Yokukansan Increases 5-HT 1A Receptors in the Prefrontal Cortex and Enhances 5-HT 1A Receptor Agonist-Induced Behavioral Responses in Socially Isolated Mice

The traditional Japanese medicine yokukansan has an anxiolytic effect, which occurs after repeated administration. In this study, to investigate the underlying mechanisms, we examined the effects of repeated yokukansan administration on serotonin 1A (5-H T 1 A ) receptor density and affinity and its expression at both mRNA and protein levels in the prefrontal cortex (PFC) of socially isolated mice. Moreover, we examined the effects of yokukansan on a 5-H T 1 A receptor-mediated behavioral response. Male mice were subjected to social isolation stress for 6 weeks and simultaneously treated with yokukansan. Thereafter, the density and affinity of 5-H T 1 A receptors were analyzed by a receptor-binding assay. Levels of 5-H T 1 A receptor protein and mRNA were also measured. Furthermore, (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT; a 5-H T 1 A receptor agonist) was injected intraperitoneally, and rearing behavior was examined. Social isolation stress alone did not affect 5-H T 1 A receptor density or affinity. However, yokukansan significantly increased receptor density and decreased affinity concomitant with unchanged protein and mRNA levels. Yokukansan also enhanced the 8-OH-DPAT-induced decrease in rearing behavior. These results suggest that yokukansan increases 5-H T 1 A receptors in the PFC of socially isolated mice and enhances their function, which might underlie its anxiolytic effects.