Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus
Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus
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DOI：
10.1046/j.1365-2826.2003.01100.x
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发表时间：
2003-11-01
影响因子：
3.2
通讯作者：
Spencer, RL
中科院分区：
文献类型：
--
作者：
Ginsberg, AB;Campeau, S;Spencer, RL
皮质酮以负反馈方式调节基础和应激诱导的下丘脑-垂体-肾上腺（HPA）轴活动。然而，这种负反馈的细胞和分子机制还没有明确的特点。通过比较室旁核（PVN）中应激诱导的c-fos和促肾上腺皮质激素释放激素（CRH）表达，我们可能能够确定急性糖皮质激素治疗是否影响PVN的净神经兴奋性输入（主要由c-fos mRNA表达表示）或直接影响PVN中细胞对该输入做出反应的能力（主要由CRH hnRNA表达表示）。在以下研究中，我们通过测量应激诱导的血浆激素浓度[皮质酮和促肾上腺皮质激素（ACTH）]和PVN中的基因表达（c-fos和CRH），观察了急性糖皮质激素（RU 28362）治疗对随后HPA轴反应性的影响。首先，我们研究了全身给药RU 28362（1-150 μ g/kg，i.p）和抑制应激诱导的皮质酮反应之间的剂量-反应关系。然后，我们通过离体放射性配体结合测定证实了最大抑制剂量的RU 28362（150 μ g/kg）进入中枢神经系统。RU 28362选择性地占据了海马和下丘脑中的大多数糖皮质激素受体，而对盐皮质激素受体没有影响。在单独的研究中，在束缚应激前1小时腹膜内注射RU 28362（150 μ g/kg）和皮质酮（5 mg/kg）。与溶剂处理的对照组相比，用RU 28362和皮质酮处理的大鼠分别显著减弱了应激诱导的皮质酮和ACTH产生。此外，用RU 28362处理显著减弱了PVN中应激诱导的CRH hnRNA表达。相比之下，无论是RU 28362，也没有皮质酮治疗应激诱导的神经元激活的c-fos mRNA和其蛋白产物在PVN的测量效果。c-fos和CRH基因表达之间的这种分离表明，在此时间范围内糖皮质激素对HPA活性的抑制不是PVN兴奋性神经输入减少的结果，而是取决于RU 28362对HPA轴固有细胞的一些直接作用。
Corticosterone regulates both basal and stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity in a negative-feedback fashion. However, the cellular and molecular mechanisms of this negative feedback have yet to be explicitly characterized. By comparing stress-induced c-fos and corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus (PVN), we may be able to determine whether acute glucocorticoid treatment affects the net neural excitatory input to the PVN (represented primarily by c-fos mRNA expression) or directly affects the ability of cells in the PVN to respond to that input (represented primarily by CRH hnRNA expression). In the following studies, we observed the effect of acute glucocorticoid (RU28362) treatment on subsequent HPA axis reactivity by measuring stress-induced plasma hormone concentration [corticosterone and adrenocorticotropic hormone (ACTH)] and gene expression (c-fos and CRH) in the PVN. First, we examined the dose-response relationship between systemically administered RU28362 (1-150 mug/kg, i.p) and suppression of the stress-induced corticosterone response. We then confirmed central nervous system access of the maximally suppressive dose of RU28362 (150 mug/kg) by an ex vivo radioligand binding assay. RU28362 selectively occupied the majority of glucocorticoid receptors in the hippocampus and hypothalamus while having no effect on mineralocorticoid receptors. In separate studies, RU28362 (150 mug/kg) and corticosterone (5 mg/kg) were injected i.p. 1 h before restraint stress. Compared to vehicle-treated controls, rats treated with RU28362 and corticosterone had substantially blunted stress-induced corticosterone and ACTH production, respectively. Furthermore, treatment with RU28362 significantly blunted stress-induced CRH hnRNA expression in the PVN. By contrast, neither RU28362 nor corticosterone treatment had an effect on stress-induced neuronal activation as measured by c-fos mRNA and its protein product in the PVN. This dissociation between c-fos and CRH gene expression suggests that glucocorticoid suppression of HPA activity within this time-frame is not a result of decreased excitatory neural input to the PVN, but instead depends on some direct effect of RU28362 on cells intrinsic to the HPA axis.