Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
J Ethnopharmacol. 2015 May 26;166:23-30. doi: 10.1016/j.jep.2015.02.046. Epub 2015 Feb 28.
Yokukansan, a traditional Japanese (Kampo) medicine, has recently been used to treat the behavioral and psychological symptoms of dementia (BPSD), including aggressiveness, excitability, and hallucination. The present study was designed to investigate the mechanisms underlying the ameliorative effects of yokukansan on BPSD using animals exhibiting hallucination-like behaviors. For this purpose, we initially examined whether chronic isolation stress increases the frequency of hallucination in response to a psychedelic drug. Using this animal model, we next examined the effects of yokukansan on drug-induced hallucination-like behaviors. Finally, we examined the density and mRNA levels of serotonin 2A (5-HT2A) receptors.
Male mice were subjected to isolation stress for six weeks. Yokukansan was incorporated into food pellets, and administered to the mice for six weeks. In some experiments, yokukansan and each of seven constituent herbs were administered orally to the mice for the last two weeks during the six-week period of isolation stress. A 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI, 2.5mg/kg), was injected into the mice, and head-twitch behaviors were quantified. The binding sites of 5-HT2A receptors on the plasma membrane of the prefrontal cortex (PFC) were assessed by a receptor-binding assay using tritium-labeled ketanserin, and the density and affinity were calculated from a Scatchard plot. The level of mRNAs was measured by PCR analyses.
Isolation stress enhanced the frequency of the DOI-induced head-twitch response, and yokukansan treatment by feeding significantly reduced this enhancement. Isolation stress significantly increased the 5-HT2A receptor density in the PFC, and yokukansan treatment by feeding as well as administration significantly down-regulated this increase. Isolation stress and yokukansan did not affect the affinity. Among seven constituent herbs, Bupleurum Root, Uncaria Hook, Japanese Angelica Root, and Glycyrrhiza down-regulated the increase, but statistically not significant, in which their efficacies were over 50% relative to yokukansan. Neither isolation stress nor yokukansan affected mRNA levels of 5-HT2A receptors.
Yokukansan attenuated drug-induced hallucination-like behaviors in isolated mice, which is suggested to be mediated by 5-HT2A receptor down-regulation in the PFC. This mechanism may underlie the ameliorative effects of yokukansan on hallucination.
Yokukansan 是一种传统的日本（汉方）药物，最近已被用于治疗痴呆症（BPSD）的行为和心理症状，包括攻击性、兴奋性和幻觉。本研究旨在使用表现出幻觉样行为的动物来研究 Yokukansan 对 BPSD 的改善作用的机制。为此，我们首先检查了慢性隔离应激是否会增加对致幻药物的幻觉频率。使用这种动物模型，我们接下来检查了 Yokukansan 对药物诱导的幻觉样行为的影响。最后，我们检查了 5-羟色胺 2A（5-HT2A）受体的密度和 mRNA 水平。
雄性小鼠接受六周的隔离应激。Yokukansan 被掺入食物丸中，并在六周内给予小鼠。在一些实验中，在六周的隔离应激期间，Yokukansan 和七种组成草药中的每一种都通过口服给予小鼠最后两周。将 5-HT2A 受体激动剂 2,5-二甲氧基-4-碘苯丙胺（DOI，2.5mg/kg）注射到小鼠中，并定量头抽搐行为。通过使用氚标记酮色林进行的受体结合测定评估前额叶皮质（PFC）质膜上的 5-HT2A 受体结合位点，并从 Scatchard 图计算密度和亲和力。通过 PCR 分析测量 mRNA 水平。
隔离应激增强了 DOI 诱导的头抽搐反应的频率，而通过喂养给予 Yokukansan 治疗显著降低了这种增强。隔离应激显著增加了 PFC 中的 5-HT2A 受体密度，而通过喂养给予 Yokukansan 治疗以及通过给药也显著下调了这种增加。隔离应激和 Yokukansan 不影响亲和力。在七种组成草药中，柴胡、钩藤、当归根和甘草下调了增加，但统计学上没有显着性，其功效相对于 Yokukansan 超过 50%。隔离应激和 Yokukansan 均不影响 5-HT2A 受体的 mRNA 水平。
Yokukansan 减轻了孤立小鼠的药物诱导的幻觉样行为，这被认为是通过 PFC 中 5-HT2A 受体下调介导的。这种机制可能是 Yokukansan 对幻觉改善作用的基础。
