Goncharova Nadezhda, Chigarova Olga, Rudenko Natalia, Oganyan Tamara
Laboratory of Experimental Endocrinology, Research Institute of Medical Primatology, Sochi, Russia.
Front Endocrinol (Lausanne). 2019 Feb 13;10:24. doi: 10.3389/fendo.2019.00024. eCollection 2019.
The study of the mechanisms underlying the increased vulnerability of the individual to stressful environmental factors in different age periods is of great relevance for prevention and effective treatment of stress-dependent diseases that are widespread in the population of aging individuals. The purpose of our study was to investigate the individual and age-related features of the glucocorticoid negative feedback in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, the key adaptive neuroendocrine system, in experiments with physically healthy young and old female rhesus monkeys with administration of mineracorticoid receptor (fludrocortisone) and glucocorticoid receptor (dexamethasone) agonists. We studied the monkeys with increased trait anxiety and depression-like behavior (DAB) characterized, as previously was shown, by the increased vulnerability to acute stress and the animals with normal standard behavior (SB) as the control. The pronounced individual differences in the reaction of HPA axis to fludrocortisone and dexamethasone in young animals were found. Young animals with DAB showed a lower sensitivity of HPA axis to the inhibitory effect of both fludrocortisone and dexamethasone compared with young animals with SB. At the same time, there were no significant intergroup differences in the concentration of ACTH and cortisol in response to placebo injection, i.e., in basal conditions. The old individuals with DAB demonstrated the essential relative resistance of HPA axis to fludrocortisone test and higher basal plasma levels of cortisol and ACTH in the evening (the period of HPA axis low circadian activity) compared to old SB animals. In the same time, the intergroup differences in the response of HPA axis to dexamethasone administration were leveled due to age-related increase in sensitivity of HPA axis to dexamethasone in animals with DAB. These data testify the pronounced intergroup and age differences in the feedback regulation of HPA axis, presumably resulting from unequal individual, and age-related changes in the activity of mineralcorticoid and glucocorticoid receptors in the brain structures supporting the functions of HPA axis. The maximum age disorders in functioning of the negative feedback mechanism in the regulation of HPA axis are characteristic of animals with DAB, which, apparently, underlie the increased vulnerability of these animals to stress exposure.
研究个体在不同年龄阶段对压力环境因素易感性增加的潜在机制，对于预防和有效治疗在老年人群中广泛存在的应激相关疾病具有重要意义。我们研究的目的是，在给身体健康的年轻和老年雌性恒河猴注射盐皮质激素受体（氟氢可的松）和糖皮质激素受体（地塞米松）激动剂的实验中，探究下丘脑 - 垂体 - 肾上腺（HPA）轴（关键的适应性神经内分泌系统）调节中糖皮质激素负反馈的个体及年龄相关特征。我们研究了特质焦虑和抑郁样行为（DAB）增加的猴子，如先前所示，其特征是对急性应激的易感性增加，以及以具有正常标准行为（SB）的动物作为对照。在年轻动物中发现了HPA轴对氟氢可的松和地塞米松反应的明显个体差异。与具有SB的年轻动物相比，具有DAB的年轻动物HPA轴对氟氢可的松和地塞米松抑制作用的敏感性较低。同时，在基础条件下，即对安慰剂注射的反应中，促肾上腺皮质激素（ACTH）和皮质醇浓度在组间没有显著差异。与具有SB的老年动物相比，具有DAB的老年个体表现出HPA轴对氟氢可的松试验的基本相对抗性，并且在晚上（HPA轴昼夜活动较低的时期）血浆皮质醇和ACTH的基础水平较高。同时，由于具有DAB的动物中HPA轴对地塞米松敏感性的年龄相关增加，HPA轴对地塞米松给药反应的组间差异趋于平衡。这些数据证明了HPA轴反馈调节中明显的组间和年龄差异，推测这是由于支持HPA轴功能的脑结构中盐皮质激素和糖皮质激素受体活性的个体差异和年龄相关变化不平等所致。HPA轴调节中负反馈机制功能的最大年龄紊乱是具有DAB的动物的特征，这显然是这些动物对应激暴露易感性增加的基础。
