Yokukansan Increases 5-HT_1AReceptors in the Prefrontal Cortex and Enhances 5-HT_1AReceptor Agonist-Induced Behavioral Responses in Socially Isolated Mice

Abstract

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-HT1A) 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-HT1A 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-HT1A receptors were analyzed by a receptor-binding assay. Levels of 5-HT1A receptor protein and mRNA were also measured. Furthermore, (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT; a 5-HT1A receptor agonist) was injected intraperitoneally, and rearing behavior was examined. Social isolation stress alone did not affect 5-HT1A 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-HT1A receptors in the PFC of socially isolated mice and enhances their function, which might underlie its anxiolytic effects.

Serotonin Receptor Binding Characteristics of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook

“…These multiple potential actions include serotonergic, glutamatergic, cholinergic, dopaminergic, adrenergic, and GABAnergic neurotransmissions as well as neuroprotection, anti-stress effect, promotion of neuroplasticity, and anti-inflammatory effect [ 63 ]. Among these neuropsychopharmacological effects, YKS, Uncaria hook, or GM has been demonstrated to enhance 5-HT 1A receptor agonist-induced decrease in rearing behavior, concomitant with up-regulation of prefrontal 5-HT 1A receptors in mice [ 64 ], or to ameliorate aggressiveness and decreased sociability [ 10 ] in isolation-stressed mice, anxiety in fear-conditioned rats [ 65 , 66 ] through their agonistic effect to 5-HT 1A receptors [ 10 ], 5-hydroxy-L-tryptophan-induced head-twitch response which are related to 5-HT 2A and 5-HT 2C receptor antagonisms [ 18 ], and 5-HT 2A receptor agonist-induced head-twitch response by down-regulating 5-HT 2A receptors in the prefrontal cortex [ 67 , 68 ]. In addition, these substances act on other neurotransmitter systems to improve symptoms, e.g., adrenergic/dopaminergic agonist-induced decrease in locomotion [ 18 , 69 ], morphine-induced tolerance/physical dependency in mice by blocking α 2A -adrenoceptors [ 70 ], norepinephrine-induced contraction of rat aorta [ 22 ], and glutamate-induced neuronal death [ 71 ].…”

Characteristics and course of patients treated with Kampo Medicine in the Department of General Medicine

“…Arai et al reported that Kampo prescription to manage psychological symptoms such as yokukansan, kamishoyosan, and kososan was used for psychopathological patients suffering from chronic pain in a multidisciplinary pain center . For example, yokukansan can influence several neurotransmitters and receptors such as serotonergic and glutamate receptors, which can provide a significant degree of control over the entire body. KM can contribute to controlling anxiety with somatic and psychological symptoms, even when the patient's condition remains unidentified.…”

Pharmacological effects of yokukansan on behavioral and psychological symptoms of dementia

“…Therefore, the partial agonist effect of YKS on 5‐HT 1A receptors may explain the positive effects of YKS on aggressive and anxiety‐like behaviors. Finally, YKS has been shown to increase expression of 5‐HT 1A receptors in the prefrontal cortex of socially isolated mice .…”