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


CONCLUSIONS
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.
Hondo
M
M
Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
Nagai
K
K
Ohno
K
K
Kisanuki
Y
Y
Willie
J T
JT
Watanabe
T
T
Yanagisawa
M
M
Sakurai
T
T
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D001921:Brain / Q000502:physiology; D004569:Electroencephalography; D004576:Electromyography; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D064446:Orexin Receptors; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000172:deficiency / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000172:deficiency / Q000378:metabolism; D012890:Sleep / Q000502:physiology*; D012895:Sleep, REM / Q000502:physiology; D014851:Wakefulness / Q000502:physiology*
D000954:Antigens, Surface; C501103:Cd200r1 protein, mouse; D064446:Orexin Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011969:Receptors, Histamine H1; D018013:Receptors, Neuropeptide
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