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首页> 外文期刊>Alcoholism: Clinical and experimental research >Targeting the Glucocorticoid Receptor Reduces Binge‐Like Drinking in High Drinking in the Dark (HDID‐1) Mice
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Targeting the Glucocorticoid Receptor Reduces Binge‐Like Drinking in High Drinking in the Dark (HDID‐1) Mice

机译：靶向糖皮质激素受体在黑暗（HDID-1）小鼠中的高饮酒中减少了狂犬病饮酒

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Background Chronic alcohol exposure can alter glucocorticoid receptor (GR) function in some brain areas that promotes escalated and compulsive‐like alcohol intake. GR antagonism can prevent dependence‐induced escalation in drinking, but very little is known about the role of GR in regulating high‐risk nondependent alcohol intake. Here, we investigate the role of GR in regulating binge‐like drinking and aversive responses to alcohol in the High Drinking in the Dark (HDID‐1) mice, which have been selectively bred for high blood ethanol (EtOH) concentrations (BECs) in the Drinking in the Dark (DID) test, and in their founder line, the HS/NPT. Methods In separate experiments, male and female HDID‐1 mice were administered one of several compounds that inhibited GR or its negative regulator, FKBP51 (mifepristone [12.5, 25, 50, 100?mg/kg], CORT113176 [20, 40, 80?mg/kg], and SAFit2 [10, 20, 40?mg/kg]) during a 2‐day DID task. EtOH consumption and BECs were measured. EtOH conditioned taste and place aversion (CTA and CPA, respectively) were measured in separate HDID‐1 mice after mifepristone administration to assess GR’s role in regulating the conditioned aversive effects of EtOH. Lastly, HS/NPT mice were administered CORT113176 during DID to assess whether dissimilar effects from those of HDID‐1 would be observed, which could suggest that selective breeding had altered sensitivity to the effects of GR antagonism on binge‐like drinking. Results GR antagonism (with both mifepristone and CORT113176) selectively reduced binge‐like EtOH intake and BECs in the HDID‐1 mice, while inhibition of FKBP51 did not alter intake or BECs. In contrast, GR antagonism had no effect on EtOH intake or BECs in the HS/NPT mice. Although HDID‐1 mice exhibit attenuated EtOH CTA, mifepristone administration did not enhance the aversive effects of EtOH in either a CTA or CPA task. Conclusion These data suggest that the selection process increased sensitivity to GR antagonism on EtOH intake in the HDID‐1 mice, and support a role for the GR as a genetic risk factor for high‐risk alcohol intake.
机译：背景技术慢性酒精曝光可以在一些脑区改变糖皮质激素受体（GR）功能，这些脑区域促进升级和强迫性酒精摄入量。 GR拮抗作用可以防止依赖引起的升级在饮酒中，但很少是众所周知的GR在调节高风险的Nodep依赖酒精摄入量的作用。在这里，我们研究了GR在黑暗（HDID-1）小鼠的高饮水中调节虱子般的饮酒和厌恶反应的作用，该小鼠已经选择性地为高血液乙醇（EtOH）浓度（BECS）培养在黑暗（DID）测试中喝酒，并在他们的创始线上，HS / NPT。在单独的实验中，施用雄性和雌性Hdid-1小鼠的几种化合物中的一种，抑制GR或其负调节剂FKBP51（MIFEPRISTONE [12.5,25,50,100×mg / kg]，Cort113176 [20,40,80在2天的任务期间，镁/ kg]，和Safit2 [10,20,40×mg / kg]）。测量EtOH消费和BEC。在米非司酮给药后在单独的HDID-1小鼠中测量EtOH条件的味道和放置厌恶（CTA和CPA），以评估GR的作用在调节EtOH的条件厌恶作用方面。最后，在施用Cort113176期间施用HS / NPT小鼠，以评估HDID-1的异常效应是否被观察到，这可能表明选择性育种改变了对GR对抗体饮酒的敏感性的敏感性。结果GR拮抗作用（用米非司酮和Cort113176）选择性地降低诸如HDID-1小鼠的静脉曲张等细胞和BEC，而FKBP51的抑制没有改变摄入或BEC。相比之下，GR对拮抗作用对EtOH摄入量或BEC在HS / NPT小鼠中没有影响。虽然HDID-1小鼠表现出衰减的EtOH CTA，但米非司酮给药并未增强EtOH在CTA或CPA任务中的厌恶作用。结论这些数据表明，选择过程对HDID-1小鼠的EtOH摄入量的碱基对族菌拮抗感增加了敏感性，并支持GR作为高风险酒精摄入的遗传危险因素的作用。

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