title: Anxiolytic effects of yokukansan, a traditional Japanese medicine, via serotonin 5-HT1A receptors on anxiety-related behaviors in rats experienced aversive stress.
abstract: BACKGROUND
  Yokukansan, a traditional Japanese medicine (Kampo), has been reported in the treatment of behavioral and psychological symptoms of dementia (BPSD) such as aggression, anxiety and depression in patients with Alzheimer's disease and other forms of senile dementia.
  
  
  OBJECTIVE
  In the present study, we investigated the anxiolytic effects of yokukansan on anxiety-related behaviors in rats that have experienced aversive stress.
  
  
  METHODS
  We used male Wistar/ST rats which received an electrical footshock as aversive stress. Yokukansan at a dose of 1.0 g/kg was administered orally once a day for 14 or 16 day before behavioral tests. To evaluate the anxiolytic effects, we used the contextual fear conditioning (CFC) test and elevated plus-maze (EPM) test. And we also investigated effects of yokukansan on locomotor activity in the Open-field (OF) test and on the change in plasma corticosterone after CFC stress, in rats that had experienced footshock stress.
  
  
  RESULTS
  In the CFC test, rats that had experienced footshock showed significant freezing behavior on re-exposure to the box 14 day after footshock stress. Yokukansan significantly suppressed freezing behavior in the CFC test. In the EPM test on the 16th day after the CFC test, yokukansan significantly increased the time spent in open arms after footshock stress compared to control rats. However, repeated administration of yokukansan on the 14th day did not affect the decrease in locomotor activity and the increase in plasma corticosterone by re-exposure to the box 14 day after footshock stress in the OF test and determination of serum corticosterone, respectively. These anxiolytic effects by yokukansan were antagonized by WAY-100635, a selective 5-HT(1A) receptor antagonist, in the CFC test, but not the EPM test. Furthermore, 5-HT(1A) receptor agonist buspirone significantly suppressed freezing behavior in the CFC test; however, buspirone induced no change in the time spent in open arms in the EPM test.
  
  
  CONCLUSIONS
  These findings suggested that yokukansan has anxiolytic effects on anxiety-like behaviors induced by both innate fear and memory-dependent fear. In particular, yokukansan produced anxiolytic effects via 5-HT(1A) receptors in memory-dependent fear induced by aversive stress. Furthermore, yokukansan could be useful as one of the therapeutic drugs for the treatment of anxiety disorders and various mental disorders that have comorbid anxiety.
authors: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. taku@kyudai.jp
authors: Taku
authors: T
authors: Yamaguchi
authors: Aki
authors: A
authors: Tsujimatsu
authors: Haruko
authors: H
authors: Kumamoto
authors: Takeshi
authors: T
authors: Izumi
authors: Yu
authors: Y
authors: Ohmura
authors: Takayuki
authors: T
authors: Yoshida
authors: Mitsuhiro
authors: M
authors: Yoshioka
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D002065:Buspirone / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D005239:Fear / Q000187:drug effects; D007564:Japan; D008297:Male; D008518:Medicine, East Asian Traditional; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D013312:Stress, Physiological
chemical_list: D014151:Anti-Anxiety Agents; D004365:Drugs, Chinese Herbal; D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; C524644:Yi-Gan San; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D002065:Buspirone; D003345:Corticosterone