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-HT_1A), α5 GABA_A 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-HT_1A and α5 GABA_A 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-HT_1A, Hippocampal 5-HTT were reduced, while PFC 5-HTT, Hippocampal α5 GABA_A 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.

Keywords:

• Combined stress
• depression
• cognitive deficit
• α5 GABA receptors
• 5-HT_1A
• 5-HTT

Acknowledgements

We would like to thank the Biomedical Resource Centre for their assistance with providing animals and helping with this study, the College of Health Sciences, University of KwaZulu-Natal, and Dr. Idu Azogu-Sepe (Serengeti-Park Hodenhagen GmbH, Germany) for her critical comments on the writing of this manuscript.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Dr. Gwladys Temkou Ngoupaye and Ms Makwena Mokgokong. The first draft of the manuscript was written by Dr. Gwladys Temkou Ngoupaye and all authors commented on previous versions of the manuscript. Ms Thobeka Madlala assisted on behavioural and neurochemical tests. Dr. Gwladys Temkou Ngoupaye, Ms Makwena Mokgokong, Ms Thobeka Madlala, and Prof Musa Vuyisile Mabandla read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Funding was provided by College of Heath Science, University of Kwazulu-Natal.