Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats
Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats
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DOI：
10.1016/j.biopsych.2006.03.063
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发表时间：
2007-01-01
影响因子：
10.6
通讯作者：
Koob, George F.
中科院分区：
文献类型：
--
作者：
Funk, Cindy K.;Zorrilla, Eric P.;Koob, George F.
背景：酒精依赖的特征是过度饮酒，对摄取失去控制，并出现戒断综合征，包括动机和身体症状。与人类酗酒者相似，酒精依赖的动物在戒断过程中表现出类似焦虑的行为和增强的酒精自我管理(这些影响被假设是由于促肾上腺皮质激素释放因子(CRF)应激系统的失调造成的)。在这里，我们使用酒精依赖的动物模型来测试CRF1受体拮抗剂对依赖大鼠过量酒精自我给药的影响。Wistar大鼠接受过自我口服乙醇的训练，他们被间歇性地暴露在乙醇蒸气中，以诱导酒精依赖。不依赖的动物是。暴露在受控制的空气中。依赖和非依赖动物在2小时的戒断后，分别系统地给予安非他明、MJL-1-109-2或R121919(CRF拮抗剂)，并测定乙醇自身给药。结果：非肽、小分子CRF1拮抗剂选择性地减少依赖动物在急性戒断时乙醇的过度自身给药。拮抗剂对非依赖大鼠的乙醇自我给药无影响。结论：CRF1受体在依赖大鼠过量酒精自我给药中起重要作用，对非依赖大鼠无作用。CRF1拮抗剂可能是治疗人类酒精中毒的令人兴奋的新药物治疗靶点。
Background: Alcohol dependence is characterized by excessive alcohol consumption, loss of control over intake, and the presence of a withdrawal syndrome, which includes both motivational and physical symptoms. Similar to human alcoholics, ethanol-dependent animals display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, (effects hypothesized to result from a dysregulation of corticotropin-releasing factor (CRF) stress systems. Here, we used an animal model of ethanol dependence to test the effects of CRF1 receptor antagonists on excessive ethanol self-administration in dependent rats.Methods. Wistar rats, trained to orally self-administer ethanol, were exposed intermittently to ethanol vapors to induce ethanol dependence. Nondependent animals were. exposed to control air. Following a 2-hour period of withdrawal, dependent and nondependent animals were systemically administered antalarmin, MJL-1-109-2, or R121919 (CRF, antagonists) and ethanol self-administration was measured.Results: The nonpeptide, small molecule CRF1 antagonists selectively reduced excessive self-administration of ethanol in dependent animals during acute withdrawal. The antagonists bad no effect on ethanol self-administration in nondependent rats. Conclusions:These data demonstrate that CRF1 receptors play an important role in mediating excessive ethanol self-administration in dependent rats, with no effect in nondependent rats. CRF1 antagonists may be exciting new pharmacotherapeutic targets for the treatment of alcoholism in humans.