Interactions of the histamine and hypocretin systems in CNS disorders

Nat Rev Neurol. 2015 Jul;11(7):401-13. doi: 10.1038/nrneurol.2015.99. Epub 2015 Jun 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Alzheimer Disease / metabolism
  • Animals
  • Histamine / metabolism*
  • Histamine Agonists / therapeutic use
  • Histamine H1 Antagonists / therapeutic use
  • Histamine H3 Antagonists / therapeutic use
  • Humans
  • Huntington Disease / metabolism
  • Narcolepsy / drug therapy
  • Narcolepsy / metabolism*
  • Neurons / metabolism*
  • Orexins / metabolism*
  • Parkinson Disease / metabolism
  • Tourette Syndrome / metabolism


  • Histamine Agonists
  • Histamine H1 Antagonists
  • Histamine H3 Antagonists
  • Orexins
  • Histamine