title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors: 1Division of Pharmacology,North-West University,Potchefstroom,South Africa.
authors: Sarel Jacobus
authors: SJ
authors: Brand
authors: 1Division of Pharmacology,North-West University,Potchefstroom,South Africa.
authors: Brian Herbert
authors: BH
authors: Harvey
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects*; D015897:Comorbidity; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy*; D004195:Disease Models, Animal; D059647:Gene-Environment Interaction; D007099:Imipramine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D055647:Rats, Transgenic; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D007099:Imipramine
keywords: animal model; antidepressant; gene-environment model; post-traumatic stress disorder; treatment-resistant depression