Selectively Bred Crossed High-Alcohol-Preferring Mice Drink to Intoxication and Develop Functional Tolerance, But Not Locomotor Sensitization During Free-Choice Ethanol Access
Selectively Bred Crossed High-Alcohol-Preferring Mice Drink to Intoxication and Develop Functional Tolerance, But Not Locomotor Sensitization During Free-Choice Ethanol Access
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DOI：
10.1111/acer.12216
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发表时间：
2014-01-01
影响因子：
3.2
通讯作者：
Grahame, Nicholas J.
中科院分区：
文献类型：
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作者：
Matson, Liana M.;Kasten, Chelsea R.;Grahame, Nicholas J.
杂交的高酒精偏好（cHAP）小鼠是由HAP1xHAP2复制系杂交而成的，它们在自由选择饮酒时表现出血液乙醇浓度（BECs），这让人想起了在酒精依赖的人类中观察到的情况。在本报告中，我们研究了cHAP小鼠自由选择饮酒、中毒、耐受性和致敏之间的关系。我们假设最初小鼠在饮酒后会出现共济失调，但随着饮酒天数的增加，对乙醇（EtOH）的共济失调作用的耐受性也会增加。方法雄性和雌性cHAP小鼠自由选择10%的EtOH和水(E)，水小鼠(W)单独饮水。在实验1中，在周期的黑暗部分监测第一次饮酒体验。当E小鼠的平均摄取量达到1.5g/kg/h时，他们与W小鼠一起在平衡木上进行脚滑测试，并评估BECs。在实验2、3和4中，在自由选择10% EtOH（0,3,14或21天）的不同持续时间后，小鼠被给予20% EtOH，并测试其在平衡木上的脚滑次数或运动刺激物反应。采血测定BEC。结果我们发现cHAP小鼠迅速获得导致共济失调的酒精摄入量。随着时间的推移，cHAP小鼠对酒精的共济失调作用产生了行为耐受性，同时酒精摄入量也在不断增加。然而，在14天的自由选择EtOH后，运动敏化没有发生。总的来说，我们观察到自由选择饮酒的增加与功能耐受性的增加并行，但没有运动敏化。这些数据支持了我们的假设，即在cHAP小鼠中，自由选择饮酒数天的增加是由对酒精行为影响的耐受性驱动的。这些数据首次证明，随着自由选择消费的增加，酒精耐受性也在增加。除了支持耐受性在饮酒中的重要性的假设外，我们的研究结果表明，cHAP小鼠可能是研究耐受性作为慢性过量EtOH消耗的贡献者和后果的独特的转化资源。
BackgroundCrossed high-alcohol-preferring (cHAP) mice were selectively bred from a cross of the HAP1xHAP2 replicate lines and demonstrate blood ethanol concentrations (BECs) during free-choice drinking reminiscent of those observed in alcohol-dependent humans. In this report, we investigated the relationship between free-choice drinking, intoxication, tolerance, and sensitization in cHAP mice. We hypothesized that initially mice would become ataxic after drinking alcohol, but that increased drinking over days would be accompanied by increasing tolerance to the ataxic effects of ethanol (EtOH).MethodsMale and female cHAP mice had free-choice access to 10% EtOH and water (E), while Water mice (W) had access to water alone. In experiment 1, the first drinking experience was monitored during the dark portion of the cycle. Once E mice reached an average intake rate of 1.5g/kg/h, they, along with W mice, were tested for footslips on a balance beam, and BECs were assessed. In experiments 2, 3, and 4, after varying durations of free-choice 10% EtOH access (0, 3, 14, or 21days), mice were challenged with 20% EtOH and tested for number of footslips on a balance beam or locomotor stimulant response. Blood was sampled for BEC determination.ResultsWe found that cHAP mice rapidly acquire alcohol intakes that lead to ataxia. Over time, cHAP mice developed behavioral tolerance to the ataxic effects of alcohol, paralleled by escalating alcohol consumption. However, locomotor sensitization did not develop following 14days of free-choice EtOH access.ConclusionsOverall, we observed increases in free-choice drinking with extended alcohol access paralleled by increases in functional tolerance, but not locomotor sensitization. These data support our hypothesis that escalating free-choice drinking over days in cHAP mice is driven by tolerance to alcohol's behavioral effects. These data are the first to demonstrate that escalating free-choice consumption is accompanied by increasing alcohol tolerance. In addition to buttressing the hypothesized importance of tolerance in drinking, our findings suggest that cHAP mice may be a unique, translational resource for studying tolerance as a contributor to and consequence of chronic, excessive EtOH consumption.