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

Authors

  • M. Hondo,

    1.  Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
    2.  Department of Pharmacology, Institute of Basic Medical Science, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • K. Nagai,

    1.  Department of Pharmacology, Institute of Basic Medical Science, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • K. Ohno,

    1.  Department of Pharmacology, Institute of Basic Medical Science, University of Tsukuba, Tsukuba, Ibaraki, Japan
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  • Y. Kisanuki,

    1.  Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
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  • J. T. Willie,

    1.  Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
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  • T. Watanabe,

    1.  Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
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  • M. Yanagisawa,

    1.  Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
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  • T. Sakurai

    1.  Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
    2.  Department of Pharmacology, Institute of Basic Medical Science, University of Tsukuba, Tsukuba, Ibaraki, Japan
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T. Sakurai, Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan. E-mail: tsakurai@med.kanazawa-u.ac.jp

Abstract

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.

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