Elsevier

Neuroscience Research

Volume 38, Issue 4, December 2000, Pages 437-446
Neuroscience Research

Is narcolepsy a REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans

https://doi.org/10.1016/S0168-0102(00)00195-4Get rights and content

Abstract

Narcolepsy is a chronic sleep disorder marked by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Since the discovery of sleep onset REM periods (SOREMPs) in narcoleptic patients, narcolepsy has often been regarded as a disorder of REM sleep generation: REM sleep intrudes in active wake or at sleep onset, resulting in cataplexy, sleep paralysis, or hypnagogic hallucinations. However, this hypothesis has not been experimentally verified. In the current study, we characterized the sleep abnormalities of genetically narcoleptic-cataplectic Dobermans, a naturally occurring animal model of narcolepsy, in order to verify this concept. Multiple sleep latency tests during the daytime revealed that narcoleptic Dobermans exhibit a shorter sleep latency and a higher frequency of SOREMPs, compared to control Dobermans. The total amount of time spent in wake and sleep during the daytime is not altered in narcoleptic dogs, but their wake and sleep patterns are fragmented, and state transitions into and from wake and other sleep stages are altered. A clear 30 min REM sleep cyclicity exists in both narcoleptic and control dogs, suggesting that generation of the ultradian rhythm of REM sleep is not altered in narcoleptics. In contrast, cataplexy displays no cyclicity and can be elicited in narcoleptic animals anytime with emotional stimulation and displays no cyclicity. Stimulation of a cholinoceptive site in the basal forebrain induces a long-lasting attack of cataplexy in narcoleptic dogs; however, bursts of rapid eye movements during this state still occur with a 30 min cyclicity. Sites and mechanisms for triggering cataplexy may therefore be different from those for REM sleep. Cataplexy and a dysfunction in the maintenance of vigilance states, but not abnormal REM sleep generation, may therefore be central to narcolepsy.

Introduction

Narcolepsy is a chronic sleep disorder that affects 0.03–0.16% of the general population (Aldrich, 1993, Nishino and Mignot, 1997, Mignot, 1998). The disease is often characterized as a tetrad of symptoms: excessive daytime sleepiness, cataplexy (a sudden loss of muscle tonus during active wake typically elicited by emotional stimulation), sleep paralysis, and hypnagogic hallucinations (Aldrich, 1993, Nishino and Mignot, 1997). The mechanisms for the occurrence of these symptoms are still largely unknown. Since the discovery that rapid eye movement (REM) sleep often occurs at sleep onset (i.e. sleep onset REM periods [SOREMPs]) in narcoleptic patients (Vogel, 1960, Rechtschaffen et al., 1963, Takahashi and Jimbo, 1963), narcolepsy has often been regarded as a disorder of REM sleep generation. In humans REM sleep usually occurs 90 min after sleep onset and re-appears every 90 min during sleep (Dement and Kleitman, 1957). It is therefore hypothesized that in narcolepsy, REM sleep can intrude in active wake or at sleep onset, resulting in cataplexy, SOREMPs, sleep paralysis and hypnagogic hallucinations, and these three symptoms are categorized as dissociated manifestations of REM sleep phenomena (Roth et al., 1969, Takahashi, 1971). Abnormal regulation of REM sleep events may therefore be central to the pathophysiology of narcolepsy, but this has not been experimentally demonstrated.

Canine narcolepsy is a naturally-occurring animal model of the disorder (Nishino and Mignot, 1997). It was recently found that genetic narcolepsy in Dobermans and Labradors is caused by mutations in the gene for hypocretin receptor-2 (Hcrtr 2), one of 2 receptors for novel neuropeptides, hypocretin-1 (Hcrt 1) and -2 (Hcrt 2) (also known as orexin A and B) (Lin et al., 1999). This discovery was immediately followed by the report that preprohypocretin (preproorexin) knockout mice also exhibit a narcolepsy-like phenotype, including cataplexy-like attacks and shorter REM latency (Chemelli et al., 1999). Furthermore, it was also found that cerebrospinal fluid Hcrt 1 levels are undetectably low in 7 out of 9 human narcoleptic subjects, indicating that a deficit in hypocretin neurotransmission is also involved in some human narcolepsy (Nishino et al., 2000b). Thus, the use of the canine model for studying the abnormal wake and sleep regulation seen in narcolepsy is warranted.

In the current study, we analyzed (1) sleep latencies and occurrence of SOREMPs during daytime nap tests; (2) abnormal sleep architectures (i.e. fragmentation and state transitions); (3) ultradian cyclicity of the occurrence of REM sleep and cataplexy through daytime 6 h sleep recordings; and (4) cyclicity of the occurrence of cataplexy, induced both by emotional stimulation and local drug administration, to examine the major disease-related sleep abnormalities in narcolepsy and to determine whether REM sleep generation is altered in narcolepsy.

Section snippets

Animals

Ten genetically narcoleptic and 6 control Doberman pinschers from the Stanford University Sleep Disorders Center Canine Colony were used for sleep recordings. All dogs were implanted with screw electrodes over the fronto-parietal (frontal; AP=31–32, L=10–11, according to (Lim et al., 1960), over the gyrus cruciatus anterior, parietal: AP= 20–22, L=10–11, over the gyrus supasylvius anterior) and fronto-occipital (AP=5–7, L=10–11, over the gyrus ectolateralis) cortices to record cortical

Results

The mean time from lights off to the beginning of each sleep stage (latency to each stage, in minutes), as well as number of occurrences (number/total number of sessions) of deep sleep, cataplexy and sleep onset REM episodes during the MSLT in narcoleptic and control canines are shown in Fig. 1. Drowsy and light sleep occurred in all sessions for both narcoleptic (n=100) and control animals (n=60), while deep sleep and REM sleep only occurred in some of the sessions (Fig. 1). We found that

Discussion

The cause of narcolepsy, a chronic sleep disorder that was first described more than 100 years ago (Gélineáu, 1880), is still not known. The disorder occurs in both sporadic and familial cases through an interplay of genetic and environmental factors (Aldrich, 1993, Mignot, 1998). Narcolepsy is believed to be associated with both non-REM (NREM) and REM sleep abnormalities: excessive daytime sleepiness and disturbed nighttime sleep, vs. cataplexy, sleep paralysis and hypnagogic hallucinations,

Acknowledgements

Authors thank Dr WC Dement for establishing the canine narcolepsy colony and scientific support, Drs K Honda, M Okura and N Fujiki for useful discussions, the staff of the Department of Comparative Medicine for animal care, and B Ripley for editing the manuscript. This work was supported by NS 27710, NS23724 and MH01600.

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