Influences of yokukansankachimpihange on aggressive behavior of zinc-deficient mice and actions of the ingredients on excessive neural exocytosis in the hippocampus of zinc-deficient rats

Exp Anim. 2016 Nov 1;65(4):353-361. doi: 10.1538/expanim.16-0028. Epub 2016 May 30.


We examined the effect of Yokukansankachimpihange (YKSCH), a form of Yokukansan containing parts of two herbaceous plants, Citrus Unshiu Peel (Chimpi) and Pinellia Tuber (Hange), on aggressive behavior of mice housed individually. Mice were fed a zinc-deficient diet for 2 weeks. In a resident-intruder test, the cumulative duration of aggressive behavior was decreased in zinc-deficient mice administrated drinking water containing YKSCH (approximately 300 mg/kg body weight/day) for 2 weeks. We tested mice for geissoschizine methyl ether (GM), which is contained in Uncaria Hook, and 18β-glycyrrhetinic acid (GA), a major metabolite of glycyrrhizin contained in Glycyrrhiza, which were contained in YKS and YKSCH. In hippocampal slices from zinc-deficient rats, excess exocytosis at mossy fiber boutons induced with 60 mM KCl was attenuated in the presence of GA (100-500 µM) or GM (100 µM). The intracellular Ca2+ level, which showed an increase induced by 60 mM KCl, was also attenuated in the presence of GA (100-500 µM) or GM (100 µM). These results suggest that GA and GM ameliorate excess glutamate release from mossy fiber boutons by suppressing the increase in intracellular Ca2+ signaling. These ameliorative actions may contribute to decreasing the aggressiveness of mice individually housed under zinc deficiency, potentially by suppressing excess glutamatergic neuron activity in the hippocampus.

MeSH terms

  • Aggression / drug effects*
  • Animals
  • Drugs, Chinese Herbal / pharmacology*
  • Exocytosis / drug effects*
  • Glycyrrhetinic Acid / analogs & derivatives
  • Glycyrrhetinic Acid / metabolism
  • Hippocampus / chemistry
  • Hippocampus / drug effects*
  • Indole Alkaloids / metabolism
  • Male
  • Mice
  • Rats
  • Rats, Wistar
  • Zinc / deficiency*


  • Drugs, Chinese Herbal
  • Indole Alkaloids
  • geissoschizine methylether
  • yokukansankachimpihange
  • 18alpha-glycyrrhetinic acid
  • Zinc
  • Glycyrrhetinic Acid