title: Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABA(A)  receptor in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Honokiol was administered i.p. at 20:00 h in mice. Flumazenil, an antagonist at the benzodiazepine site of the GABA(A) 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.
  
  
  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.
  
  
  CONCLUSIONS
  Honokiol promoted NREM sleep by modulating the benzodiazepine site of the GABA(A) receptor, suggesting potential applications in the treatment of insomnia, especially for patients who experience difficulty in falling and staying asleep.
authors.affiliation: Department of Pharmacology, Shanghai Medical College of Fudan University, China. quweimin@fudan.edu.cn
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Qu
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yue
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Kun
authors.initials: K
authors.lastname: Fan
authors.forename: Chang-Rui
authors.initials: CR
authors.lastname: Chen
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Hou
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Huang
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004576:Electromyography; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression; D007274:Injections, Intraperitoneal; D017705:Lignans / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012890:Sleep / Q000187:drug effects*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy / Q000503:physiopathology; D012895:Sleep, REM / Q000187:drug effects; D013997:Time Factors; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D005442:Flumazenil; D018757:GABA Modulators; D017705:Lignans; D016760:Proto-Oncogene Proteins c-fos; D011963:Receptors, GABA-A; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols