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Development and treatment of cognitive inflexibility in sub-chronic stress–re-stress (SRS) model of PTSD

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Abstract

Background

Cognitive inflexibility is one of the major clinical symptoms of post-traumatic stress disorder (PTSD). Studies have examined the impact of traumatic events on anxiety. However, there were limited reports on the effect of traumatic episodes on cognitive flexibility. Therefore, animal models developing cognitive inflexibility would provide new insight of pathophysiology and pharmacotherapy of PTSD.

Methods

Male Wistar rats were subjected to stress–re-stress (SRS) procedure by restraining them for 2 h followed by foot shock (FS) and halothane exposure on day 2 (D-2). Then, the rats were exposed every week to FS as re-stress cue up to D-32. Donepezil (3 mg/kg; po) and sertraline (10 mg/kg; po) dosing was started from D-8 and continued up to D-32.

Results

SRS exposure caused cognitive inflexibility by producing deficits in intra-dimension (ID) and extra-dimension (ED) set-shifting which was significantly attenuated by donepezil. However, sertraline mitigated only ID shift in SRS-subjected rats. SRS-induced PTSD-like symptoms such as fear response, anxiety-like behaviour and cognitive deficits were attenuated by both donepezil and sertraline. Donepezil did not modulate the SRS-induced hypothalamic–pituitary–adrenal (HPA) axis dysfunction and activation of serotonergic and nor-adrenergic system. Interestingly, exposure of SRS caused a decrease in acetylcholine level and increase in acetylcholine esterase activity in prefrontal cortex (PFC) and hippocampus (HIP) which was only mitigated by donepezil. Donepezil significantly attenuated SRS-induced down-regulation of choline-acetyl transferase and α-7 nicotinic acetylcholine receptor expressions in PFC and HIP.

Conclusion

Cognitive inflexibility is developed in the SRS model along with other PTSD-like symptoms which were attenuated by donepezil.

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Abbreviations

ACh:

Acetylcholine

AChE:

Acetylcholine esterase

ACTH:

Adrenocorticotropic hormone

α-7nAChR:

Alpha-7 nicotinic acetylcholine receptor

AMY:

Amygdala

ChAT:

Choline-acetyl transferase

CORT:

Corticosterone

ED:

Extra-dimensional shift

EPM:

Elevated plus maze

FS:

Foot shock

HIP:

Hippocampus

HPA axis:

Hypothalamic–pituitary–adrenal axis

ID:

Intra-dimensional shift

MANOVA:

Multivariate analysis of variance

NE:

Norepinephrine

PFC:

Prefrontal cortex

PTSD:

Post-traumatic stress disorder

5-HT:

Serotonin

SRS:

Stress–re-stress

SSRIs:

Selective serotonin re-uptake inhibitors

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Acknowledgements

SKP is thankful to teaching assistantship from IIT-(BHU) Varanasi

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Authors and Affiliations

  1. Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, 221005, India

    Santosh Kumar Prajapati & Sairam Krishnamurthy

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  1. Santosh Kumar Prajapati
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Contributions

SK and SKP conducted the study, analysed the results, wrote and checked the manuscript.

Corresponding author

Correspondence to Sairam Krishnamurthy.

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Declaration from the author that there is no conflict of interest.

Ethical approval

All animal experiments were performed according to the principle guidelines of the National Institute of Health Guidelines (publication number 85–23, revised 2013), on animal care experimentation. All the experimental methods were approved by the Central Animal Ethical Committee of Banaras Hindu University, Varanasi, India (Approval No. Dean/2016/CAEC/324).

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Prajapati, S.K., Krishnamurthy, S. Development and treatment of cognitive inflexibility in sub-chronic stress–re-stress (SRS) model of PTSD. Pharmacol. Rep 73, 464–479 (2021). https://doi.org/10.1007/s43440-020-00198-9

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