Elsevier

Behavioural Brain Research

Volume 262, 1 April 2014, Pages 8-13
Behavioural Brain Research

Research report
The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy

https://doi.org/10.1016/j.bbr.2013.12.045Get rights and content

Highlights

  • Intranasal orexin-A administration affects sleep and vigilance.

  • Orexin-A reduces wake-REM sleep transitions in the day.

  • Orexin-A reduces REM sleep duration.

  • Orexin-A improves attention in narcolepsy with cataplexy.

  • Our results support orexin-A to be a REM sleep stabilizing factor.

Abstract

Narcolepsy with cataplexy is a sleep dysregulation disorder with alterations of REM sleep, i.e., sleep onset REM periods and REM sleep instability. Deficient orexin-A (hypocretin-1) signaling is assumed to be a major cause of narcolepsy with cataplexy. In this study we investigated fourteen subjects with narcolepsy with cataplexy in a within-subject, random-order crossover, placebo-controlled design. Patients received double-blinded intranasal orexin-A (435 nmol) or sterile water (placebo) in the morning. Administration was preceded by an adaptation night and followed by a modified maintenance of wakefulness test, attention testing and a second full night of polysomnographic recording. We found comparable sleep behavior during the adaptation nights between both conditions. After orexin-A administration patients had less wake-REM sleep transitions and a decreased REM sleep duration. In the subsequent night, patients showed an increased N2 duration. In the test of divided attention, patients had fewer false reactions after orexin-A administration. Our results support orexin-A to be a REM sleep stabilizing factor and provide functional signs for effects of orexin-A on sleep alterations and attention in narcolepsy with cataplexy.

Introduction

Narcolepsy, a disease characterized by excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations, sleep onset rapid eye movement (REM) sleep, and cataplexy, in addition is associated with more specific abnormalities of nocturnal sleep [1]. Sleep latency is typically reduced, sleep architecture is disturbed with increased wake (W) after sleep onset and light sleep (N1), decreased slow-wave sleep (SWS), and frequent sleep stage shifts [2], [3], [4], [5]. Another disturbance of nocturnal sleep found in narcolepsy with cataplexy is the disruption of REM sleep phases [3], [6]. Apart from sleep dysregulation, neuropsychological impairments have been described in narcoleptic patients, concerning in particular deficits in attention [7]. Whereas narcoleptics showed no differences to healthy controls in most short-term attention tests, deficits in divided attention have been reported, also under stimulant medication [7], [8].

Soon after the first description of the neuropeptide orexin-A, also called hypocretin-1 [9], [10], evidence arose that its absence might contribute to the pathogenesis of narcolepsy [11], [12]. There were findings indicating an inhibiting effect of intracerebral orexin-A on sleep in general and on REM-sleep in particular [13], [14], [15], [16]. Further studies showed neurons producing orexin-A to be active during wakefulness, seeking behavior and to a lesser extent also in phases of REM-sleep with muscle twitches in animals [17], [18]. In a microdialysis study in epileptics Blouin et al. found that in humans orexin-A levels were not linked to arousal per se, but were maximal during positive emotion, social interaction and awakening, and had low levels during sleep [19]. Animals with a deficient orexinergic system showed symptoms similar to human narcolepsy with cataplexy such as disturbed sleep-wake-rhythm, sleep attacks during active phases, and cataplexies [20], [21], [22], [23]. Conclusive evidence for the role of orexin-A in the pathogenesis of narcolepsy, however, came from Mignot and coworkers who found distinctly reduced or absent cerebrospinal fluid (CSF) orexin-A concentrations in a large proportion of patients with narcolepsy [24]. This observation was confirmed and found to be highly specific for the human leukocyte antigen (HLA) subtype (DQ-B1*0602) positive narcolepsy with cataplexy [25], [26], [27], [28].

Considering the symptoms of narcolepsy, it seems reasonable to assume that the function of orexin-A extends beyond that of a wakefulness-inducing factor [13], [14], [29], [30]. Patients with narcolepsy do not show increased sleep duration in a 24 h interval compared to healthy controls [3]. Instead, narcoleptic patients have a problem to maintain sleep during the night and wakefulness during the day [3], [31]. Similar observations were made in animal models of narcolepsy [23], [32]. A hypothetic explanation for this would be that orexinergic neurons act as a stabilizer of wakefulness, thus preventing inappropriate switches into sleep [33].

In an earlier study we have confirmed the observation by Montplaisir and colleagues that increased numbers of switches between REM sleep and wake (i.e., wake-REM sleep transitions) are highly specific for narcolepsy with cataplexy [3], [6]. Furthermore, intranasal administration of orexin-A in the evening had a stabilizing effect on nocturnal sleep as indicated by a reduction in wake-REM sleep transitions and an inhibiting effect on REM sleep that was most pronounced in the second half of the night, whereas a slight wake-promoting effect was not statistically significant [34].

We therefore hypothesized that in patients with narcolepsy with cataplexy, administration of intranasal orexin-A in the morning would increase wake-REM sleep stability and decrease REM sleep quantity as seen for nocturnal sleep. Furthermore, we presumed a reduction of daytime sleepiness and sleep onset REM after intranasal orexin-A administration in these patients. Finally, we hypothesized an improved performance in a divided attention task after orexin-A administration.

Section snippets

Study design

The local ethics committee approved the study and subjects’ informed consent was obtained according to the Declaration of Helsinki. The study was conducted in the Centre of Sleep Medicine, Department of Psychiatry and Psychotherapy, Christian-Albrechts-University, Kiel, from June 2010 to October 2012.

We investigated in a double blind, placebo-controlled experimental design the influence of a single dose of intranasally administered orexin-A on daytime naps. Each subject participated in two

Patient characteristics

We included 14 patients with narcolepsy with proven cataplexies (age, 42.7 ± 11.4 years, 6 men, 8 women). Duration of disease ranges from 4 to 50 years (21.0 ± 13.5). 3 patients had CSF orexin-A lower than 110 pg/ml. 12 patients had narcolepsy-associated HLA-type. The 2 patients without HLA analysis had CSF orexin-A lower than 110 pg/ml. All patients had an UNS score above 17 (25.1 ± 5.8). D-MEQ showed that 2 patients were moderate evening types, 5 were intermediate types, 4 were moderate morning

REM sleep modulating effect

We demonstrate that intranasally administered orexin-A decreases daytime REM-sleep duration and reduces wake-REM sleep transitions in patients with narcolepsy. We also found further non-significant REM sleep-modulating effects of intranasal orexin-A, i.e., an increase in REM sleep latency and a reduction in sleep onset REM periods. These findings confirm and extend our previous observation of a REM sleep-stabilizing effect of orexin-A administered to narcoleptic patients before night sleep [34]

Conclusion

Our study provides further evidence for a functional effect of intranasal administration of orexin-A in patients with narcolepsy with cataplexy. We confirmed the role of orexin-A as a REM sleep stabilizing factor and provide functional evidence for short and long-term effects of orexin-A on sleep alterations and attention in narcolepsy with cataplexy. This information can become useful to develop new medication in the future.

Acknowledgements

We thank the patients for participating in this study and Nicola Wendisch for her excellent technical assistance. This study was financially supported by the German Research Foundation (SFB 654). Parts of this work were performed within the doctoral theses of S.L.W.

References (53)

  • D.J. Buysse et al.

    The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research

    Psychiatry Res

    (1989)
  • K. Doghramji et al.

    A normative study of the maintenance of wakefulness test (MWT)

    Electroen Clin Neuro

    (1997)
  • B.A. Kummangal et al.

    Intracerebroventricular injection of orexin-2 receptor antagonist promotes REM sleep

    Behav Brain Res

    (2013)
  • J.J. Lochhead et al.

    Intranasal delivery of biologics to the central nervous system

    Adv Drug Deliver Rev

    (2012)
  • S.V. Dhuria et al.

    Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system

    J Pharm Sci

    (2009)
  • K. Mattarozzi et al.

    Clinical, behavioural and polysomnographic correlates of cataplexy in patients with narcolepsy/cataplexy

    Sleep Med Rev

    (2008)
  • American Academy of Sleep Medicine

    International Classification of Sleep Disorders, Second Edition (ICSD-2): Diagnostic and Coding Manual

    (2005)
  • T.L. Baker et al.

    Comparative polysomnographic study of narcolepsy and idiopathic central nervous system hypersomnia

    Sleep

    (1986)
  • J. Montplaisir et al.

    Twenty-four-hour recording in REM-narcoleptics with special reference to nocturnal sleep disruption

    Biol Psychiatry

    (1978)
  • R. Wittig et al.

    Narcolepsy and disturbed nocturnal sleep

    Clin Electroencephalogr

    (1983)
  • S.L. Weinhold et al.

    Wake–REM sleep transitions for measuring REM sleep disturbance: comparison between narcolepsy, idiopathic hypersomnia and healthy controls

    Sleep Biol Rhythms

    (2011)
  • M. Rieger et al.

    Attention deficits in patients with narcolepsy

    Sleep

    (2003)
  • L. de Lecea et al.

    The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity

    Proc Natl Acad Sci

    (1998)
  • T. Sakurai et al.

    Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior

    Cell

    (1998)
  • C. Peyron et al.

    A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains

    Nat Med

    (2000)
  • J.J. Hagan et al.

    Orexin A activates locus coeruleus cell firing and increases arousal in the rat

    Proc Natl Acad Sci

    (1999)
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