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Exploring a post-traumatic stress disorder paradigm in Flinders sensitive line rats to model treatment-resistant depression II: response to antidepressant augmentation strategies

Published online by Cambridge University Press:  03 October 2016

Sarel Jacobus Brand  and
Brian Herbert Harvey
Sarel Jacobus Brand
Affiliation:
Centre of Excellence for Pharmaceutical Sciences, Division of Pharmacology, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa
Brian Herbert Harvey*
Affiliation:
Centre of Excellence for Pharmaceutical Sciences, Division of Pharmacology, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa MRC Unit on Anxiety and Stress Disorders, North-West University, Potchefstroom, South Africa
*
Brian Herbert 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: [email protected]
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Abstract

Objective

Post-traumatic stress disorder (PTSD) displays high co-morbidity with major depression and treatment-resistant depression (TRD). Earlier work demonstrated exaggerated depressive-like symptoms in a gene×environment model of TRD and an abrogated response to imipramine. We extended the investigation by studying the behavioural and monoaminergic response to multiple antidepressants, viz. venlafaxine and ketamine with/without imipramine.

Methods

Male Flinders sensitive line (FSL) rats, a genetic model of depression, were exposed to a time-dependent sensitisation (TDS) model of PTSD and compared with stress naive controls. 7 days after the TDS procedures, immobility and coping (swimming and climbing), behaviours in the forced swim test (FST) as well as hippocampal and cortical 5-hydroxyindoleacetic acid (5HIAA) and noradrenaline (NA) levels were analysed. Response to imipramine, venlafaxine and ketamine treatment (all 10 mg/kg×7 days) alone and in combination were subsequently studied.

Results

TDS exacerbated depressive-like behaviour of FSL rats in the FST. Imipramine, venlafaxine and ketamine were ineffective as monotherapy in TDS-exposed FSL rats. However, combining imipramine with either venlafaxine or ketamine resulted in significant anti-immobility effects and enhanced coping behaviours. Only ketamine+imipramine (frontal-cortical 5HIAA and NA), ketamine alone (frontal-cortical and hippocampal NA) and venlafaxine+imipramine (frontal-cortical NA) altered monoamine responses versus untreated TDS-exposed FSL rats.

Conclusion

Exposure of FSL rats to TDS inhibits antidepressant response at behavioural and neurochemical levels. Congruent with TRD, imipramine plus venlafaxine or ketamine overcame treatment resistance in these animals. These data further support the hypothesis that exposure of FSL rats to a PTSD-like paradigm produces a valid animal model of TRD and warrants further investigation.

Keywords

animal modelNMDA antagonistnoradrenaline reuptake inhibitorserotonin reuptake inhibitorstress re-stress
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 29 , Issue 4 , August 2017 , pp. 207 - 221
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Copyright
© Scandinavian College of Neuropsychopharmacology 2016 

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