title: Chronic free-choice drinking in crossed high alcohol preferring mice leads to sustained blood ethanol levels and metabolic tolerance without evidence of liver damage.
abstract: BACKGROUND
  Crossed high alcohol preferring (cHAP) mice were selectively bred from a cross of the HAP1 × HAP2 replicate lines, and we demonstrate blood ethanol concentrations (BECs) 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 (EtOH) consumption, including metabolic tolerance and liver pathology. Cytochrome p450 2E1 (CYP2E1) induction plays a prominent role in driving both metabolic tolerance and EtOH-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 BECs are similar to those observed in mice given an EtOH 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 EtOH accumulation in these mice. In experiments 1 and 2, mice were injected with EtOH following 3 to 4 weeks of access to water or 10% EtOH and water, and blood samples were taken to assess metabolic tolerance. In experiment 3, 24 mice had 4 weeks of access to 10% EtOH 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, EtOH-exposed mice metabolized EtOH faster than EtOH-naïve mice, demonstrating metabolic tolerance (p < 0.05). In experiment 3, EtOH-drinking mice showed greater expression of hepatic CYP2E1 than water controls, consistent with the development of metabolic tolerance (p < 0.05). EtOH 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 BECs throughout the active period, leading to the development of metabolic tolerance and evidence of CYP2E1 induction. Together, these results provide additional support for the cHAP mice as a highly translational rodent model of alcoholism.
authors: Department of Psychology , Indiana University Purdue University at Indianapolis (IUPUI), Indianapolis,IN 46202, USA.
authors: Liana
authors: L
authors: Matson
authors: Suthat
authors: S
authors: Liangpunsakul
authors: David
authors: D
authors: Crabb
authors: Amy
authors: A
authors: Buckingham
authors: Ruth Ann
authors: RA
authors: Ross
authors: Meredith
authors: M
authors: Halcomb
authors: Nicholas
authors: N
authors: Grahame
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000428:Alcohol Drinking / Q000097:blood* / Q000378:metabolism* / Q000523:psychology; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D002755:Choice Behavior / Q000187:drug effects*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004361:Drug Tolerance / Q000235:genetics*; D000431:Ethanol / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006824:Hybridization, Genetic; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D017440:Photoperiod
chemical_list: D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D000444:Aldehyde Dehydrogenase