Review Article | Published:

Interactions of the histamine and hypocretin systems in CNS disorders

Nature Reviews Neurology volume 11, pages 401413 (2015) | Download Citation

Abstract

Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep–wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy-associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system.

Key points

  • Over-the-counter histamine H1 receptor antagonists (antihistamines) block the effects of histamine, have sedating properties and are commonly used to treat insomnia

  • A large increase in the number of histamine neurons is seen in type 1 narcolepsy (narcolepsy with cataplexy), but not in animal models of narcolepsy

  • Low levels of cerebrospinal fluid (CSF) hypocretin are characteristic of type 1 narcolepsy; changes in CSF histamine levels are small and variable in this disorder

  • In several neurological disorders including Parkinson and Alzheimer diseases, hypocretin-containing cells degenerate while the number of histamine cells and histamine levels are in the normal range

  • Histamine H3 receptor antagonists and inverse agonists promote histamine release and are a promising class of drugs for the promotion of wakefulness, as has been shown in patients with narcolepsy

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Acknowledgements

We thank the National Institutes of Health (NS14610, MH064109, DA034748) and the Medical Research Service of the US Department of Veterans Affairs for support. L.S. is supported by a 2014 NARSAD Young Investigator Grant from the Brain & Behaviour Research Foundation. The authors want to thank Dr Ronald McGregor for drawing Figure 4.

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Affiliations

  1. Department of Psychiatry and Brain Research Institute, UCLA School of Medicine, Veterans' Affairs Greater Los Angeles Healthcare System (VA GLAHS), 16111 Plummer Street North Hills, 151A3, CA 91343, USA.

    • Ling Shan
    •  & Jerome M. Siegel
  2. Centre de Référence Nationale Maladies Rares, Narcolepsie et Hypersomnie Idiopathique, Département de Neurologie, Hôpital Gui-de-Chauliac, INSERM U1061, 80 avenue Augustin Fliche, Montpellier 34295, France.

    • Yves Dauvilliers

Authors

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Contributions

All authors participated in writing the article, and provided substantial contributions to the discussion of content and to the editing the manuscript before submission.

Competing interests

Y.D. has received funds for speaking and board engagements from Bioprojet, Jazz and UCB Pharma. L.S. and J.S. declare no competing interests.

Corresponding author

Correspondence to Jerome M. Siegel.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrneurol.2015.99

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