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Chronic Free‐Choice Drinking in Crossed High Alcohol Preferring Mice Leads to Sustained Blood Ethanol Levels and Metabolic Tolerance Without Evidence of Liver Damage
Author(s) -
Matson Liana,
Liangpunsakul Suthat,
Crabb David,
Buckingham Amy,
Ross Ruth Ann,
Halcomb Meredith,
Grahame Nicholas
Publication year - 2013
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2012.01873.x
Subject(s) - ethanol , steatosis , alcohol , medicine , endocrinology , metabolism , liver injury , chemistry , biology , biochemistry
Background Crossed high alcohol preferring ( cHAP ) mice were selectively bred from a cross of the HAP 1 × HAP 2 replicate lines, and we demonstrate blood ethanol concentrations ( BEC s) during free‐choice drinking that are reminiscent of those observed in alcohol‐dependent humans. Therefore, this line may provide an unprecedented opportunity to learn about the consequences of excessive voluntary ethanol ( E t OH ) consumption, including metabolic tolerance and liver pathology. Cytochrome p450 2 E 1 ( CYP 2 E 1) induction plays a prominent role in driving both metabolic tolerance and E t OH ‐induced liver injury. In this report, we sought to characterize cHAP drinking by assessing whether pharmacologically relevant BEC levels are sustained throughout the active portion of the light–dark cycle. Given that cHAP intakes and BEC s are similar to those observed in mice given an E t OH liquid diet, we assessed whether free‐choice exposure results in metabolic tolerance, hepatic enzyme induction, and hepatic steatosis. Methods In experiment 1, blood samples were taken across the dark portion of a 12:12 light–dark cycle to examine the pattern of E t OH accumulation in these mice. In experiments 1 and 2, mice were injected with E t OH following 3 to 4 weeks of access to water or 10% E t OH and water, and blood samples were taken to assess metabolic tolerance. In experiment 3, 24 mice had 4 weeks of access to 10% E t OH and water or water alone, followed by necropsy and hepatological assessment. Results In experiment 1, cHAP mice mean BEC values exceeded 80 mg/dl at all sampling points and approached 200 mg/dl during the middle of the dark cycle. In experiments 1 and 2, E t OH ‐exposed mice metabolized E t OH faster than E t OH ‐naïve mice, demonstrating metabolic tolerance ( p < 0.05). In experiment 3, E t OH ‐drinking mice showed greater expression of hepatic CYP 2 E 1 than water controls, consistent with the development of metabolic tolerance ( p < 0.05). E t OH access altered neither hepatic histology nor levels of alcohol dehydrogenase and aldehyde dehydrogenase. Conclusions These results demonstrate that excessive intake by cHAP mice results in sustained BEC s throughout the active period, leading to the development of metabolic tolerance and evidence of CYP 2 E 1 induction. Together, these results provide additional support for the cHAP mice as a highly translational rodent model of alcoholism.