Nguyen Elizabeth T, Streicher Joshua, Berman Sarah, Caldwell Jody L, Ghisays Valentina, Estrada Christina M, Wulsin Aynara C, Solomon Matia B
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States; Neuroscience Graduate Program, University of Cincinnati College of Medicine, United States.
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, United States.
Physiol Behav. 2017 Sep 1;178:82-92. doi: 10.1016/j.physbeh.2017.01.020. Epub 2017 Jan 14.
Aberrant glucocorticoid secretion is implicated in the pathophysiology of stress-related disorders (i.e., depression, anxiety). Glucocorticoids exert biological effects via mineralocorticoid (MR) and glucocorticoid (GR) receptors. Previous data from our laboratory indicate that GR antagonism/modulation (i.e., mifepristone, CORT 108297) regulate endocrine, behavioral, and central stress responses. Because of the dynamic interplay between MR and GR on HPA axis regulation and emotionality, compounds targeting both receptors are of interest for stress-related pathology. We investigated the effects of CORT 118335 (a dual selective GR modulator/MR antagonist) on endocrine, behavioral, and central (c-Fos) stress responses in male rats. Rats were treated for five days with CORT 118335, imipramine (positive control), or vehicle and exposed to restraint or forced swim stress (FST). CORT 118335 dampened corticosterone responses to both stressors, without a concomitant antidepressant-like effect in the FST. Imipramine decreased corticosterone responses to restraint stress; however, the antidepressant-like effect of imipramine in the FST was independent of circulating glucocorticoids. These findings indicate dissociation between endocrine and behavioral stress responses in the FST. CORT 118335 decreased c-Fos expression only in the CA1 division of the hippocampus. Imipramine decreased c-Fos expression in the basolateral amygdala and CA1 and CA3 divisions of the hippocampus. Overall, the data indicate differential effects of CORT 118335 and imipramine on stress-induced neuronal activity in various brain regions. The data also highlight a complex relationship between neuronal activation in stress and mood regulatory brain regions and the ensuing impact on endocrine and behavioral stress responses.
异常的糖皮质激素分泌与应激相关疾病（如抑郁症、焦虑症）的病理生理学有关。糖皮质激素通过盐皮质激素（MR）和糖皮质激素（GR）受体发挥生物学作用。我们实验室之前的数据表明，GR拮抗/调节（即米非司酮、CORT 108297）可调节内分泌、行为和中枢应激反应。由于MR和GR在HPA轴调节和情绪方面存在动态相互作用，针对这两种受体的化合物对于应激相关病理学具有重要意义。我们研究了CORT 118335（一种双重选择性GR调节剂/MR拮抗剂）对雄性大鼠内分泌、行为和中枢（c-Fos）应激反应的影响。大鼠连续五天接受CORT 118335、丙咪嗪（阳性对照）或赋形剂治疗，并暴露于束缚或强迫游泳应激（FST）中。CORT 118335减弱了对两种应激源的皮质酮反应，在FST中没有伴随的抗抑郁样作用。丙咪嗪降低了对束缚应激的皮质酮反应；然而，丙咪嗪在FST中的抗抑郁样作用与循环糖皮质激素无关。这些发现表明FST中内分泌和行为应激反应之间存在分离。CORT 118335仅降低海马体CA1区的c-Fos表达。丙咪嗪降低了基底外侧杏仁核以及海马体CA1和CA3区的c-Fos表达。总体而言，数据表明CORT 118335和丙咪嗪对不同脑区应激诱导的神经元活动有不同影响。数据还突出了应激和情绪调节脑区中神经元激活之间的复杂关系，以及随之对内分泌和行为应激反应的影响。
