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 (OX₂R). 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 (OX₁R) mediated pathways, we analysed the phenotype of Histamine‐1 receptor (H₁R) and OX₁R double‐deficient (H₁R^−/−;OX₁R^−/−) mice. These mice lack OX₁R‐mediated pathways in addition to deficiency of H₁R, which is thought to be the most important system in downstream of OX₂R.

Methods:  We used H₁R deficient (H₁R^−/−) mice, H₁R^−/−;OX₁R^−/− mice, OX₁R and OX₂R double‐deficient (OX₁R^−/−;OX₂R^−/−) 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 H₁R^−/− mice, consistent with previous studies. H₁R^−/−;OX₁R^−/− mice also showed a sleep/wake phenotype comparable to that of wild type mice, while OX₁R^−/−; OX₂R^−/− mice showed severe fragmentation of sleep/wake states.

Conclusion:  Our observations showed that regulation of the sleep/wake states is completely achieved by OX₂R‐expressing neurones without involving H₁R‐mediated pathways. The maintenance of basal physiological sleep/wake states is fully achieved without both H₁ and OX₁ receptors. Downstream pathways of OX₂R other than the histaminergic system might play an important role in the maintenance of sleep/wake states.