Effect of agomelatine on memory deficits and hippocampal gene expression induced by chronic social defeat stress in mice

Abstract

Chronic stress is known to induce not only anxiety and depressive-like phenotypes in mice but also cognitive impairments, for which the action of classical antidepressant compounds remains unsatisfactory. In this context, we investigated the effects of chronic social defeat stress (CSDS) on anxiety-, social- and cognitive-related behaviors, as well as hippocampal Bdnf, synaptic plasticity markers (PSD-95, Synaptophysin, Spinophilin, Synapsin I and MAP-2), and epigenetic modifying enzymes (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) gene expression in C57BL/6J mice. CSDS for 10 days provoked long-lasting anxious-like phenotype in the open field and episodic memory deficits in the novel object recognition test. While total Bdnf mRNA level was unchanged, Bdnf exon IV, MAP-2, HDAC2, HDAC6 and MLL3 gene expression was significantly decreased in the CSDS mouse hippocampus. In CSDS mice treated 3 weeks with 50 mg/kg/d agomelatine, an antidepressant with melatonergic receptor agonist and 5-HT2C receptor antagonist properties, the anxious-like phenotype was not reversed, but the treatment successfully prevented the cognitive impairments and hippocampal gene expression modifications. Altogether, these data evidenced that, in mice, agomelatine was effective in alleviating stress-induced altered cognitive functions, possibly through a mechanism involving BDNF signaling, synaptic plasticity and epigenetic remodeling.

Association of lymphoid tissue‐resident commensal bacteria in mice with depressive‐like behaviors induced by chronic social defeat stress

“…Two‐stage SIT were employed to divide the CSDS into SUS and RES groups, as described in the literature 27 . The test consisted in two consecutive 2.5 minutes sessions, under low light conditions.…”

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

“…For example, short‐ and long‐term reductions in the histone deacetylase (HDAC) levels (specifically HDAC 2), in the NAc and hippocampus have been observed in defeated mice. On the contrary, increases in histone acetyltransferase (HAT) activity have been described in the same structure (Covington et al., ; Martin et al., ; Montagud‐Romero, Montesinos et al., ). In addition, a downregulation of HDAC6 (in raphe neurons and in the hippocampus) and HDAC5 (in NAc and PFC) has been reported a few weeks after the last SD, changes that were reverted by the HDAC inhibitor imipramine (Espallergues et al., ; Fuchikami et al., ; Martin et al., ; Renthal et al., ).…”

“…On the contrary, increases in histone acetyltransferase (HAT) activity have been described in the same structure (Covington et al., ; Martin et al., ; Montagud‐Romero, Montesinos et al., ). In addition, a downregulation of HDAC6 (in raphe neurons and in the hippocampus) and HDAC5 (in NAc and PFC) has been reported a few weeks after the last SD, changes that were reverted by the HDAC inhibitor imipramine (Espallergues et al., ; Fuchikami et al., ; Martin et al., ; Renthal et al., ). However, in a long‐term evaluation, the level of HDAC6 continued to be significantly elevated more than 1 month after the last agonistic encounter (Jianhua, Wei, Xiaomei, & Shao‐Hui, ), with an increase in the mRNA expression of different classes of HDAC enzymes in the PFC (Erburu et al., ).…”

Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats

“…Kopschina Feltes and colleagues observed in Wistar rats that the effect of a similar RSD protocol was observed 1 week after RSD but was resolved after 90 days (Kopschina Feltes et al 2019). Martin and colleagues used a modified 10-day RSD protocol on C57BL mice and found that the transient effect of RSD had normalized after 18 days (Martin et al 2017). Gottschalk et al found that a 5-day RSD protocol has a significant effect on anhedonia 3 days after the last RSD exposure (Gottschalk et al 2018).…”