Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABAA receptor in mice

Authors

  • Wei-Min Qu,

    Corresponding author
    1. Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai, China
    2. Institutes of Brain Science, Shanghai Medical College of Fudan University, Shanghai, China
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    • W-MQ and X-FY equally contributed to this work.

  • Xiao-Fang Yue,

    1. Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai, China
    2. State Key Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, Shanghai, China
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    • W-MQ and X-FY equally contributed to this work.

  • Yu Sun,

    1. Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai, China
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  • Kun Fan,

    1. Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai, China
    2. Department of Neuroscience, Anatomy, Histology and Embryology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
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  • Chang-Rui Chen,

    1. Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai, China
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  • Yi-Ping Hou,

    1. Department of Neuroscience, Anatomy, Histology and Embryology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
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  • Yoshihiro Urade,

    1. Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka, Japan
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  • Zhi-Li Huang

    1. Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai, China
    2. Institutes of Brain Science, Shanghai Medical College of Fudan University, Shanghai, China
    3. State Key Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, Shanghai, China
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Wei-Min Qu or Zhi-Li Huang, Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai 200032, China. E-mail: quweimin@fudan.edu.cn or huangzljp@yahoo.com.cn

Abstract

BACKGROUND AND PURPOSE Decoctions of the Chinese herb houpu contain honokiol and are used to treat a variety of mental disorders, including depression. Depression commonly presents alongside sleep disorders and sleep disturbances, which appear to be a major risk factor for depression. Here, we have evaluated the somnogenic effect of honokiol and the mechanisms involved.

EXPERIMENTAL APPROACH Honokiol was administered i.p. at 20:00 h in mice. Flumazenil, an antagonist at the benzodiazepine site of the GABAA receptor, was administered i.p. 15 min before honokiol. The effects of honokiol were measured by EEG and electromyogram (EMG), c-Fos expression and in vitro electrophysiology.

KEY RESULTS Honokiol (10 and 20 mg·kg−1) significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep and increased the amount of NREM sleep. Honokiol increased the number of state transitions from wakefulness to NREM sleep and, subsequently, from NREM sleep to wakefulness. However, honokiol had no effect on either the amount of REM sleep or EEG power density of both NREM and REM sleep. Honokiol increased c-Fos expression in ventrolateral preoptic area (VLPO) neurons, as examined by immunostaining, and excited sleep-promoting neurons in the VLPO by whole-cell patch clamping in the brain slice. Pretreatment with flumazenil abolished the somnogenic effects and activation of the VLPO neurons by honokiol.

CONCLUSION AND IMPLICATIONS Honokiol promoted NREM sleep by modulating the benzodiazepine site of the GABAA receptor, suggesting potential applications in the treatment of insomnia, especially for patients who experience difficulty in falling and staying asleep.

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