Histamine-1 receptor is not required as a downstream effector of orexin-2 receptor in maintenance of basal sleep/wake states

Acta Physiol (Oxf). 2010 Mar;198(3):287-94. doi: 10.1111/j.1748-1716.2009.02032.x. Epub 2009 Aug 20.


Aim: The effect of orexin on wakefulness has been suggested to be largely mediated by activation of histaminergic neurones in the tuberomammillary nucleus (TMN) via orexin receptor-2 (OX(2)R). However, orexin receptors in other regions of the brain might also play important roles in maintenance of wakefulness. To dissect the role of the histaminergic system as a downstream mediator of the orexin system in the regulation of sleep/wake states without compensation by the orexin receptor-1 (OX(1)R) mediated pathways, we analysed the phenotype of Histamine-1 receptor (H(1)R) and OX(1)R double-deficient (H(1)R(-/-);OX(1)R(-/-)) mice. These mice lack OX(1)R-mediated pathways in addition to deficiency of H(1)R, which is thought to be the most important system in downstream of OX(2)R.

Methods: We used H(1)R deficient (H(1)R(-/-)) mice, H(1)R(-/-);OX(1)R(-/-) mice, OX(1)R and OX(2)R double-deficient (OX(1)R(-/-);OX(2)R(-/-)) mice, and wild type controls. Rapid eye movement (REM) sleep, non-REM (NREM) sleep and awake states were determined by polygraphic electroencephalographic/electromyographic recording.

Results: No abnormality in sleep/wake states was observed in H(1)R(-/-) mice, consistent with previous studies. H(1)R(-/-);OX(1)R(-/-) mice also showed a sleep/wake phenotype comparable to that of wild type mice, while OX(1)R(-/-); OX(2)R(-/-) mice showed severe fragmentation of sleep/wake states.

Conclusion: Our observations showed that regulation of the sleep/wake states is completely achieved by OX(2)R-expressing neurones without involving H(1)R-mediated pathways. The maintenance of basal physiological sleep/wake states is fully achieved without both H(1) and OX(1) receptors. Downstream pathways of OX(2)R other than the histaminergic system might play an important role in the maintenance of sleep/wake states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / metabolism*
  • Brain / physiology
  • Electroencephalography
  • Electromyography
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / physiology
  • Orexin Receptors
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / metabolism*
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Histamine H1 / deficiency
  • Receptors, Histamine H1 / metabolism*
  • Receptors, Neuropeptide / deficiency
  • Receptors, Neuropeptide / metabolism
  • Sleep / physiology*
  • Sleep, REM / physiology
  • Wakefulness / physiology*


  • Antigens, Surface
  • Cd200r1 protein, mouse
  • Orexin Receptors
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine H1
  • Receptors, Neuropeptide