Amisulpride alleviates chronic mild stress-induced cognitive deficits: Role of prefrontal cortex microglia and Wnt/β-catenin pathway.

Accumulating evidence indicates the role of microglial activation and sustained neuroinflammation in the pathogenesis of cognitive dysfunction, a common feature associated with depressive disorders. It also indicates the role of Wnt/β-catenin pathway in regulation of microglia-mediated neuroinflammation. Amisulpride exhibits antidepressant and pro-cognitive activities in several clinical and experimental studies. Hitherto, the direct effects of amisulpride on Wnt/β-catenin signaling and microglial activity have not been thoroughly studied. This study aimed at investigating the effects of chronic amisulpride treatment on Wnt/β-catenin signaling and pro-inflammatory microglial activation and its role in alleviation of depressive-like behavior and cognitive deficits elicited by unpredictable chronic mild stress (UCMS). The effects of amisulpride (3 mg/kg/day) were investigated on behavioral/cognitive deficits, expression of Wnt/β-catenin pathway and microglial activation in the prefrontal cortex (PFC) of UCMS-exposed male Wistar rats. UCMS induced depressive-like behavior with impairment of performance in novel object recognition test and attentional set-shifting task. These behavioral deficits were associated with decreased total β-catenin and increased pro-inflammatory microglial activation. Amisulpride improved UCMS-induced behavioral/cognitive deficits, ameliorated Wnt/β-catenin signaling dysregulation and pro-inflammatory microglial activation. This work highlights the antidepressant and pro-cognitive effects of amisulpride in UCMS-exposed rats that could be mediated by modulation of Wnt/β-catenin pathway activity and amelioration of pro-inflammatory microglial activation in the prefrontal cortex. This could provide new insights into the putative mechanisms behind the antidepressant and pro-cognitive effects exerted by amisulpride.