Jensen Bryan E, Townsley Kayla G, Grigsby Kolter B, Metten Pamela, Chand Meher, Uzoekwe Miracle, Tran Alex, Firsick Evan, LeBlanc Katherine, Crabbe John C, Ozburn Angela R
Department of Behavioral Neuroscience, Oregon Health & Science University, and VA Portland Health Care System, Portland, OR 97239, USA.
Brain Sci. 2021 Feb 4;11(2):189. doi: 10.3390/brainsci11020189.
Alcohol use disorder (AUD) is a devastating psychiatric disorder that has significant wide-reaching effects on individuals and society. Selectively bred mouse lines are an effective means of exploring the genetic and neuronal mechanisms underlying AUD and such studies are translationally important for identifying treatment options. Here, we report on behavioral characterization of two replicate lines of mice that drink to intoxication, the High Drinking in the Dark (HDID)-1 and -2 mice, which have been selectively bred (20+ generations) for the primary phenotype of reaching high blood alcohol levels (BALs) during the drinking in the dark (DID) task, a binge-like drinking assay. Along with their genetically heterogenous progenitor line, Hs/Npt, we tested these mice on: DID and drinking in the light (DIL); temporal drinking patterns; ethanol sensitivity, through loss of righting reflex (LORR); and operant self-administration, including fixed ratio (FR1), fixed ratio 3:1 (FR3), extinction/reinstatement, and progressive ratio (PR). All mice consumed more ethanol during the dark than the light and both HDID lines consumed more ethanol than Hs/Npt during DIL and DID. In the dark, we found that the HDID lines achieved high blood alcohol levels early into a drinking session, suggesting that they exhibit front loading like drinking behavior in the absence of the chronicity usually required for such behavior. Surprisingly, HDID-1 (female and male) and HDID-2 (male) mice were more sensitive to the intoxicating effects of ethanol during the dark (as determined by LORR), while Hs/Npt (female and male) and HDID-2 (female) mice appeared less sensitive. We observed lower HDID-1 ethanol intake compared to either HDID-2 or Hs/Npt during operant ethanol self-administration. There were no genotype differences for either progressive ratio responding, or cue-induced ethanol reinstatement, though the latter is complicated by a lack of extinguished responding behavior. Taken together, these findings suggest that genes affecting one AUD-related behavior do not necessarily affect other AUD-related behaviors. Moreover, these findings highlight that alcohol-related behaviors can also differ between lines selectively bred for the same phenotype, and even between sexes within those same line.
酒精使用障碍（AUD）是一种具有毁灭性的精神障碍，对个人和社会有着重大的广泛影响。选择性培育的小鼠品系是探索AUD潜在遗传和神经机制的有效手段，此类研究对于确定治疗方案具有重要的转化意义。在此，我们报告了两个重复品系小鼠的行为特征，即黑暗中高饮（HDID）-1和-2小鼠，它们已被选择性培育（20多代），以在黑暗中饮酒（DID）任务（一种类似暴饮的饮酒试验）中达到高血液酒精水平（BAL）这一主要表型。连同它们基因异质的祖系Hs/Npt，我们对这些小鼠进行了以下测试：DID和光照下饮酒（DIL）；饮酒时间模式；通过翻正反射丧失（LORR）测试乙醇敏感性；以及操作性自我给药，包括固定比率（FR1）、固定比率3:1（FR3）、消退/恢复和累进比率（PR）。所有小鼠在黑暗中摄入的乙醇都比在光照下多，并且两个HDID品系在DIL和DID期间摄入的乙醇都比Hs/Npt多。在黑暗中，我们发现HDID品系在饮酒过程早期就达到了高血液酒精水平，这表明它们在没有通常所需的慢性条件下表现出类似暴饮的饮酒行为。令人惊讶的是，HDID-1（雌性和雄性）和HDID-2（雄性）小鼠在黑暗中对乙醇的中毒作用更敏感（通过LORR确定），而Hs/Npt（雌性和雄性）和HDID-2（雌性）小鼠似乎不太敏感。在操作性乙醇自我给药过程中，我们观察到HDID-1的乙醇摄入量低于HDID-2或Hs/Npt。对于累进比率反应或线索诱导的乙醇恢复，没有基因型差异，不过后者因缺乏消退反应行为而变得复杂。综上所述，这些发现表明影响一种与AUD相关行为的基因不一定会影响其他与AUD相关的行为。此外，这些发现突出表明，在为相同表型选择性培育的品系之间，甚至在同一品系的不同性别之间，与酒精相关的行为也可能存在差异。
