CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis.
CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis.
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DOI：
10.1038/npp.2009.209
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发表时间：
2010-05
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最近的证据表明，促肾上腺皮质激素释放因子（CRF）受体（CRFR）信号参与调节酗酒样酒精消耗在C57 BL/6 J小鼠。在这份报告中，进行了一系列的实验，以进一步表征CRFR信号在酗酒样乙醇消费中的作用。通过脑室内（i. c. v.）评估了中央CRFR信号传导的作用输注非选择性CRFR拮抗剂α-螺旋CRF 9 -41（0、1、5、10 μg/1 μl）。通过i. c. v.输注选择性CRF 2型受体（CRF 2 R）激动剂尿皮质素（Ucn）3（0、0.05、0.1或0.5 μg/1 μl）评估了中枢CRF 2型受体（CRF 2 R）信号传导的作用。通过用腹膜内（i. p.）分别注射皮质酮合成抑制剂甲吡酮（0、50、100、150 μg/kg）或糖皮质激素受体拮抗剂米非司酮（0、25、50 μg/kg）;最后，我们确定CRF 1 R拮抗剂CP-154，526（CP; 0，10，15 mg/kg，i. p.），通过比较CP在肾上腺切除（ADX）和正常小鼠中的有效性，我们发现抑制狂饮需要正常的HPA轴信号传导。结果显示，相对于溶剂处理，i. c. v.输注1 μg剂量的α-螺旋CRF 9 -41显著减弱了酗酒样乙醇消耗，并且i. c. v.输注Ucn 3剂量依赖性地减弱了酗酒样饮酒。另一方面，甲吡酮非选择性地减少了乙醇和蔗糖的消耗，米非司酮并没有改变乙醇的饮用，和狂欢样饮酒与血浆皮质酮水平没有相关性。最后，腹膜内注射CP显著减弱ADX和正常小鼠的酒精摄入量。总之，这些结果表明，C57 BL/6 J小鼠中的暴食样乙醇摄入量受到CRF 1 R和CRF 2 R信号传导的调节，因此CRF 1 R的阻断或CRF 2 R的激活有效地减少了过量的乙醇摄入。此外，正常的HPA轴信号传导并不是实现暴饮暴食行为所必需的。
Recent evidence suggests that corticotropin-releasing factor (CRF) receptor (CRFR) signaling is involved in modulating binge-like ethanol consumption in C57BL/6J mice. In this report, a series of experiments were performed to further characterize the role of CRFR signaling in binge-like ethanol consumption. The role of central CRFR signaling was assessed with intracerebroventricular (i.c.v.) infusion of the nonselective CRFR antagonist, α-helical CRF9–41 (0, 1, 5, 10 μg/1 μl). The contribution of central CRF type 2 receptor (CRF2R) signaling was assessed with i.c.v. infusion of the selective CRF2R agonist, urocortin (Ucn) 3 (0, 0.05, 0.1, or 0.5 μg/1 μl). The role of the hypothalamic–pituitary–adrenal (HPA) axis was assessed by pretreating mice with intraperitoneal (i.p.) injection of (1) the corticosterone synthesis inhibitor, metyrapone (0, 50, 100, 150 μg/kg) or (2) the glucocorticoid receptor antagonist, mifepristone (0, 25, 50 μg/kg), and (3) by using radioimmunoassay to determine whether binge-like ethanol intake influenced plasma corticosterone levels. Finally, we determined whether the ability of the CRF1R antagonist, CP-154,526 (CP; 0, 10, 15 mg/kg, i.p.), to blunt binge-like drinking required normal HPA axis signaling by comparing the effectiveness of CP in adrenalectomized (ADX) and normal mice. Results showed that i.c.v. infusion of a 1 μg dose of α-helical CRF9–41 significantly attenuated binge-like ethanol consumption relative to vehicle treatment, and i.c.v. infusion of Ucn 3 dose-dependently blunted binge-like drinking. On the other hand, metyrapone nonselectively reduced both ethanol and sucrose consumption, mifepristone did not alter ethanol drinking, and binge-like drinking did not correlate with plasma corticosterone levels. Finally, i.p. injection of CP significantly attenuated binge-like ethanol intake in both ADX and normal mice. Together, these results suggest that binge-like ethanol intake in C57BL/6J mice is modulated by CRF1R and CRF2R signaling, such that blockade of CRF1R or activation of CRF2R effectively reduces excessive ethanol intake. Furthermore, normal HPA axis signaling is not necessary to achieve binge-like drinking behavior.
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影响因子：
3
作者：
Hauger, Richard L.;Risbrough, Victoria;Dautzenberg, Frank M.
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