Department of Psychology , IUPUI, Indianapolis, Indiana.
Alcohol Clin Exp Res. 2014 Jan;38(1):267-74. doi: 10.1111/acer.12216. Epub 2013 Aug 1.
Crossed high-alcohol-preferring (cHAP) mice were selectively bred from a cross of the HAP1 × HAP2 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).
Male 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 ≥1.5 g/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 21 days), 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.
We 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 14 days of free-choice EtOH access.
Overall, 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.
交叉高酒精偏好（cHAP）小鼠是从 HAP1×HAP2 重复系的杂交中选择性繁殖而来的，它们在自由选择饮酒期间表现出类似于酒精依赖人类的血液乙醇浓度（BEC）。在本报告中，我们研究了 cHAP 小鼠的自由选择饮酒、醉酒、耐受和敏化之间的关系。我们假设，最初小鼠在饮酒后会出现共济失调，但随着天数的增加，它们对乙醇（EtOH）的共济失调效应的耐受会增加。
雄性和雌性 cHAP 小鼠可以自由选择摄入 10% EtOH 和水（E），而 Water 小鼠（W）只能摄入水。在实验 1 中，在周期的黑暗部分监测首次饮酒体验。一旦 E 组小鼠的平均摄入量达到≥1.5 g/kg/h，它们与 W 组小鼠一起在平衡木上测试滑脚，并评估 BEC。在实验 2、3 和 4 中，在自由选择 10% EtOH 摄入不同时间（0、3、14 或 21 天）后，用 20% EtOH 对小鼠进行挑战，并在平衡木上测试滑脚次数或运动刺激反应。采集血液样本以测定 BEC。
我们发现 cHAP 小鼠迅速摄入导致共济失调的酒精。随着时间的推移，cHAP 小鼠对酒精的共济失调效应产生了行为性耐受，同时酒精摄入量也在增加。然而，在 14 天的自由选择 EtOH 摄入后，并没有出现运动敏化。
总的来说，我们观察到随着酒精摄入的增加，自由选择饮酒也随之增加，同时伴随着功能性耐受的增加，但没有运动敏化。这些数据支持我们的假设，即在 cHAP 小鼠中，随着时间的推移，自由选择饮酒的增加是由对酒精行为效应的耐受驱动的。这些数据首次表明，随着自由选择消耗的增加，酒精耐受也随之增加。除了支持耐受在饮酒中的假设重要性外，我们的发现还表明，cHAP 小鼠可能是一个独特的转化资源，可用于研究耐受作为慢性、过量乙醇消耗的一个促成因素和后果。
