Ethanol Tolerance and Withdrawal Severity in High Drinking in the Dark Selectively Bred Mice

Portland Alcohol Research Center, Department of Behavioral Neuroscience, Oregon Health, Portland, OR 97239, USA.
Alcoholism Clinical and Experimental Research (Impact Factor: 3.21). 02/2012; 36(7):1152-61. DOI: 10.1111/j.1530-0277.2011.01715.x
Source: PubMed


Mouse lines are being selectively bred in replicate for high blood ethanol concentrations (BECs) achieved after limited access of ethanol (EtOH) drinking early in the circadian dark phase. High Drinking in the Dark-1 (HDID-1) mice are in selected generation S21, and the replicate HDID-2 line in generation S14. Tolerance and withdrawal symptoms are 2 of the 7 diagnostic criteria for alcohol dependence. Withdrawal severity has been found in mouse studies to be negatively genetically correlated with EtOH preference drinking.
To determine other traits genetically correlated with high DID, we compared naïve animals from both lines with the unselected, segregating progenitor stock, HS/Npt. Differences between HDID-1 and HS would imply commonality of genetic influences on DID and these traits.
Female HDID-1 and HDID-2 mice tended to develop less tolerance than HS to EtOH hypothermia after their third daily injection. A trend toward greater tolerance was seen in the HDID males. HDID-1, HDID-2, and control HS lines did not differ in the severity of acute or chronic withdrawal from EtOH as indexed by the handling-induced convulsion (HIC). Both HDID-1 and HDID-2 mice tended to have greater HIC scores than HS regardless of drug treatment.
These results show that tolerance to EtOH's hypothermic effects may share some common genetic control with reaching high BECs after DID, a finding consistent with other data regarding genetic contributions to EtOH responses. Withdrawal severity was not negatively genetically correlated with DID, unlike its correlation with preference drinking, underscoring the genetic differences between preference drinking and DID. HDID lines showed greater basal HIC scores than HS, suggestive of greater central nervous system excitability.


Available from: Pamela Metten
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    • "The same adaptations that produce functional tolerance have been linked to physiological dependence and the accompanying symptoms of ethanol withdrawal (Ghezzi & Atkinson, 2011;Koob & Le Moal, 2006;Martin, 1968). However, the correlation between the capacity to acquire tolerance and increased drinking behavior is complex, and may depend both on the way tolerance was induced and the way it was measured (Crabbe et al., 2012;Fritz, Grahame, & Boehm, 2013;Matson, Kasten, Boehm, & Grahame, 2014). Nevertheless, it is probable that the later M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT adaptations, which produce the addicted state, bear some resemblance to or are built upon the early adaptations that underlie tolerance. "
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    • "Many animals (and most HDID-1 mice) will achieve intoxicating blood alcohol levels in this test, which is thus considered to provide a valid model of binge-like drinking. Despite this susceptibility to binge-like drinking, however, HDID-1 mice show little evidence for excessive voluntary drinking under 24-h access conditions (Crabbe, Spence, Brown, & Metten, 2011; Rosenwasser et al., 2012), nor do they differ from controls in their ethanol withdrawal sensitivity (Crabbe et al., 2012). We found that HDID-1 mice display shortening of free-running period relative to unselected HS/Npt controls under LL, but not in DD. "
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    • "n important factor in the escalating ethanol consumption of HAP2 mice over the course of continuous - access drinking . Numerous studies with selectively bred rodent lines have demonstrated that a genetic predisposition for various forms of excessive alcohol consumption is associated with unique responses to alcohol intoxication in naïve animals ( Crabbe , Kruse , et al . , 2012 ; Fritz et al . , 2013 , 2014 ; Grahame et al . , 2000 ; Waller et al . , 1983 ) ."
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