Yueju pill, a classic Chinese Medicine formulated, was recently found to produce rapid antidepressant-like effects in a PKA-CREB signaling-dependent manner. In our study, we found that the Yueju pill induced a remarkable increase in PACAP. The intracerebroventricular injection of PACAP agonist induced a rapid antidepressant-like effect; conversely, the intrahippocampal infusion of a PACAP antagonist reversed the antidepressant response of the Yueju pill. Mice with hippocampal PACAP knockdown via viral-mediated RNAi displayed depression-like behavior. PACAP knockdown also blunted the antidepressant effect of the Yueju pill. PACAP knockdown resulted in down-regulated CREB and expression of the synaptic protein PSD95 at both baselines and after administration of the Yueju pill. However, administration of the Yueju pill in the knockdown mice promoted PACAP and PKA levels. Chronically stressed mice showed deficient hippocampal PACAP-PKA-CREB signaling and depression-like behavior, which were reversed by a single dose of the Yueju pill. In this study, we demonstrated that the up-regulation of PACAP induced activating of PKA-CREB signaling would play a part in the rapid antidepressant-like effects of the Yueju pill. We also identified iridoids fraction of Gardenia jasminoides Ellis (GJ-IF), a vital component of the Yueju pill, was identified to recapitulate rapid antidepressant-like behavior through increased hippocampal PACAP expression of the Yueju pill. The promotion of hippocampal PACAP may collectively represent a novel mechanism of rapid antidepressant-like effect.

越橘丸是一种经典的中药配方，最近发现它能以 PKA-CREB ​​信号依赖的方式产生快速的抗抑郁样作用。在我们的研究中，我们发现越菊丸可显着增加 PACAP。脑室内注射 PACAP 激动剂可诱导快速的抗抑郁样作用；相反，海马内注射 PACAP 拮抗剂可逆转越橘丸的抗抑郁反应。通过病毒介导的 RNAi 敲除海马 PACAP 的小鼠表现出抑郁样行为。PACAP 敲除也削弱了越剧丸的抗抑郁作用。PACAP 敲低导致基线和服用越橘丸后 CREB ​​和突触蛋白 PSD95 的表达下调。然而，在基因敲低小鼠体内服用越鞠丸可提高 PACAP 和 PKA 水平。长期承受压力的小鼠表现出海马 PACAP-PKA-CREB ​​信号传导缺陷和抑郁样行为，单剂量越橘丸可以逆转这种行为。在这项研究中，我们证明了 PACAP 诱导的 PKA-CREB ​​信号激活的上调在越橘丸的快速抗抑郁样作用中发挥了一定作用。我们还鉴定了越橘丸的重要成分栀子中的环烯醚萜类成分（GJ-IF），其通过增加越橘丸的海马 PACAP 表达来重现快速抗抑郁样行为。海马 PACAP 的促进可能共同代表了一种快速抗抑郁样作用的新机制。