Calogero A E, Liapi C, Chrousos G P
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
J Endocrinol Invest. 1991 Apr;14(4):277-86. doi: 10.1007/BF03346812.
Corticosteroid type I and II receptors mediate the negative feedback effects of these hormones at various central nervous system sites involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. To examine the effects of chronic treatment with dexamethasone (DEX), a type 2 receptor agonist, on the regulation of this axis, male Sprague-Dawley rats weighing 200-250 g were given daily injections of DEX for 1,2,3, and 4 weeks or were treated with a subcutaneously implanted DEX-releasing minipump for one week. At the end of treatment, the animals were weighed and brains and truncal blood were collected. Daily intermittent DEX treatment reduced the body weight of the rats in a time-dependent fashion, but had little or no effect on their wet brain weight. Plasma ACTH and corticosterone, measured by RIA, were fully suppressed after one week of intermittent treatment and did not show any further reduction in rats treated for longer periods. In these animals, the content of immunoreactive corticotropin-releasing hormone (iCRH), arginine vasopressin (AVP), ACTH and beta-endorphin (beta-EP) in the hypothalamus, hippocampus, cerebral cortex and cerebellum and pituitary ACTH content did not show any difference compared to vehicle-treated rats. In contrast, continuous DEX treatment increased iCRH content in the cortex, reduced AVP content in the cerebellum, increased ACTH content in the hippocampus, decreased ACTH and beta-EP content in the hypothalamus, and reduced pituitary ACTH content. Hypothalami explanted from rats treated with DEX for one week released lower basal amounts of iCRH in vitro and did not respond to a maximally stimulatory concentration of serotonin (5-HT), a known CRH secretagogue. Continuous DEX administration suppressed also potassium chloride-induced iCRH release. Interestingly, hypothalami explanted from rats receiving daily injection of vehicle, but not from unhandled, untreated controls, did not respond to 5-HT with an increase of iCRH release in vitro. In conclusion, prolonged and continuous, but not intermittent, administration of DEX had a strong effect on brain neuropeptide content. Both regimens of DEX reduced the hypothalamic iCRH responsiveness to stimuli in vitro. Chronic handling also decreased the responsiveness of the hypothalamus to a stimulatory neurotransmitter and may confound the interpretation of data pertinent to inhibitory mechanisms.
I型和II型皮质类固醇受体介导这些激素在参与下丘脑-垂体-肾上腺（HPA）轴调节的各个中枢神经系统部位的负反馈作用。为了研究2型受体激动剂地塞米松（DEX）长期治疗对该轴调节的影响，对体重200 - 250 g的雄性Sprague-Dawley大鼠每日注射DEX，持续1、2、3和4周，或用皮下植入的释放DEX的微型泵治疗1周。治疗结束时，对动物称重并收集大脑和躯干血液。每日间歇性DEX治疗以时间依赖性方式降低大鼠体重，但对其湿脑重影响很小或无影响。通过放射免疫分析（RIA）测定，血浆促肾上腺皮质激素（ACTH）和皮质酮在间歇性治疗1周后被完全抑制，在接受更长时间治疗的大鼠中未显示出进一步降低。在这些动物中，下丘脑、海马、大脑皮层和小脑中免疫反应性促肾上腺皮质激素释放激素（iCRH）、精氨酸加压素（AVP）、ACTH和β-内啡肽（β-EP）的含量以及垂体ACTH含量与给予赋形剂处理的大鼠相比没有任何差异。相比之下，持续DEX治疗增加了皮层中的iCRH含量，降低了小脑中的AVP含量，增加了海马中的ACTH含量，降低了下丘脑中的ACTH和β-EP含量，并降低了垂体ACTH含量。从接受DEX治疗1周的大鼠中取出的下丘脑在体外释放的基础iCRH量较低，并且对已知的CRH促分泌剂5-羟色胺（5-HT）的最大刺激浓度没有反应。持续给予DEX也抑制了氯化钾诱导的iCRH释放。有趣的是，从每日注射赋形剂的大鼠中取出的下丘脑，而不是从未处理、未治疗的对照大鼠中取出的下丘脑，在体外对5-HT没有反应，不会增加iCRH释放。总之，长期持续而非间歇性给予DEX对脑内神经肽含量有强烈影响。两种DEX给药方案均降低了下丘脑iCRH在体外对刺激的反应性。长期处理也降低了下丘脑对刺激性神经递质的反应性，可能会混淆与抑制机制相关的数据解释。
