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

Objectives: 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. Methods: Behavioural responses, and brain molecular and morphological changes were evaluated after each treatment procedure in PSS-exposed and unexposed rats. Results: 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. Conclusions: These findings suggest that agomelatine may be a potential agent in the acute aftermath of traumatic stress exposure.