Redei E, Branch B J, Gholami S, Lin E Y, Taylor A N
Department of Anatomy, University of California, Los Angeles.
Endocrinology. 1988 Dec;123(6):2736-43. doi: 10.1210/endo-123-6-2736.
Acute ethanol exposure produces activation of the brain-pituitary-adrenal (BPA) axis, resulting in the release of ACTH, beta-endorphin, and glucocorticoids. While elevated levels of plasma glucocorticoids are also found after chronic ethanol administration, plasma ACTH and beta-endorphin are normal or reduced. It is also unclear whether chronic ethanol exposure results in tolerance to the stimulatory effect of ethanol on BPA activity. To determine the site and mechanism of ethanol action on the BPA axis we studied the CRF secretory profile in a superfused rat hypothalamic preparation after chronic ethanol administration in vivo and the CRF responses after acute ethanol exposure in vitro. Superfused hypothalami from normal and pair-fed control rats released CRF-like immunoreactive material (CRF-LI) in a pulsatile manner, with a mean (+/- SE) frequency of 5.1 +/- 0.7 pulses/h. In contrast, the pulse frequency of CRF-LI release from hypothalami of rats receiving chronic ethanol treatment (fed an alcohol-containing liquid diet for 2 weeks) increased dramatically; the basal mean CRF level, pulse amplitude, and pulse duration remained unchanged. Hypothalamic CRF content was decreased. This chronic ethanol exposure also altered the dose-response characteristics of CRF release when ethanol was introduced acutely, as a pulse, into the in vitro preparation. Acute exposure to 20 mg/100 ml ethanol produced greater release of CRF-LI from control hypothalami than from chronic ethanol-exposed hypothalami. A further elevation above basal levels was produced by 200 mg/100 ml ethanol in control, but not ethanol-exposed, hypothalami. Secretion of CRF from ethanol-exposed hypothalami in response to depolarizing concentrations of potassium chloride was suppressed. Chronic ethanol treatment had no effect on CRF-LI and CRF bioactivity responses to stimulation with acetylcholine. These findings suggest the presence of a high frequency pulse-generating mechanism for CRF release in the hypothalamus. This pulsatile secretory mechanism is altered by chronic ethanol exposure of the animals in vivo. Chronic intoxication resulted in tolerance to the stimulatory effect of ethanol on CRF release in vitro.
急性乙醇暴露会导致脑-垂体-肾上腺（BPA）轴激活，从而促使促肾上腺皮质激素（ACTH）、β-内啡肽和糖皮质激素释放。虽然长期给予乙醇后血浆糖皮质激素水平也会升高，但血浆ACTH和β-内啡肽水平正常或降低。长期乙醇暴露是否会导致对乙醇对BPA活性的刺激作用产生耐受性也尚不清楚。为了确定乙醇作用于BPA轴的部位和机制，我们研究了在体内长期给予乙醇后，超灌流大鼠下丘脑制剂中的促肾上腺皮质激素释放因子（CRF）分泌情况，以及在体外急性乙醇暴露后的CRF反应。来自正常和配对喂养对照大鼠的超灌流下丘脑以脉冲方式释放CRF样免疫反应物质（CRF-LI），平均（±标准误）频率为5.1±0.7次脉冲/小时。相比之下，接受长期乙醇处理（喂食含酒精液体饲料2周）的大鼠下丘脑释放CRF-LI的脉冲频率显著增加；基础平均CRF水平、脉冲幅度和脉冲持续时间保持不变。下丘脑CRF含量降低。当在体外制剂中急性以脉冲形式引入乙醇时，这种长期乙醇暴露也改变了CRF释放的剂量反应特性。急性暴露于20mg/100ml乙醇时，对照下丘脑释放的CRF-LI比长期乙醇暴露的下丘脑更多。在对照下丘脑而非乙醇暴露的下丘脑中，200mg/100ml乙醇使基础水平进一步升高。乙醇暴露的下丘脑对去极化浓度的氯化钾的反应中，CRF分泌受到抑制。长期乙醇处理对CRF-LI和CRF对乙酰胆碱刺激的生物活性反应没有影响。这些发现表明下丘脑中存在一种用于CRF释放的高频脉冲产生机制。这种脉冲分泌机制在体内因动物长期乙醇暴露而改变。慢性中毒导致对乙醇在体外对CRF释放的刺激作用产生耐受性。
