Solomon Matia B, Wulsin Aynara C, Rice Taylor, Wick Dayna, Myers Brent, McKlveen Jessica, Flak Jonathan N, Ulrich-Lai Yvonne, Herman James P
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati Metabolic Diseases Institute, Cincinnati, OH 45237, USA; Department of Psychology, University of Cincinnati, Cincinnati, OH 45221, USA.
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati Metabolic Diseases Institute, Cincinnati, OH 45237, USA.
Horm Behav. 2014 Apr;65(4):363-71. doi: 10.1016/j.yhbeh.2014.02.002. Epub 2014 Feb 11.
Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10mg/kg), CORT 108297 (30mg/kg and 60mg/kg), imipramine (10mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest that CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.
临床前和临床研究已采用糖皮质激素受体（GR）拮抗剂进行治疗，试图限制过量糖皮质激素产生的有害行为和生理影响。在此，我们使用两种化合物研究了GR拮抗剂对神经内分泌和行为应激反应的影响：米非司酮，一种也是孕酮受体拮抗剂的GR拮抗剂；以及CORT 108297，一种缺乏抗孕激素活性的特异性GR拮抗剂。鉴于其对神经内分泌和行为应激反应的充分记录的影响，丙咪嗪（三环类抗抑郁药）用作阳性对照。雄性大鼠用米非司酮（10mg/kg）、CORT 108297（30mg/kg和60mg/kg）、丙咪嗪（10mg/kg）或赋形剂治疗五天，并接受强迫游泳试验（FST）或束缚应激。相对于赋形剂，丙咪嗪有力地抑制了促肾上腺皮质激素（ACTH）对FST和束缚暴露的反应。丙咪嗪还减少了FST中的不动时间，这与抗抑郁作用一致。两种剂量的CORT 108297都有力地抑制了FST和束缚应激时皮质酮的峰值反应。然而，只有较高剂量的CORT 108297（60mg/kg）显著减少了FST中的不动时间。相比之下，米非司酮在两种应激源作用下均诱导了皮质酮的长期分泌，并适度减少了FST中的不动时间。综上所述，数据表明每种化合物对神经内分泌应激反应有不同影响，也突出了FST中皮质酮反应与不动时间之间的分离。在本研究的背景下，我们的数据表明CORT 108297可能是减轻与糖皮质激素分泌过多相关的神经内分泌和行为状态的有吸引力的替代物。
