serotonergic Uptake Inhibitors Are More Potent for Suppressing Canine Cataplexy Than Their Parent Compounds

Nishino, Seiji; Arrigoni, Janis; Shelton, Jeff; Dement, William C.; Mignot, Emmanuel

doi:10.1093/sleep/16.8.706

Cited by 73 publications

(19 citation statements)

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“…Although the receptor affected in canine narcolepsy, the Hcrt-2 subtype, is not present in the locus ceruleus (which contains the Hcrt-1 subtype), the dysfunctional Hcrt-2 receptors may result in abnormal activity in Hcrt cells, thereby affecting postsynaptic cells with both receptors types. The effectiveness of anti-cataplectic therapeutic agents is strongly correlated with the extent to which they act as noradrenergic agonists (39), suggesting that these drugs are compensating for the lack of Hcrt drive to the locus ceruleus. The activity of locus ceruleus and reticulospinal cells projecting to motoneurons excited by Hcrt is tightly linked to motor activity (23,47,49,50).…”

Section: Discussionmentioning

confidence: 99%

Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement

John

Maidment

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

132

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Section: Discussionmentioning

confidence: 99%

Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement

John

Maidment

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

132

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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: 99%

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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“…We have demonstrated that local perfusion of cholinergic compounds (such as carbachol) into the medial pontine reticular formation (mPRF) induces prolonged episodes of muscle atonia (cataplexy) with or without REMs (Reid et al, 1994a), and that acetylcholine release in the mPRF increases during cataplexy (Reid et al, 1994b). Other pharmacological data indicated that cataplexy is also controlled by noradrenergic Nishino et al, 1993), and possibly dopaminergic mechanisms . Abnormalities of both systems have also been reported.…”

Section: Indexing Terms: Narcolepsy; Acetylcholine; Norepinephrine; Pmentioning

confidence: 99%

Mesopontine organization of cholinergic and catecholaminergic cell groups in the normal and narcoleptic dog

et al. 1997

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Canine narcolepsy is a unique experimental model of a human sleep disorder characterized by excessive daytime sleepiness and cataplexy. There is a consensus recognition of an imbalance between cholinergic and catecholaminergic systems in narcolepsy although the underlying mechanisms remain poorly understood. Possible substrates could be an abnormal organization, numbers and/or ratio of cholinergic to catecholaminergic cells in the brain of narcoleptic dogs. Therefore, we sought to characterize the corresponding neuronal populations in normal and narcoleptic dogs (Doberman Pinscher) by using choline acetyltransferase (ChAT), nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase, tyrosine hydroxylase (TH), and dopamine beta-hydroxylase (DBH). Cholinergic cell groups were found in an area extending from the central to the gigantocellular tegmental field and the periventricular gray corresponding to the pedunculopontine tegmental nucleus (PPT), the laterodorsal tegmental nucleus (LDT), and the parabrachial nucleus. An almost perfect co-localization of ChAT and NADPH-diaphorase was also observed. Catecholaminergic cell groups detected included the ventral tegmental area, the substantia nigra, and the locus coeruleus nucleus (LC). The anatomical distribution of catecholaminergic neurons was unusual in the dog in two important aspects: i) TH- and/or DBH-immunoreactive neurons of the LC were found almost exclusively in the reticular formation and not within the periventricular gray, ii) very few, if any TH-positive neurons were found in the central gray and dorsal raphe. Quantitative analysis did not reveal any significant differences in the organization and the number of cells identified in the LDT, PPT, and LC of normal and narcoleptic dogs. Moreover, the cholinergic to catecholaminergic ratio was found identical in the two groups. In conclusion, the present results do not support the hypothesis that the neurochemical imbalance in narcolepsy could result from abnormal organization, numbers, or ratio of the corresponding neuronal populations.

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Desmethyl Metabolites of Serotonergic Uptake Inhibitors Are More Potent for Suppressing Canine Cataplexy Than Their Parent Compounds

Cited by 73 publications

References 0 publications

Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement

Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement

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

Mesopontine organization of cholinergic and catecholaminergic cell groups in the normal and narcoleptic dog

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