Repeated treatment with yokukansan, a traditional Japanese herbal medicine, suppresses the increase in the conditioned fear response induced by sigma1 (σ1) receptor agonist in mice

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  • Ohno, Rintaro
  • Miyagishi, Hiroko
  • TSUJI, Minoru
  • Saito, Atsumi
  • Miyagawa, Kazuya
  • Kurokawa, Kazuhiro
  • Takeda, Hiroshi

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Yokukansan is a traditional Japanese herbal medicine that has been reported to improve stress-related psychiatric symptoms such as anxiety. Recently, we found that repeated treatment with yokukansan synergistically enhances the anxiolytic-like effect of fluvoxamine, an antidepressant that preferentially activates brain 5-HT neurotransmission, in the contextual fear conditioning paradigm in mice. A growing body of evidence indicates that fluvoxamine has affinity for and acts as an agonist for sigma1 (σ1) receptor. Therefore, the present study examined whether σ1 receptor plays a role in the enhancing effect of yokukansan on the anxiolytic-like effect of fluvoxamine in mice, as estimated by the contextual fear conditioning paradigm. A single administration of SA4503 (1 mg/kg, i.p.), a selective σ1 receptor agonist, before the test session significantly enhanced freezing behavior in mice. In a combination study, the enhancing effect of SA4503 (1 mg/kg,i.p.) on freezing behavior was significantly attenuated in mice that had been repeatedly pretreated with yokukansan (1 g/kg, p.o.) once a day for 6 days after the conditioning session. These results indicate that chronic treatment with yokukansan downregulates σ1 receptor-mediated signaling, which positively modulates the conditioned fear response, and this may be related, at least in part, to the mechanism of the synergistic interaction between yokukansan and fluvoxamine regarding anxiety.

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