Selective activation of the hypothalamic vasopressinelgic system in mice deficient for the corticotropin-releasing hormone receptor 1 is dependent on glucocorticoids
Selective activation of the hypothalamic vasopressinelgic system in mice deficient for the corticotropin-releasing hormone receptor 1 is dependent on glucocorticoids
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DOI：
10.1210/en.141.11.4262
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发表时间：
2000-11-01
期刊：
影响因子：
4.8
通讯作者：
Wurst, W
中科院分区：
文献类型：
--
作者：
Müller, MB;Landgraf, R;Wurst, W
CRH受体1 （CRHR1）的缺乏严重损害下丘脑-垂体-肾上腺皮质（HPA）系统的应激反应，并减少小鼠的焦虑相关行为。有趣的是，在缺乏CRHR1 （CRHR1(-/-)）的小鼠中，ACTH的基础血浆水平是正常的，这表明垂体ACTH分泌存在代偿机制。因此，我们研究了下丘脑神经肽精氨酸加压素（AVP）和催产素（OXT）对纯合子和杂合子Crhr1突变体在基础和不同胁迫条件下HPA系统调节的影响。Crhr1（-/-）小鼠的基础血浆AVP浓度显著升高。在Crhr1（-/-）突变体的室旁核中，AW信使RNA的表达增加，同时中位隆起的AW样免疫反应性显著增加。给药AVP v -1受体拮抗剂显著降低突变小鼠的基础血浆ACTH水平。在持续使用皮质酮治疗后，纯合子Crhr1（-/-）小鼠的血浆AVP水平与野生型小鼠没有区别，从而证明糖皮质激素缺乏是Crhr1（-/-）小鼠抗利尿激素系统代偿性激活的主要驱动力。不同条件下的血浆OXT水平和室旁核中OXT信使RNA的表达在基因型之间均无差异。综上所述，我们的数据揭示了Crhr1（-/-）突变体中下丘脑抗利尿激素系统的选择性代偿激活，而不是催产素系统，以维持基础ACTH分泌和HPA系统的活性。
Deficiency of CRH receptor 1 (CRHR1) severely impairs the stress response of the hypothalamic-pituitary-adrenocortical (HPA) system and reduces anxiety-related behavior in mice. Intriguingly, in mice deficient for the CRHR1 (Crhr1(-/-)), basal plasma levels of ACTH are normal, suggesting the presence of compensatory mechanisms for pituitary ACTH secretion. We therefore studied the impact of the hypothalamic neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) on HPA system regulation in homozygous and heterozygous Crhr1 mutants under basal and different stress conditions. Basal plasma AVP concentrations were significantly elevated in Crhr1(-/-) mice. AW messenger RNA expression was increased in the paraventricular nucleus of Crhr1(-/-) mutants together with a marked increase in AW-like immunoreactivity in the median eminence. Administration of an AVP V-1-receptor antagonist significantly decreased basal plasma ACTH levels in mutant mice. After continuous treatment with corticosterone, plasma AVP levels in homozygous Crhr1(-/-) mice were indistinguishable from those in wild-type littermates, thus providing evidence that glucocorticoid deficiency is the major driving force behind compensatory activation of the vasopressinergic system in Crhr1(-/-) mice. Neither plasma OXT levels under several different conditions nor OXT messenger RNA expression in the paraventricular nucleus were different between the genotypes. Taken together, our data reveal a selective compensatory activation of the hypothalamic vasopressinergic, but not the oxytocinergic system, to maintain basal ACTH secretion and HPA system activity in Crhr1(-/-) mutants.