Alteration of the α5 GABA receptor and 5HTT lead to cognitive deficits associated with major depressive-like behaviors in a 14-day combined stress rat model

Abstract

Introduction: Current models used to study the pathophysiology of major depressive disorder (MDD) are laborious and time consuming. This study examined the effect of a 14-day combined stress model (CS; corticosterone injection and restraint stress) in male Sprague-Dawley rats and also compare the effect of CS versus 28-day corticosterone treatment on depressive-like behaviour and cognitive deficits. Materiel and methods: Depressive-like behaviours and cognitive deficits were assessed in the forced swim test (FST), sucrose preference (SPT), Morris water maze (MWM) and novel object recognition (NORT) tests. Real-time PCR and ELISA were respectively used to detect expression of the serotonin transporter (5-HTT), serotonin 1 A receptor (5-HT1A), α5 GABAA receptor, and the concentrations of corticosterone (plasma), GABA and acetylcholinesterase (AChE) in the hippocampus and Prefrontal cortex (PFC). Results CS group showed increased immobility time in the FST, time to reach the MWM platform, higher corticosterone level, and increased expressions of hippocampal and PFC 5-HT1A and α5 GABAA receptors, and AChE compared to their control groups. In contrast, reductions in SPT ratio, discrimination index in NORT, time in target quadrant, and hippocampal 5-HTT expression was noted relative to their control group. Compared to the 28-day corticosterone only group, PFC 5-HT1A, Hippocampal 5-HTT were reduced, while PFC 5-HTT, Hippocampal α5 GABAA receptors, and AChE concentrations were higher in the CS group. Conclusion: Our CS model induced depressive-like behaviour with early cognitive deficits in rats affecting both hippocampus and PFC. The CS model may be useful in investigating new and comprehensive treatment strategies for MDD.