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


CONCLUSIONS
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.
1Centre of Excellence for Pharmaceutical Sciences,Division of Pharmacology, Faculty of Health Sciences,North-West University,Potchefstroom,South Africa.
Sarel Jacobus
SJ
Brand
1Centre of Excellence for Pharmaceutical Sciences,Division of Pharmacology, Faculty of Health Sciences,North-West University,Potchefstroom,South Africa.
Brian Herbert
BH
Harvey
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007099:Imipramine / Q000008:administration & dosage / Q000494:pharmacology*; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D055647:Rats, Transgenic; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy*; D000069470:Venlafaxine Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology*
D000928:Antidepressive Agents; D007649:Ketamine; D000069470:Venlafaxine Hydrochloride; D007099:Imipramine
NMDA antagonist; animal model; noradrenaline reuptake inhibitor; serotonin reuptake inhibitor; stress re-stress