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

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. Conclusions: 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 H-1 and OX1 receptors. Downstream pathways of OX2R other than the histaminergic system might play an important role in the maintenance of sleep/wake states.