Exploring a post-traumatic stress disorder paradigm in Flinders sensitive line rats to model treatment-resistant depression II: response to antidepressant augmentation strategies.
Sarel Jacobus Brand, Brian Herbert Harvey
Acta Neuropsychiatrica August 2017 DOI: 10.1017/neu.2016.50 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Male Flinders sensitive line (FSL) rats, a genetic model of depression, exposed to a time-dependent sensitisation (TDS) model of PTSD and stress-naive controls |
| Interventions | Imipramine Venlafaxine Ketamine |
| Dose | 10 mg/kg for 7 days |
| Duration | 7 days of treatment; behavioural and neurochemical analyses 7 days after TDS procedures |
| Measures | Forced swim test (FST) immobility, swimming, and climbing behaviours; hippocampal and cortical 5-hydroxyindoleacetic acid (5HIAA) and noradrenaline (NA) levels |
| Topics | Depression PTSD |
| Keywords | Nmda antagonist Animal model Noradrenaline reuptake inhibitor Serotonin reuptake inhibitor Stress re-stress |
| Key findings | Exposure of FSL rats to the TDS paradigm inhibited antidepressant response: imipramine, venlafaxine, and ketamine were ineffective as monotherapy at reducing forced-swim immobility or enhancing coping behaviours. Combining imipramine with venlafaxine or ketamine produced significant anti-immobility and coping effects, and several treatments altered frontal-cortical and hippocampal 5HIAA and noradrenaline levels. The authors propose this supports the FSL-plus-TDS model as a valid animal model of treatment-resistant depression. |
Abstract
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. 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. 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. 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.
Comparable studies
Other preclinical and animal studies on PTSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Pharmahuasca and DMT Rescue ROS Production and Differentially Expressed Genes Observed after Predator and Psychosocial Stress: Relevance to Human PTSD. Rats exposed to a 30-day stress regimen | 2022 | Preclinical animal study with in vitro assays | |
| Ketamine ameliorates post-traumatic social avoidance by erasing the traumatic memory encoded in VTA-innervated BLA engram cells. Mice | 2024 | Experimental animal study | |
| Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors Male and female mice | 2024 | Experimental study | |
| Molecular signatures of astrocytes and microglia maladaptive responses to acute stress are rescued by a single administration of ketamine in a rodent model of PTSD. Rats | 2024 | Animal study | |
| Psilocybe cubensis extract potently prevents fear memory recall and freezing behavior in short- but not long-term in a rat model of posttraumatic stress disorder. Male rats | 2024 | Preclinical study |
Citations in the library
Cites 9
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- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Potential involvement of serotonergic signaling in ketamine's antidepressant actions: A critical review. Progress in Neuro-Psychopharmacology and Biological Psychiatry November 3, 2016
- Repeated ketamine administration redeems the time lag for citalopram's antidepressant-like effects European Psychiatry June 1, 2015
- Repeated Ketamine Exposure Induces an Enduring Resilient Phenotype in Adolescent and Adult Rats Biological Psychiatry June 19, 2013
and 4 more in the library