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

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

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Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.



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.


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.


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.


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.

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