Effects of agomelatine on behaviour, circadian expression of period 1 and period 2 clock genes and neuroplastic markers in the predator scent stress rat model of PTSD

<b>Objectives:</b> The therapeutic value of the antidepressant agomelatine in the aftermath of traumatic experience and early post-reminder has been questioned. Herein, agomelatine, its vehicle or melatonin agonist were administered either acutely 1 h post-stressor or repeatedly (7 days) after early post-reminder in a post-traumatic stress rat model (PSS) using the scent of predator urine. <b>Methods:</b> Behavioural responses, and brain molecular and morphological changes were evaluated after each treatment procedure in PSS-exposed and unexposed rats. <b>Results:</b> When administered immediately after PSS, agomelatine induced a significant reduction of anxiety-like behaviour as assessed in the elevated-plus-maze and acoustic startle response at 8 days post-administration. Concomitantly, agomelatine significantly decreased Per1/Per2 expression in the CA1/CA3 areas, suprachiasmatic nucleus and basolateral amygdala, thereby partially restoring genes expression overregulated by PSS. Agomelatine further significantly increased cell growth and facilitated dendritic growth and arbour in dentate gyrus (DG) granule and apical CA1 cells and upregulated brain-derived neurotrophic factor protein in the DG and cortex III versus vehicle. When administered early post-reminder over 7 days before testing, agomelatine was ineffective on behavioural responses pattern, molecular and morphological changes induced by PSS. <b>Conclusions:</b> These findings suggest that agomelatine may be a potential agent in the acute aftermath of traumatic stress exposure.

**研究目的**：创伤事件后及早期提醒阶段，抗抑郁药阿戈美拉汀（agomelatine）的治疗价值一直饱受质疑。本研究借助捕食者尿液气味构建创伤后应激（post-traumatic stress, PSS）大鼠模型，分别在应激后1小时单次给予阿戈美拉汀、赋形剂或褪黑素受体激动剂，或在早期提醒后连续给药7天。
**研究方法**：针对暴露于PSS模型及未暴露PSS模型的大鼠，在每一轮给药流程后均评估其行为学反应，以及脑内分子与形态学变化。
**研究结果**：当在PSS造模后即刻给药时，给药后第8天通过高架十字迷宫与听觉惊反射实验评估发现，阿戈美拉汀可显著降低焦虑样行为。与此同时，阿戈美拉汀可显著下调CA1/CA3区、视交叉上核及基底外侧杏仁核的Per1/Per2基因表达，部分恢复PSS诱导的基因表达异常上调。此外，相较于赋形剂组，阿戈美拉汀可显著促进齿状回（dentate gyrus, DG）颗粒细胞及CA1区顶细胞的细胞增殖与树突生长、分支形成，并上调DG及大脑皮层III区的脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）蛋白表达。而若在造模早期提醒后连续给药7天再进行行为测试，阿戈美拉汀对PSS诱导的行为学反应、分子及形态学变化均无显著干预效果。
**研究结论**：上述研究结果表明，阿戈美拉汀或许可作为创伤应激暴露后急性期的潜在治疗药物。