Behavior Genetics

, Volume 41, Issue 2, pp 288–302 | Cite as

Derivation and Characterization of Replicate High- and Low-Alcohol Preferring Lines of Mice and a High-Drinking Crossed HAP Line

  • Brandon Oberlin
  • Christina Best
  • Liana Matson
  • Angela Henderson
  • Nicholas Grahame


Selectively breeding lines of mice and rats to differ in alcohol intake has proven useful for defining which traits correlate with high alcohol drinking behavior, as well as for creating animal models of alcoholism. This study reports the derivation of two novel sets of selected lines, High Alcohol Preferring (HAP) and Low Alcohol Preferring (LAP) replicate 2 and 3 lines. Mice were mass-selected using the same procedure as in the replicate 1 lines: using HS/Ibg as a progenitor, mice were selected for differences in 2-bottle choice intake of 10% alcohol during a 4-week testing period. In addition, another high-drinking line, the crossed HAP (cHAP) line was selectively bred from a progenitors that were a cross of replicate 1 (S27) × replicate 2 (S21) HAP lines. All lines were characterized for saccharin intake. Overall, the response to selection of the HAP and LAP replicate 2 and 3 lines was quite similar. As anticipated, following selection, the cHAP line drank more than either parent HAP line (consuming 26.0 g/kg per day of alcohol by S11), suggesting that this method of crossing replicate lines and selecting from that cross captures more alleles than any single selected line, as well as producing a line with exceptionally high voluntary alcohol intake. As expected, saccharin consumption was highly associated with alcohol consumption; data from 7 lines (HAP 1, 2, and 3, LAP 1, 2, and 3, and cHAP) indicated a genetic correlation between 10% alcohol and 0.32% saccharin intake of 0.91. Overall, these findings show the practicality of developing replicate lines divergent in alcohol preference, and validate a novel procedure for generating very high-drinking mouse populations.


Alcoholism Ethanol Drinking Selected line Genetic Sweet preference 


  1. Agabio R, Carai MA et al (2000) Dissociation of ethanol and saccharin preference in sP and sNP rats. Alcohol Clin Exp Res 24(1):24–29PubMedCrossRefGoogle Scholar
  2. Belknap JK, Crabbe JC et al (1993) Voluntary consumption of ethanol in 15 inbred mouse strains. Psychopharmacology 112(4):503–510PubMedCrossRefGoogle Scholar
  3. Belknap JK, Richards SP et al (1997) Short-term selective breeding as a tool for QTL mapping: ethanol preference drinking in mice. Behav Genet 27(1):55–66PubMedCrossRefGoogle Scholar
  4. Bice PJ, Foroud T et al (2006) Identification of QTLs influencing alcohol preference in the High Alcohol Preferring (HAP) and Low Alcohol Preferring (LAP) mouse lines. Behav Genet 36(2):248–260PubMedCrossRefGoogle Scholar
  5. Bice P, Valdar W et al (2009) Genomewide SNP screen to detect quantitative trait Loci for alcohol preference in the high alcohol preferring and low alcohol preferring mice. Alcohol Clin Exp Res 33(3):531–537PubMedCrossRefGoogle Scholar
  6. Blednov YA, Metten P et al (2005) Hybrid C57BL/6J × FVB/NJ mice drink more alcohol than do C57BL/6J mice. Alcohol Clin Exp Res 29(11):1949–1958PubMedCrossRefGoogle Scholar
  7. Blednov YA, Ozburn AR et al (2010) Hybrid mice as genetic models of high alcohol consumption. Behav Genet 40(1):93–110PubMedCrossRefGoogle Scholar
  8. Carroll ME, Morgan AD et al (2008) Selective breeding for differential saccharin intake as an animal model of drug abuse. Behav Pharmacol 19(5–6):435–460PubMedCrossRefGoogle Scholar
  9. Chester JA, Lumeng L et al (2003) High- and low-alcohol-preferring mice show differences in conditioned taste aversion to alcohol. Alcohol Clin Exp Res 27(1):12–18PubMedGoogle Scholar
  10. Colombo G (1997) ESBRA-Nordmann 1996 Award Lecture: ethanol drinking behaviour in Sardinian alcohol-preferring rats. Alcohol Alcohol 32(4):443–453PubMedGoogle Scholar
  11. Crabbe JC (1989) Genetic animal models in the study of alcoholism. Alcohol Clin Exp Res 13(1):120–127PubMedCrossRefGoogle Scholar
  12. Crabbe JC, Phillips TJ et al (1990) Estimation of genetic correlation: interpretation of experiments using selectively bred and inbred animals. Alcohol Clin Exp Res 14(2):141–151PubMedCrossRefGoogle Scholar
  13. Crabbe JC, Metten P et al (2009) A line of mice selected for high blood ethanol concentrations shows drinking in the dark to intoxication. Biol Psychiatry 65(8):662–670PubMedCrossRefGoogle Scholar
  14. Crawley JN (2007) What’s wrong with my mouse? Behavioral phenotyping of transgenic and knockout mice. Wiley-Interscience, Hoboken, NJGoogle Scholar
  15. Dess NK, Badia-Elder NE et al (1998) Ethanol consumption in rats selectively bred for differential saccharin intake. Alcohol 16(4):275–278PubMedCrossRefGoogle Scholar
  16. Eriksson K (1968) Ethyl alcohol consumption: valid measurement in albino rats. Science 161(836):76–77PubMedCrossRefGoogle Scholar
  17. Falconer DS, Mackay TFC (1996) Introduction to quantitative genetics. Addison Wesley Longman, EssexGoogle Scholar
  18. Flint J, Valdar W et al (2005) Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet 6(4):271–286PubMedCrossRefGoogle Scholar
  19. Foroud T, Bice P et al (2002) Mapping of QTL influencing saccharin consumption in the selectively bred alcohol-preferring and -nonpreferring rat lines. Behav Genet 32(1):57–67PubMedCrossRefGoogle Scholar
  20. Goldman D, Oroszi G et al (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6(7):521–532PubMedCrossRefGoogle Scholar
  21. Grahame NJ (2000) Selected lines and inbred strains. Tools in the hunt for the genes involved in alcoholism. Alcohol Res Health 24(3):159–163PubMedGoogle Scholar
  22. Grahame NJ, Li TK et al (1999) Selective breeding for high and low alcohol preference in mice. Behav Genet 29(1):47–57PubMedCrossRefGoogle Scholar
  23. Green AS, Grahame NJ (2008) Ethanol drinking in rodents: is free-choice drinking related to the reinforcing effects of ethanol? Alcohol 42(1):1–11PubMedCrossRefGoogle Scholar
  24. Grisel JE, Metten P et al (2002) Mapping of quantitative trait loci underlying ethanol metabolism in BXD recombinant inbred mouse strains. Alcohol Clin Exp Res 26(5):610–616PubMedCrossRefGoogle Scholar
  25. Jacquot C, Croft AP et al (2008) “Effects of the glucocorticoid antagonist, mifepristone, on the consequences of withdrawal from long term alcohol consumption. Alc Clin Exp Res 32(12):2107–2116CrossRefGoogle Scholar
  26. Kampov-Polevoy AB, Kasheffskaya OP et al (1996) Pain sensitivity and saccharin intake in alcohol-preferring and -nonpreferring rat strains. Physiol Behav 59(4–5):683–688PubMedCrossRefGoogle Scholar
  27. Kampov-Polevoy A, Garbutt JC et al (1997) Evidence of preference for a high-concentration sucrose solution in alcoholic men. Am J Psychiatry 154(2):269–270PubMedGoogle Scholar
  28. Kampov-Polevoy AB, Garbutt JC et al (1999) Association between preference for sweets and excessive alcohol intake: a review of animal and human studies. Alcohol Alcohol 34(3):386–395PubMedGoogle Scholar
  29. Kranzler HR, Sandstrom KA et al (2001) Sweet taste preference as a risk factor for alcohol dependence. Am J Psychiatry 158(5):813–815PubMedCrossRefGoogle Scholar
  30. Le AD, Israel Y et al (2001) Genetic selection for high and low alcohol consumption in a limited-access paradigm. Alcohol Clin Exp Res 25(11):1613–1620PubMedCrossRefGoogle Scholar
  31. Li TK, Lumeng L et al (1993) Selective breeding for alcohol preference and associated responses. Behav Genet 23(2):163–170PubMedCrossRefGoogle Scholar
  32. Lu K, McDaniel AH, Tordoff MG et al (2005) “No relationship between sequence variation in protein coding regions of the Tas1r3 gene and saccharin preference in rats. Chem Senses 30(3):231–240PubMedCrossRefGoogle Scholar
  33. Lumeng L, Hawkins TD et al (1977) Alcohol and aldehyde metabolizing systems. Academic Press, New YorkGoogle Scholar
  34. Mardones J, Segovia-Riquelme N (1983) Thirty-two years of selection of rats by ethanol preference: UChA and UChB strains. Neurobehav Toxicol Teratol 5(2):171–178PubMedGoogle Scholar
  35. Mennella JA, Pepino MY et al (2010) Sweet preferences and analgesia during childhood: effects of family history of alcoholism and depression. Addiction 105(4):666–675PubMedCrossRefGoogle Scholar
  36. Murphy JM, Stewart RB et al (2002) Phenotypic and genotypic characterization of the Indiana University rat lines selectively bred for high and low alcohol preference. Behav Genet 32(5):363–388PubMedCrossRefGoogle Scholar
  37. Oberlin BG, Grahame NJ (2009) High alcohol preferring mice are more impulsive than low alcohol preferring mice as measured in the delay discounting task. Alcohol Clin Exp Res 33(7):1–10CrossRefGoogle Scholar
  38. Phillips TJ, Crabbe JC et al (1994) Localization of genes affecting alcohol drinking in mice. Alcohol Clin Exp Res 18(4):931–941PubMedCrossRefGoogle Scholar
  39. Phillips TJ, Shen EH et al (2002) Forward, relaxed, and reverse selection for reduced and enhanced sensitivity to ethanol’s locomotor stimulant effects in mice. Alcohol Clin Exp Res 26(5):593–602PubMedGoogle Scholar
  40. Rodriguez LA, Plomin R et al (1995) Alcohol acceptance, preference, and sensitivity in mice. II. Quantitative trait loci mapping analysis using BXD recombinant inbred strains. Alcohol Clin Exp Res 19(2):367–373PubMedCrossRefGoogle Scholar
  41. Sinclair JD, Kampov-Polevoy A et al (1992) Taste preferences in rat lines selected for low and high alcohol consumption. Alcohol 9(2):155–160PubMedCrossRefGoogle Scholar
  42. Stewart RB, Russell RN et al (1994) Consumption of sweet, salty, sour, and bitter solutions by selectively bred alcohol-preferring and alcohol-nonpreferring lines of rats. Alcohol Clin Exp Res 18(2):375–381PubMedCrossRefGoogle Scholar
  43. Tampier L, Quintanilla ME (2005) Saccharin consumption and the effect of a long-term exposure to a sweetened alcoholic solution in high- (UChB) and low- (UChA) alcohol-drinking rats. Alcohol 37(1):47–52PubMedCrossRefGoogle Scholar
  44. Tremblay KA, Bona JM et al (2009) Effects of a diagnosis or family history of alcoholism on the taste intensity and hedonic value of sucrose. Am J Addict 18(6):494–499PubMedCrossRefGoogle Scholar
  45. Waller MB, McBride WJ et al (1982) Induction of dependence on ethanol by free-choice drinking in alcohol-preferring rats. Pharmacol Biochem Behav 16(3):501–507PubMedCrossRefGoogle Scholar
  46. Waller MB, McBride WJ et al (1983) Initial sensitivity and acute tolerance to ethanol in the P and NP lines of rats. Pharmacol Biochem Behav 19(4):683–686PubMedCrossRefGoogle Scholar
  47. Yoneyama N, Crabbe JC et al (2008) Voluntary ethanol consumption in 22 inbred mouse strains. Alcohol 42(3):149–160PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Brandon Oberlin
    • 1
  • Christina Best
    • 1
  • Liana Matson
    • 1
  • Angela Henderson
    • 1
  • Nicholas Grahame
    • 1
  1. 1.Department of PsychologyIndiana University Purdue University at IndianapolisIndianapolisUSA

Personalised recommendations