Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden University, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden University, Leiden, the Netherlands; PTSD Lab, Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, PR China.
Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden University, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden University, Leiden, the Netherlands; Department Translational Neuroscience, Brain Center Rudolf Magnus, Utrecht University Medical Center, Utrecht University, Utrecht, the Netherlands.
Psychoneuroendocrinology. 2019 Sep;107:169-178. doi: 10.1016/j.psyneuen.2019.05.014. Epub 2019 May 16.
Stressors activate a wide spectrum of interacting hormonal and neuronal systems resulting in behavioral and physiological responses, with consequences for the development of psychopathology. Several recent studies demonstrated that treatment with the glucocorticoid receptor (GR) antagonist RU486 during adulthood normalized effects of early life stress. We aimed to evaluate the potential of RU486 to reverse stress-induced changes in an animal model of adult stress.
We employed the single-prolonged stress (SPS) model as a multimodal stress exposure protocol in male rats. SPS rats and unstressed controls were treated with RU486 on days 8, 9, 10 after stress exposure and the effects of treatment were evaluated after another 4 days. We determined body weight gain, corticosterone levels, behavioral reactivity in anxiety tests, and brain gene expression of c-fos, corticosteroid receptors, drivers of the stress response and genes (epi-)genitally linked to PTSD.
RU486 affected body weight gain, corticosterone levels and open field behavior only in SPS rats. RU486 had history-independent effects in reducing fear in the elevated plus maze and fear conditioning behavior. Gene expression analysis showed a diversity of in- and interdependent effects of stress and RU486.
The effects of RU486 applied 1 week after stress and measured 4 days after treatment demonstrate that in the state of post-SPS the GR-dependence of homeostatic processes has changed. This suggests that GR-mediated processes are part of allostatic regulation after adult stress. The normalization of a number of SPS-effects after RU486 treatment reinforces the potential of targeting GR for treatment of stress-related psychopathologies.
应激源激活了广泛相互作用的激素和神经元系统，导致行为和生理反应，对精神病理学的发展产生影响。最近的几项研究表明，成年期用糖皮质激素受体（GR）拮抗剂 RU486 治疗可使早期生活应激的影响正常化。我们旨在评估 RU486 在成年应激动物模型中逆转应激诱导变化的潜力。
我们采用单一延长应激（SPS）模型作为多模态应激暴露方案，对雄性大鼠进行应激。SPS 大鼠和未应激对照大鼠在应激后第 8、9、10 天用 RU486 治疗，4 天后评估治疗效果。我们测定体重增加、皮质酮水平、焦虑测试中的行为反应以及 c-fos、糖皮质激素受体、应激反应驱动基因和与 PTSD 遗传相关的基因的脑基因表达。
RU486 仅影响 SPS 大鼠的体重增加、皮质酮水平和旷场行为。RU486 具有减轻高架十字迷宫和恐惧条件反射行为中恐惧的独立于既往史的作用。基因表达分析显示应激和 RU486 的相互影响和相互依存的多样性。
应激后 1 周应用 RU486 并在治疗后 4 天测量的结果表明，在 SPS 后状态下，稳态过程的 GR 依赖性已经改变。这表明 GR 介导的过程是成年后应激的适应性调节的一部分。RU486 治疗后许多 SPS 效应的正常化增强了针对 GR 治疗应激相关精神病理学的潜力。
