Site of action of acute alcohol administration in stimulating the rat hypothalamic-pituitary-adrenal axis: Comparison between the effect of systemic and intracerebroventricular injection of this drug on pituitary and hypothalamic responses
Site of action of acute alcohol administration in stimulating the rat hypothalamic-pituitary-adrenal axis: Comparison between the effect of systemic and intracerebroventricular injection of this drug on pituitary and hypothalamic responses
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DOI：
10.1210/en.2004-0110
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发表时间：
2004-10-01
期刊：
影响因子：
4.8
通讯作者：
Rivier, C
中科院分区：
文献类型：
--
作者：
Lee, S;Selvage, D;Rivier, C
酒精的外周注射刺激下丘脑-垂体-肾上腺（HPA）轴的活动，但这种药物在大多数身体隔室中的快速渗透使得难以确定其特定的作用部位。在这里，我们确定酒精是否可以直接影响促皮质激素。我们首先确定酒精是否在大脑中起作用，刺激下丘脑室旁核（PVN）的神经元，该核合成促肾上腺皮质激素释放因子（CRF）和加压素（VP）。为了验证这一假设，我们脑室内注射酒精（icv; 5穆尔的200-proof; 86 μ mol），并将这些结果与ip给药（3.0 g/kg）后获得的结果进行比较。尽管icv酒精不会引起神经元损伤，也不会导致全身循环中药物的可检测水平，但icv酒精显著上调PVN CRF杂合RNA水平，并增加血浆ACTH水平，这一变化与ip模型中观察到的变化相当。为了确定酒精是否刺激促肾上腺皮质激素的CRF和/或VP独立，我们注射药物ip或icv和测量的变化，垂体前叶阿黑皮素原（POMC）的成绩单和促肾上腺皮质激素释放的存在或不存在的内源性CRF和/或VP。通过核糖核酸酶保护试验测定，脑室内和ip酒精显著增加POMC初级转录水平，在对应于ACTH释放的时间过程中。去除CRF和VP后，POMC和ACTH反应均完全消失。总的来说，这些结果表明，酒精诱导的促肾上腺皮质激素的激活并不代表药物对垂体的直接影响，但需要CRF和VP。
The peripheral injection of alcohol stimulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis, but the ready penetration of this drug in most bodily compartments has made it difficult to identify its specific sites of action. Here we determined whether alcohol can directly influence the corticotropes. We first determined whether alcohol acted within the brain to stimulate neurons in the paraventricular nucleus (PVN) of the hypothalamus, which synthesizes corticotropin-releasing factor (CRF) and vasopressin (VP). To test this hypothesis, we injected alcohol intracerebroventricularly (icv; 5 mul of 200-proof; 86 mumol) and compared these results with those obtained after its ip administration (3.0 g/kg). Although not causing neuronal damage and not leading to detectable levels of the drug in the general circulation, icv alcohol significantly up-regulated PVN CRF heteronuclear RNA levels and increased plasma ACTH levels, a change comparable to the one observed in the ip model. To determine whether alcohol stimulated the corticotropes independently of CRF and/or VP, we injected the drug ip or icv and measured changes in anterior pituitary proopiomelanocortin (POMC) transcripts and ACTH release in the presence or absence of endogenous CRF and/or VP. Intracerebroventricular and ip alcohol significantly increased POMC primary transcript levels, measured by ribonuclease protection assay, over a time-course that corresponded to ACTH release. Both the POMC and the ACTH responses were completely abolished by removal of CRF and VP. Collectively, these results indicate that alcohol-induced activation of the corticotropes does not represent a direct influence of the drug on the pituitary but requires CRF and VP.