Yokukansan Increases 5-HT1A Receptors in the Prefrontal Cortex and Enhances 5-HT1A Receptor Agonist-Induced Behavioral Responses in Socially Isolated Mice.

Toshiyuki Ueki,Tomohisa Hattori,Yoshio Kase,Kazushige Mizoguchi,Yasushi Ikarashi,Akinori Nishi,Takuji Yamaguchi

doi:10.1155/2015/726471

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.

Highlights

The serotonin (5-hydroxytryptamine, 5-HT) system is widely distributed throughout the brain [1] and is one of the main targets for the pharmacologic treatment of depression, mania, schizophrenia, autism, obsessive-compulsive disorder, and anxiety disorders [2]
We previously demonstrated that repeated yokukansan administration ameliorated aggressive behaviors in rats injected with the 5-HT neurotoxin para-chloroamphetamine [18] and in mice subjected to isolation stress [19]
To explore the mechanisms underlying the anxiolytic effects of repeated yokukansan administration in isolationstressed mice, we focused on the 5-HT1A receptors in the prefrontal cortex (PFC), which are involved in emotional behavior [22]

Summary

Introduction

The serotonin (5-hydroxytryptamine, 5-HT) system is widely distributed throughout the brain [1] and is one of the main targets for the pharmacologic treatment of depression, mania, schizophrenia, autism, obsessive-compulsive disorder, and anxiety disorders [2]. Stimulation of 5-HT1A receptors mediates anxiolytic and antiaggressive effects [4, 5]. These 5-HT1A receptors are located both pre- and postsynaptically. Presynaptic 5-HT1A receptors are present on serotonergic neurons as somatodendritic autoreceptors in the dorsal and medial raphe nuclei, whereas postsynaptic 5-HT1A receptors are found at high density in the limbic regions and in the frontal and entorhinal cortices [6, 7]. A serotonergic deficit in the dorsal raphe nuclei and reduced 5-HT1A receptor density in the raphe nuclei and hippocampus were reported in patients with Alzheimer’s disease (AD) [8,9,10,11]. 5-HT1A receptor agonists have been used successfully for the treatment of anxiety disorders in humans [13]

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