1Centre of Excellence for Pharmaceutical Sciences,Division of Pharmacology, Faculty of Health Sciences,North-West University,Potchefstroom,South Africa.
Acta Neuropsychiatr. 2017 Aug;29(4):207-221. doi: 10.1017/neu.2016.50. Epub 2016 Oct 3.
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.
创伤后应激障碍（PTSD）与重度抑郁症和治疗抵抗性抑郁症（TRD）高度共病。早期的工作表明，在 TRD 的基因×环境模型中，抑郁样症状加剧，而米帕明的反应减弱。我们通过研究多种抗抑郁药，即文拉法辛和氯胺酮以及米帕明的行为和单胺能反应，扩展了这项研究。
雄性弗林德斯敏感系（FSL）大鼠，一种抑郁症的遗传模型，暴露于时间依赖性敏感化（TDS）的 PTSD 模型中，并与应激未暴露的对照组进行比较。TDS 程序 7 天后，分析强迫游泳试验（FST）中的不动和应对（游泳和攀爬）行为、海马和皮质 5-羟吲哚乙酸（5HIAA）和去甲肾上腺素（NA）水平以及单独和联合使用米帕明、文拉法辛和氯胺酮的反应。
TDS 加剧了 FSL 大鼠在 FST 中的抑郁样行为。米帕明、文拉法辛和氯胺酮单独治疗 TDS 暴露的 FSL 大鼠均无效。然而，将米帕明与文拉法辛或氯胺酮联合使用会导致显著的抗不动作用和增强的应对行为。只有氯胺酮+米帕明（额皮质 5HIAA 和 NA）、氯胺酮单独（额皮质和海马 NA）和文拉法辛+米帕明（额皮质 NA）改变了未经处理的 TDS 暴露的 FSL 大鼠的单胺反应。
FSL 大鼠暴露于 TDS 会抑制行为和神经化学水平的抗抑郁反应。与 TRD 一致，米帕明加文拉法辛或氯胺酮克服了这些动物的治疗抵抗。这些数据进一步支持了这样一种假设，即 FSL 大鼠暴露于 PTSD 样范式会产生有效的 TRD 动物模型，值得进一步研究。
