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Exploring a post-traumatic stress disorder paradigm in Flinders sensitive line rats to model treatment-resistant depression I: bio-behavioural validation and response to imipramine

Published online by Cambridge University Press:  30 August 2016

Sarel Jacobus Brand  and
Brian Herbert Harvey
Sarel Jacobus Brand
Affiliation:
Division of Pharmacology, North-West University, Potchefstroom, South Africa
Brian Herbert Harvey*
Affiliation:
Division of Pharmacology, North-West University, Potchefstroom, South Africa Center of Excellence for Pharmaceutical Sciences, MRC Unit on Anxiety and Stress Disorders, North-West University, Potchefstroom, South Africa
*
Brian H. Harvey, Center of Excellence for Pharmaceutical Sciences, MRC Unit on Stress and Anxiety Disorders, North-West University (Potchefstroom Campus), Hoffman Street, Potchefstroom, 2531, South Africa. Tel: +27 18 299-2238; Fax: +27 87 231 5432; E-mail: brian.harvey@nwu.ac.za
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Abstract

Objective

Co-morbid depression with post-traumatic stress disorder (PTSD) is often treatment resistant. In developing a preclinical model of treatment-resistant depression (TRD), we combined animal models of depression and PTSD to produce an animal with more severe as well as treatment-resistant depressive-like behaviours.

Methods

Male Flinders sensitive line (FSL) rats, a genetic animal model of depression, were exposed to a stress re-stress model of PTSD [time-dependent sensitisation (TDS)] and compared with stress-naive controls. Seven days after TDS stress, depressive-like and coping behaviours as well as hippocampal and cortical noradrenaline (NA) and 5-hydroxyindoleacetic acid (5HIAA) levels were analysed. Response to sub-chronic imipramine treatment (IMI; 10 mg/kg s.c.×7 days) was subsequently studied.

Results

FSL rats demonstrated bio-behavioural characteristics of depression. Exposure to TDS stress in FSL rats correlated negatively with weight gain, while demonstrating reduced swimming behaviour and increased immobility versus unstressed FSL rats. IMI significantly reversed depressive-like (immobility) behaviour and enhanced active coping behaviour (swimming and climbing) in FSL rats. The latter was significantly attenuated in FSL rats exposed to TDS versus unstressed FSL rats. IMI reversed reduced 5HIAA levels in unstressed FSL rats, whereas exposure to TDS negated this effect. Lowered NA levels in FSL rats were sustained after TDS with IMI significantly reversing this in the hippocampus.

Conclusion

Combining a gene-X-environment model of depression with a PTSD paradigm produces exaggerated depressive-like symptoms that display an attenuated response to antidepressant treatment. This work confirms combining FSL rats with TDS exposure as a putative animal model of TRD.

Keywords

animal modelantidepressantgene-environment modelpost-traumatic stress disordertreatment-resistant depression
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 29 , Issue 4 , August 2017 , pp. 193 - 206
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Copyright
© Scandinavian College of Neuropsychopharmacology 2016 

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