Cassano W J, D'mello A P
University of the Sciences, Philadelphia, PA 19104, USA.
Neuroendocrinology. 2001 Sep;74(3):167-77. doi: 10.1159/000054683.
Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis stimulates the release of both facilitatory and inhibitory components. We proposed that the transient removal of the inhibitory component, corticosterone, during a stressor would leave the HPA axis in a state of hyper-responsiveness (facilitated state). Consistent with this expectation, we have previously observed that aminoglutethimide (AG)-induced removal of corticosterone during an immobilization stressor resulted in the hypersecretion of both ACTH and corticosterone to a subsequent stressor. In the present study we determined the effect of stressor duration on the magnitude of facilitation. AG plus a 10-min immobilization (IMM(10)) stress on day 1 resulted in facilitation of the HPA axis. This was reflected in higher ACTH and corticosterone responses to an injection stress on day 2 as compared to appropriate control rats. AG plus a 60-min immobilization (IMM(60)) stress on day 1 resulted in significantly greater facilitation as compared to the AG+IMM(10) pretreatment. It is apparent that facilitation of the HPA axis is dependent on the duration of stress. Stress can alter plasma corticosterone-binding globulin levels and AG administration can cause accumulation of the corticosterone biosynthetic precursor, adrenal cholesterol. In order to rule out these peripheral reasons for the hypersecretion of ACTH and corticosterone in our paradigm, we measured the plasma free fraction of corticosterone and adrenal mitochondrial cholesterol levels on day 2 after different pretreatments on day 1. AG+IMM(60) pretreatment caused a significant increase in the plasma free fraction of corticosterone. Hypersecretion of ACTH and corticosterone in this group, despite an enhanced feedback signal, suggests central loci for the origin of facilitation. Also, AG treatment on day 1 did not result in accumulation of free or esterified adrenal cholesterol levels on day 2, and therefore cannot account for the hypersecretion of corticosterone. In our final study we attempted to determine if serotonin released during the first stressor is partially responsible for stress-induced facilitation of the HPA axis. We administered 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), a 5HT(1A) agonist, either alone or in conjunction with stress and examined the effects of these pretreatments on the magnitude of facilitation. Interestingly, DPAT administered in lieu of stress produced facilitation similar in magnitude to that produced by IMM(10). DPAT administered in conjunction with IMM(10) augmented stress-induced facilitation. Our results suggest that stress-induced facilitation of the HPA axis is associated with the release of serotonin during stress.
应激诱导的下丘脑-垂体-肾上腺（HPA）轴激活会刺激促分泌和抑制性成分的释放。我们提出，在应激源作用期间短暂去除抑制性成分皮质酮，会使HPA轴处于高反应性状态（易化状态）。与这一预期一致，我们之前观察到，在固定应激期间，氨鲁米特（AG）诱导的皮质酮去除导致促肾上腺皮质激素（ACTH）和皮质酮对随后应激源的分泌过多。在本研究中，我们确定了应激源持续时间对易化程度的影响。第1天给予AG加10分钟固定（IMM(10)）应激导致HPA轴易化。这表现为与适当的对照大鼠相比，第2天对注射应激的ACTH和皮质酮反应更高。与AG+IMM(10)预处理相比，第1天给予AG加60分钟固定（IMM(60)）应激导致显著更大的易化。显然，HPA轴的易化取决于应激的持续时间。应激可改变血浆皮质酮结合球蛋白水平，给予AG可导致皮质酮生物合成前体肾上腺胆固醇的积累。为了排除我们实验范式中ACTH和皮质酮分泌过多的这些外周原因，我们在第1天进行不同预处理后，于第2天测量了皮质酮的血浆游离分数和肾上腺线粒体胆固醇水平。AG+IMM(60)预处理导致皮质酮的血浆游离分数显著增加。尽管反馈信号增强，但该组中ACTH和皮质酮的分泌过多表明易化起源于中枢位点。此外，第1天给予AG治疗在第2天并未导致游离或酯化肾上腺胆固醇水平的积累，因此不能解释皮质酮的分泌过多。在我们的最终研究中，我们试图确定在第一个应激源作用期间释放的5-羟色胺是否部分负责应激诱导的HPA轴易化。我们单独或与应激联合给予8-羟基-2-（二正丙基氨基）四氢萘（DPAT），一种5-羟色胺受体1A（5HT(1A)）激动剂，并检查这些预处理对易化程度的影响。有趣的是，用DPAT替代应激产生的易化程度与IMM(10)产生的相似。DPAT与IMM(10)联合给予增强了应激诱导的易化。我们的结果表明，应激诱导的HPA轴易化与应激期间5-羟色胺的释放有关。
