title: Kososan, a standardized traditional Japanese herbal medicine, reverses sleep disturbance in socially isolated mice via GABAA-benzodiazepine receptor complex activation.
abstract: OBJECTIVE
  Kososan (KSS), a traditional Japanese medicine with a distinct aroma, is clinically used to treat affective disorders but its antidepressant-like effect has not been thoroughly investigated. In this study, we investigated the effects of inhaled and orally administered KSS on sleep disturbances in socially isolated mice.
  
  
  METHODS
  Four-weeks-old male ddy mice were housed either in social isolation or in groups for 4-6 weeks before the experiment. KSS was orally administered (0.5 or 1.0 g/kg) or inhaled (0.5, 1.0, or 2.5 g/0.125 m(3)) 60 min before pentobarbital administration. Stress levels in mice were evaluated by the duration of pentobarbital-induced sleeping time.
  
  
  RESULTS
  Sleeping time was shorter in socially-isolated mice than in group-housed mice. Oral and inhaled KSS prolonged sleeping time in stressed mice, but had no effect on sleeping time of group-housed mice. Prolonged sleeping time after oral KSS was significantly inhibited (p<0.05) by bicuculline (3 mg/kg, i.p.), a GABAA antagonist, but not by flumazenil (3 mg/kg, i.p.), a selective benzodiazepine antagonist. Prolonged sleeping time after KSS inhalation was significantly inhibited (p<0.05) by flumazenil but not by bicuculline.
  
  
  CONCLUSIONS
  Our findings suggest that KSS activates GABAA-benzodiazepine receptor complex and reverses shortened pentobarbital-induced sleep caused by social isolation.
authors.affiliation: Department of Hospital Administration, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: naoh@juntendo.ac.jp.
authors.forename: Naoko
authors.initials: N
authors.lastname: Koga
authors.affiliation: Center for Advanced Kampo Medicine and Clinical Research, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Tsumura Research Laboratory, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Center for Advanced Kampo Medicine and Clinical Research, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Keiko K
authors.initials: KK
authors.lastname: Lee
authors.affiliation: Department of Hospital Administration, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Center for Advanced Kampo Medicine and Clinical Research, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D058785:GABA-A Receptor Agonists / Q000627:therapeutic use*; D058787:GABA-A Receptor Antagonists; D008297:Male; D008518:Medicine, East Asian Traditional; D051379:Mice; D010634:Phenobarbital; D008517:Phytotherapy / Q000379:methods*; D012890:Sleep / Q000187:drug effects; D012893:Sleep Wake Disorders / Q000188:drug therapy*; D012934:Social Isolation
chemical_list: D004365:Drugs, Chinese Herbal; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C400346:koso-san; D010634:Phenobarbital
keywords: GABA(A)-benzodiazepine receptor; Kososan; Sleep; Social isolation stress