Modeling the Diagnostic Criteria for Alcohol Dependence with Genetic Animal Models

  • John C. CrabbeEmail author
  • Kenneth S. Kendler
  • Robert J. Hitzemann
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 13)


A diagnosis of alcohol dependence (AD) using the DSM-IV-R is categorical, based on an individual’s manifestation of three or more symptoms from a list of seven. AD risk can be traced to both genetic and environmental sources. Most genetic studies of AD risk implicitly assume that an AD diagnosis represents a single underlying genetic factor. We recently found that the criteria for an AD diagnosis represent three somewhat distinct genetic paths to individual risk. Specifically, heavy use and tolerance versus withdrawal and continued use despite problems reflected separate genetic factors. However, some data suggest that genetic risk for AD is adequately described with a single underlying genetic risk factor. Rodent animal models for alcohol-related phenotypes typically target discrete aspects of the complex human AD diagnosis. Here, we review the literature derived from genetic animal models in an attempt to determine whether they support a single-factor or multiple-factor genetic structure. We conclude that there is modest support in the animal literature that alcohol tolerance and withdrawal reflect distinct genetic risk factors, in agreement with our human data. We suggest areas where more research could clarify this attempt to align the rodent and human data.


Withdrawal Tolerance Genetic correlations Gene expression 



Alko Alcohol/Nonalcohol rat selected lines


Alcohol dependence


Alcohol dehydrogenase


Acute functional tolerance


Aldehyde dehydrogenase


Blood ethanol concentration


Basolateral amygdala


Recombinant inbred strains derived from crossing C57BL/6J and DBA/2J inbreds


A common inbred strain of mice


Region of hippocampus


Central nucleus of the amygdala


A common inbred strain of mice


Diagnostic and Statistical Manual of the American Psychiatric Association


Family history positive/negative


Gamma aminobutyric acid


Gene encoding the glutamate-aspartate transporter


Gene encoding a glutamate transporter


Genes encoding glutamate receptor subunits


Gene encoding the guanine nucleotide binding protein beta 1 subunit


Gene ontology


High/Low Acute Functional Tolerance mouse selected lines


High/Low Alcohol Preferring mouse selected lines


High Drinking in the Dark mouse selected line


Handling-induced convulsion




High/Low Rapid Tolerance mouse selected lines


Nucleus accumbens


Preferring/Non-preferring rat selected lines


Quantitative trait locus/loci


Gene encoding a stearoyl-CoA desaturase isoform


Gene encoding the sodium channel 4b subunit


Single nucleotide polymorphism




Weighted gene covariance network analysis


Withdrawal Seizure-Prone/-Resistant mouse selected lines



The authors are supported by grants AA11408, AA017828, AA10760, AA13519, AA 11034 and AA 13484 from the NIH and by grants from the US Department of Veterans Affairs.


  1. Allison DB, Cui X, Page GP, Sabripour M (2006) Microarray data analysis: from disarray to consolidation and consensus. Nat Rev Genet 7:55--65PubMedGoogle Scholar
  2. Bell RL, Rodd ZA, Lumeng L, Murphy JM, McBride WJ (2006) The alcohol-preferring P rat and animal models of excessive alcohol drinking. Addict Biol 11:270–288PubMedGoogle Scholar
  3. Bell RL, Kimpel MW, McClintick JN, Strother WN, Carr LG, Liang T, Rodd ZA, Mayfield RD, Edenberg HJ, McBride WJ (2009) Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption. Pharmacol Biochem Behav 94(1):131–147PubMedCentralPubMedGoogle Scholar
  4. Belknap JK, Atkins AL (2001) The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies. Mamm Genome 12:893–899PubMedGoogle Scholar
  5. Berta J, Wilson JR (1992) Seven generations of genetic selection for ethanol dependence in mice. Behav Genet 22(3):345–359PubMedGoogle Scholar
  6. Bice PJ, Foroud T, Carr LG, Zhang L, Liu L, Grahame NJ, Lumeng L, Li T-K, Belknap JK (2006) Identification of QTLs influencing alcohol preference in the High Alcohol Preferring (HAP) and Low Alcohol Preferring (LAP) mouse lines. Behav Genet 36:248–260PubMedGoogle Scholar
  7. Bjork K, Hansson AC, Sommer WH (2010) Genetic variation and brain gene expression in rodent models of alcoholism. Int Rev Neurobiol 91:129–171PubMedGoogle Scholar
  8. Browman KE, Crabbe JC, Li T-K (2000) Genetic strategies in preclinical substance abuse research. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: a fourth generation of progress [CD-ROM version 3]. Lippincott Williams & WilkinsGoogle Scholar
  9. Chen G, Kozell LB, Hitzemann RJ, Buck KJ (2008) Involvement of the limbic basal ganglia in ethanol withdrawal convulsivity in mice is influenced by a chromosome 4 locus. J Neurosci 28:9840–9849PubMedCentralPubMedGoogle Scholar
  10. Chen CC, Lu RB, Chen YC, Wang MF, Chang YC, Li TK, Yin SJ (1999) Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet 65:795–807PubMedCentralPubMedGoogle Scholar
  11. Chen G, Reilly MT, Kozell LB, Hitzemann RJ, Buck KJ (2009) Differential activation of limbic circuitry associated with chronic ethanol withdrawal in DBA/2J and C57BL/6J mice. Alcohol 43:411–420PubMedCentralPubMedGoogle Scholar
  12. Churchill GA, Airey DC, Allayee H et al (2004) The collaborative cross, a community resource for the genetic analysis of complex traits. Nat Genet 36:1133--1137PubMedGoogle Scholar
  13. Cicero TJ, Meyer ER, Bell RD (1979) Effects of ethanol on the hypothalamic-pituitary-luteinizing hormone axis and testicular steroidogenesis. J Pharmacol Exp Ther 208(2):210–215PubMedGoogle Scholar
  14. Cloninger CR (1987) Neurogenetic adaptive mechanisms in alcoholism. Science 236:410–416PubMedGoogle Scholar
  15. Crabbe JC (1998) Provisional mapping of quantitative trait loci for chronic ethanol withdrawal severity in BXD recombinant inbred mice. J Pharmacol Exp Ther 286:263–271PubMedGoogle Scholar
  16. Coleman SK, Cai C, Mottershead DG, Haapalahti JP, Keinanen K (2003) Surface expression of GluR-D AMPA receptor is dependent on an interaction between its C-terminal domain and a 4.1 protein. J Neurosci 23:798–806PubMedGoogle Scholar
  17. Crabbe JC (2008) Neurogenetic studies of alcohol addiction. Philos Trans R Soc Lond B Biol Sci 363:3201–3211PubMedGoogle Scholar
  18. Crabbe JC (2010) Consilience of rodent and human phenotypes relevant for alcohol dependence: introduction to the special issue. Addict Biol 15:103–108PubMedCentralPubMedGoogle Scholar
  19. Crabbe JC, Rigter H, Uijlen J, Strijbos C (1979) Rapid development of tolerance to the hypothermic effect of ethanol in mice. J Pharmacol Exp Ther 208(1):128–133PubMedGoogle Scholar
  20. Crabbe JC, Janowsky JS, Young ER, Kosobud A, Stack J, Rigter H (1982) Tolerance to ethanol hypothermia in inbred mice: genotypic correlations with behavioral responses. Alcohol Clin Exp Res 6(4):446–458PubMedGoogle Scholar
  21. Crabbe JC, Young ER, Kosobud A (1983) Genetic correlations with ethanol withdrawal severity. Pharmacol Biochem Behav 18(Suppl.1):541–547PubMedGoogle Scholar
  22. Crabbe JC, Kosobud A, Young ER, Tam BR, McSwigan JD (1985) Bidirectional selection for susceptibility to ethanol withdrawal seizures in Mus musculus. Behav Genet 15:521–536PubMedGoogle Scholar
  23. Crabbe JC, Phillips TJ, Kosobud A, Belknap JK (1990) Estimation of genetic correlation: interpretation of experiments using selectively bred and inbred animals. Alcohol Clin Exp Res 14(2):141–151PubMedGoogle Scholar
  24. Crabbe JC, Merrill CD, Belknap JK (1991) Acute dependence on depressant drugs is determined by common genes in mice. J Pharmacol Exp Ther 257(2):663–667PubMedGoogle Scholar
  25. Crabbe JC, Belknap JK, Mitchell SR, Crawshaw LI (1994) Quantitative trait loci mapping of genes that influence the sensitivity and tolerance to ethanol-induced hypothermia in BXD recombinant inbred mice. J Pharmacol Exp Ther 269:184–192PubMedGoogle Scholar
  26. Crabbe JC, Phillips TJ, Gallaher EJ, Crawshaw LI, Mitchell SR (1996) Common genetic determinants of the ataxic and hypothermic effects of ethanol in BXD/Ty recombinant inbred mice: genetic correlations and quantitative trait loci. J Pharmacol Exp Ther 277:624–632PubMedGoogle Scholar
  27. Crabbe JC, Phillips TJ, Harris RA, Arends MA, Koob GF (2006) Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol 11:195–269PubMedGoogle Scholar
  28. Crabbe JC, Metten P, Rhodes JS, Yu C-H, Brown LL, Phillips TJ, Finn DA (2009) A line of mice selected for high blood ethanol concentrations shows drinking in the dark to intoxication. Biol Psychiatry 65:662–670PubMedCentralPubMedGoogle Scholar
  29. Crabbe JC, Bell RL, Ehlers CL (2010a) Human and laboratory rodent low response to alcohol: is better consilience possible? Addict Biol 15:125–144PubMedCentralPubMedGoogle Scholar
  30. Crabbe JC, Phillips TJ, Belknap JK (2010b) The complexity of alcohol drinking: studies in rodent genetic models. Behav Genet 40:737–750PubMedCentralPubMedGoogle Scholar
  31. Crabbe JC, Spence SE, Brown LL, Metten P (2011) Alcohol preference drinking in a mouse line selectively bred for high drinking in the dark. Alcohol 45:427–440PubMedCentralPubMedGoogle Scholar
  32. Cronise K, Finn DA, Metten P, Crabbe JC (2005) Scheduled access to ethanol results in motor impairment and tolerance in female C57BL/6J mice. Pharmacol Biochem Behav 81:943–953PubMedGoogle Scholar
  33. Dhaher R, Finn DA, Snelling CC, Hitzemann RJ (2008) Lesions of the extended amygdala in C57BL/6J mice do not block the intermittent ethanol vapor-induced increase in ethanol consumption. Alcohol Clin Exp Res 32:197–208PubMedGoogle Scholar
  34. Dhaher R, Finn DA, Oberbeck DL, Yoneyama N, Snelling CC, Wu W, Hitzemann RJ (2009) Electrolytic lesions of the medial nucleus accumbens shell selectively decrease ethanol consumption without altering preference in a limited access procedure in C57BL/6J mice. Pharmacol Biochem Behav 92:335–342PubMedGoogle Scholar
  35. Dick DM, Smith G, Olausson P, Mitchell SM, Leeman RF, O’Malley SS, Sher K (2010) Understanding the construct of impulsivity and its relationship to alcohol use disorders. Addict Biol 15:217–226PubMedCentralPubMedGoogle Scholar
  36. Edenberg HJ, Foroud T (2006) The genetics of alcoholism: identifying specific genes through family studies. Addict Biol 11:386–396PubMedGoogle Scholar
  37. Ehlers CL, Walter NAR, Dick DM, Buck KJ, Crabbe JC (2010) A comparison of selected quantitative trait loci associated with alcohol use phenotypes in humans and mouse models. Addict Biol 15:185–199Google Scholar
  38. Enoch MA, Goldman D (2001) The genetics of alcoholism and alcohol abuse. Curr Psychiatry Rep 3:144–151PubMedGoogle Scholar
  39. Erwin VG, Deitrich RA (1996) Genetic selection and characterization of mouse lines for acute functional tolerance to ethanol. J Pharmacol Exp Ther 279:1310–1317PubMedGoogle Scholar
  40. Fahlke C, Hansen S, Engel JA, Hard H (1994) Effects of ventral striatal 6-OHDA lesions or amphetamine sensitization on ethanol consumption in the rat. Pharmacol Biochem Behav 47:345–349PubMedGoogle Scholar
  41. Fidler TL, Dion AM, Powers MS, Ramirez JJ, Mulgrew JA, Smitasin PJ, Crane AT, Cunningham CL (2011) Intragastric self-infusion of ethanol in high- and low-drinking mouse genotypes after passive ethanol exposure. Genes Brain Behav 10(3):264–275PubMedCentralPubMedGoogle Scholar
  42. Finn DA, Ford MM, Wiren KM, Roselli CE, Crabbe JC (2004) The role of pregnane neurosteroids in ethanol withdrawal: behavioral genetic approaches. Pharmacol Ther 101:91–112PubMedGoogle Scholar
  43. Finn DA, Belknap JK, Cronise K, Yoneyama N, Murillo A, Crabbe JC (2005) A procedure to produce high alcohol intake in mice. Psychopharmacology 178:471–480PubMedGoogle Scholar
  44. Flatscher-Bader T, van der Brug M, Hwang JW, Gochee PA, Matsumoto I, Niwa S, Wilce PA (2005) Alcohol-responsive genes in the frontal cortex and nucleus accumbens of human alcoholics. J Neurochem 93:359–370PubMedGoogle Scholar
  45. Friedman HJ (1980) Assessment of physical dependence on and withdrawal from ethanol in animals. In: Rigter H, Crabbe JC (eds) Alcohol Tolerance and Dependence. Elsevier/North-Holland Biomedical Press, Amsterdam, pp 93–121Google Scholar
  46. Gallaher EJ, Jones GE, Belknap JK, Crabbe JC (1996) Identification of genetic markers for initial sensitivity and rapid tolerance to ethanol-induced ataxia using quantitative trait locus analysis in BXD recombinant inbred mice. J Pharmacol Exp Ther 277:604–612PubMedGoogle Scholar
  47. Gehle VM, Erwin VG (2000) The genetics of acute functional tolerance and initial sensitivity to ethanol for an ataxia test in the LSxSS RI strains. Alcohol Clin Exper Res 24:579–587Google Scholar
  48. Goldman D, Ducci F (2007) Deconstruction of vulnerability to complex diseases: enhanced effect sizes and power of intermediate phenotypes. Scientific World J 7:124–130Google Scholar
  49. Goldstein DB (1972) Relationship of alcohol dose to intensity of withdrawal signs in mice. J Pharmacol Exp Ther 180:203–215PubMedGoogle Scholar
  50. Goldstein DB, Pal N (1971) Alcohol dependence produced in mice by inhalation of ethanol: grading the withdrawal reaction. Science 172:288–290PubMedGoogle Scholar
  51. Grant BF (2000) Theoretical and observed subtypes of DSM-IV alcohol abuse and dependence in a general population sample. Drug Alcohol Depend 60:287–293PubMedGoogle Scholar
  52. Grant JD, Agrawal A, Bucholz KK, Madden PA, Pergadia ML, Nelson EC, Lynskey MT, Todd RD, Todorov AA, Hansell NK, Whitfield JB, Martin NG, Heath AC (2009) Alcohol consumption indices of genetic risk for alcohol dependence. Biol Psychiatry 66:795–800PubMedCentralPubMedGoogle Scholar
  53. Harper CG, Kril JJ (1990) Neuropathology of alcoholism. Alcohol Alcohol 25:207–216PubMedGoogle Scholar
  54. Hashimoto JG, Wiren KM (2008) Neurotoxic consequences of chronic alcohol withdrawal: Expression profiling reveals importance of gender over withdrawal severity. Neuropsychopharmacol 33:1084–1096Google Scholar
  55. Heilig M, Egli M, Crabbe JC, Becker HC (2010) Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addict Biol 15:169–184PubMedCentralPubMedGoogle Scholar
  56. Hitzemann RJ, Edmunds S, Wu W, Malmanger B, Walter NAR, Belknap JK, Darakjian P, McWeeney S (2009) Detection of reciprocal quantitative trait loci for acute ethanol withdrawal and ethanol consumption in heterogeneous stock mice. Psychopharmacology (Berl) 203:713--722Google Scholar
  57. Hoffman PL, Miles MF, Edenberg HJ, Sommer W, Tabakoff B, Wehner JM, Lewohl JM (2003) Gene expression in brain: a window on ethanol dependence, neuroadaptation, and preference. Alcohol Clin Exp Res 27:155–168PubMedGoogle Scholar
  58. Hu W, Saba L, Kechris K, Bhave SV, Hoffman PL, Tabakoff B (2008) Genomic insights into acute alcohol tolerance. J Pharmacol Exp Ther 326:792–800PubMedCentralPubMedGoogle Scholar
  59. Iancu OD, Darakjian P, Walter NAR, Malmanger B, Oberbeck DL, Belknap JK, McWeeney S, Hitzemann RJ (2010) Genetic diversity and striatal gene networks: focus on the heterogeneous stock-collaborative cross (HS-CC) mouse. BMC Genomics 11:585PubMedCentralPubMedGoogle Scholar
  60. Ikemoto S, McBride WJ, Murphy JM, Lumeng L, Li T-K (1997) 6-OHDA-lesions of the nucleus accumbens disrupt the acquisition but not the maintenance of ethanol consumption in the alcohol-preferring P line of rats. Alcohol Clin Exp Res 21:1042–1046PubMedGoogle Scholar
  61. Isbell H, Fraser HF, Wikler A, Belleville RE, Eisenman AJ (1955) An experimental study of the etiology of “rum fits” and delirium tremens. Quart J Studies Alcohol 16:1–33Google Scholar
  62. Kalant H (1998) Research on tolerance: what can we learn from history? Alcohol Clin Exp Res 22:67–76PubMedGoogle Scholar
  63. Kalant H, LeBlanc AE, Gibbins RJ (1971) Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev 23:135–191PubMedGoogle Scholar
  64. Khanna JM, Kalant H, Shah G, Weiner J (1991) Rapid tolerance as an index of chronic tolerance. Pharmacol Biochem Behav 38:427–432PubMedGoogle Scholar
  65. Kirstein SL, Davidson KL, Ehringer MA, Sikela JM, Erwin VG, Tabakoff B (2002) Quantitative trait loci affecting initial sensitivity and acute functional tolerance to ethanol-induced ataxia and brain cAMP signaling in BXD recombinant inbred mice. J Pharmacol Exp Ther 302:1238–1245PubMedGoogle Scholar
  66. Kliethermes CL (2005) Anxiety-like behaviors following chronic ethanol exposure. Neurosci Biobehav Rev 28:837–850PubMedGoogle Scholar
  67. Koob GF, Le Moal M (2005) Neurobiology of Addiction. Academic Press, New YorkGoogle Scholar
  68. Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35:217–238PubMedGoogle Scholar
  69. Kosobud A, Crabbe JC (1986) Ethanol withdrawal in mice bred to be genetically prone or resistant to ethanol withdrawal seizures. J Pharmacol Exp Ther 238(1):170–327PubMedGoogle Scholar
  70. Kosobud AE, Crabbe JC (1995) Genetic influences on the development of physical dependence and withdrawal in animals. In: Begleiter H, Kissin B (eds) The genetics of alcoholism. Oxford Univ Press, Oxford, pp 221–256Google Scholar
  71. Kryger R, Wilce PA (2010) The effects of alcoholism on the human basolateral amygdala. Neuroscience 167:361–371PubMedGoogle Scholar
  72. Lander ES (2011) Initial impact of the sequencing of the human genome. Nature 470:187–197PubMedGoogle Scholar
  73. Lewohl JM, Wang L, Miles MF, Zhang L, Dodd PR, Harris RA (2000) Gene expression in human alcoholism: microarray analysis of frontal cortex. Alcohol Clin Exp Res 24:1873–1882PubMedGoogle Scholar
  74. Lesscher HM, van Kerkhof LW, Vanderschuren LJ (2010) Inflexible and indifferent alcohol drinking in male mice. Alcohol Clin Exp Res 34:1219–1225PubMedGoogle Scholar
  75. Leeman RF, Heilig M, Cunningham CL, Stephens DN, Duka T, O’Malley SS (2010) Ethanol consumption: how should we measure it? Achieving consilience between human and animal phenotypes. Addict Biol 15:109–124PubMedCentralPubMedGoogle Scholar
  76. Liu J, Lewohl JM, Harris RA, Iyer VR, Dodd PR, Randall PK, Mayfield RD (2006) Patterns of gene expression in the frontal cortex discriminate alcoholic from nonalcoholic individuals. Neuropsychopharmacology 31:1574–1582PubMedGoogle Scholar
  77. Lopez MF, Becker HC (2005) Effect of pattern and number of chronic ethanol exposures on subsequent voluntary ethanol intake in C57BL/6J mice. Psychopharmacology (Berl) 181:688–696Google Scholar
  78. Majchrowicz E (1975) Induction of physical dependence upon ethanol and the associated behavioral changes in rats. Psychopharmacologia 43:245–254PubMedGoogle Scholar
  79. Mardis ER (2011) A decade’s perspective on DNA sequencing technology. Nature 470:198–203PubMedGoogle Scholar
  80. Mardones J, Segovia-Riquelme N (1983) Thirty-two years of selection of rats by ethanol preference: UChA and UChB strains. Neurobehav Toxicol Teratol 5:171–178PubMedGoogle Scholar
  81. Matthews DB, Bhave SV, Belknap JK, Brittingham C, Chesler EJ, Hitzemann RJ, Hoffmann PL, Lu L, McWeeney S, Miles MF, Tabakoff B, Williams RW (2005) Complex genetics of interactions of alcohol and CNS function and behavior. Alcohol Clin Exp. Res 29:1706–1719PubMedGoogle Scholar
  82. Mayfield RD, Lewohl JM, Dodd PR, Herlihy A, Liu J, Harris RA (2002) Patterns of gene expression are altered in the frontal and motor cortices of human alcoholics. J Neurochem 81:802–813PubMedGoogle Scholar
  83. McBride WJ, Kimpel MW, Schultz JA, McClintick JN, Edenberg HJ, Bell RL (2010) Changes in gene expression in regions of the extended amygdala of alcohol-preferring rats after binge-like alcohol drinking. Alcohol 44:171–183PubMedCentralPubMedGoogle Scholar
  84. McClearn GE (1979) Genetics and alcoholism simulacra. Alcohol Clin Exp Res 3:255–258PubMedGoogle Scholar
  85. McClearn GE, Rodgers DA (1959) Differences in alcohol preference among inbred strains of mice. Quart J Studies Alcohol 20:691–695Google Scholar
  86. Melendez RI (2011) Intermittent (every-other-day) drinking induces rapid escalation of ethanol intake and preference in adolescent and adult C57BL/6J mice. Alcohol Clin Exp Res 35(4):652–835PubMedCentralPubMedGoogle Scholar
  87. Melendez RI, Middaugh LD, Kalivas PW (2006) Development of an alcohol deprivation and escalation effect in C57BL/6J mice. Alcohol Clin Exp Res 30:2017–2025PubMedGoogle Scholar
  88. Mellanby E (1919) Alcohol: its absorption into and disappearance from the blood under different conditions. Medical Research Committee, LondonGoogle Scholar
  89. Metten P, Crabbe JC (1994) Common genetic determinants of severity of acute withdrawal from ethanol, pentobarbital and diazepam in inbred mice. Behav Pharmacol 5:533–547PubMedGoogle Scholar
  90. Metten P, Crabbe JC (1996) Dependence and withdrawal. In Deitrich RA, Erwin VG (eds) Pharmacological Effects of Ethanol on the Nervous System, Boca Raton FL: CRC Press, pp 269–290Google Scholar
  91. Metten P, Crabbe JC (2005) Alcohol withdrawal severity in inbred mouse (Mus musculus) strains. Behav Neurosci 119:911–925PubMedGoogle Scholar
  92. Metten P, Belknap JK, Crabbe JC (1998) Drug withdrawal convulsions and susceptibility to convulsants after short-term selective breeding for acute ethanol withdrawal. Behav Brain Res 95:113–122PubMedGoogle Scholar
  93. Metten P, Sorensen ML, Cameron AJ, Yu C-H, Crabbe JC (2010) Withdrawal severity after chronic intermittent ethanol in inbred mouse strains. Alcohol Clin Exp Res 34:1552–1564PubMedCentralPubMedGoogle Scholar
  94. Moller C, Wiklund L, Sommer W, Thorsell A, Heilig M (1997) Decreased experimental anxiety and voluntary ethanol consumption in rats following central but not basolateral amygdala lesions. Brain Res 760:94–101PubMedGoogle Scholar
  95. Mulligan MK, Ponomarev I, Hitzemann RJ, Belknap JK, Tabakoff B, Harris RA, Crabbe JC, Blednov YA, Grahame NJ, Phillips TJ, Finn DA, Hoffman PL, Iyer VR, Koob GF, Bergeson SE (2006) Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc Natl Acad Sci USA 103:6368–6373PubMedGoogle Scholar
  96. Newlin DB, Thomson JB (1990) Alcohol challenge with sons of alcoholics: a critical review and analysis. Psychol Bull 108(3):383–402PubMedGoogle Scholar
  97. Okamoto M, Boisse NR, Rosenberg HC, Rosen R (1978) Characteristics of functional tolerance during barbiturate physical dependence production. J Pharmacol Exp Ther 207:906–915PubMedGoogle Scholar
  98. Oldham MC, Horvath S, Geschwind DH (2006) Conservation and evolution of gene coexpression networks in human and chimpanzee brains. Proc Natl Acad Sci USA 103:17973–17978PubMedGoogle Scholar
  99. Oldham MC, Konopka G, Iwamoto K, Langfelder P, Kato T, Horvath S, Geschwind DH (2008) Functional organization of the transcriptome in human brain. Nat Neurosci 11:1271–1282PubMedCentralPubMedGoogle Scholar
  100. Palmer AA, Phillips TJ (2002) Quantitative trait locus (QTL) mapping in mice. In: Liu Y, Lovinger DM (eds) Methods in Alcohol-related Neuroscience Research. CRC Press, Boca Raton, pp 1–30Google Scholar
  101. Pandey SC, Zhang D, Mittal N, Nayyar D (1999) Potential role of the gene transcription factor cyclic AMP-responsive element binding protein in ethanol withdrawal-related anxiety. J Pharmacol Exp Ther 288:866–878PubMedGoogle Scholar
  102. Peirce JL, Li H, Wang J, Manly KF, Hitzemann RJ, Belknap JK, Rosen GD, Goodwin S, Sutter TR, Williams RW, Lu L (2006) How replicable are mRNA expression QTL? Mamm Genome 17:643–656PubMedGoogle Scholar
  103. Phillips TJ, Lessov CN, Harland RD, Mitchell SR (1996) Evaluation of potential genetic associations between ethanol tolerance and sensitization in BXD/Ty recombinant inbred mice. J Pharmacol Exp Ther 277:613–623PubMedGoogle Scholar
  104. Ponomarev I, Crabbe JC (2004) Characterization of acute functional tolerance to the hypnotic effects of ethanol in mice. Alcohol Clin Exp Res 28:991–997PubMedGoogle Scholar
  105. Pozhitkov AE, Boube I, Brouwer MH, Noble PA (2010) Beyond Affymetrix arrays: expanding the set of known hybridization isotherms and observing pre-wash signal intensities. Nucleic Acids Res 38:e28PubMedCentralPubMedGoogle Scholar
  106. Prescott CA, Sullivan PF, Kuo PH, Webb BT, Vittum J, Patterson DG, Thiselton DL, Myers JM, Devitt M, Halberstadt LJ, Robinson VP, Neale MC, van den Oord EJ, Walsh D, Riley BP, Kendler KS (2006) Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4. Mol Psychiatry 11:603–611PubMedGoogle Scholar
  107. Price JL (2007) Definition of the orbital cortex in relation to specific connections with limbic and visceral structures and other cortical regions. Ann NY Acad Sci 1121:54–71PubMedGoogle Scholar
  108. Rassnick S, Stinus L, Koob GF (1993) The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat. Brain Res 623:16–24PubMedGoogle Scholar
  109. Rimondini R, Arlinde C, Sommer W, Heilig M (2002) Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol. FASEB J 16:27–35PubMedGoogle Scholar
  110. Roberto M, Madamba SG, Moore SD, Tallent MK, Siggins GR (2003) Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons. Proc Natl Acad Sci USA 100:2053–2058PubMedGoogle Scholar
  111. Rustay NR, Crabbe JC (2004) Genetic analysis of rapid tolerance to ethanol’s incoordinating effects in mice: inbred strains and artificial selection. Behav Genet 34:441–451PubMedGoogle Scholar
  112. Saba LM, Bennett B, Hoffman PL, Barcomb K, Ishii T, Kechris K, Tabakoff B (2011) A systems genetic analysis of alcohol drinking by mice, rats and men: Influence of brain GABAergic transmission. Neuropharmacology 60(7–8):1269–1280PubMedCentralPubMedGoogle Scholar
  113. Sandberg R, Yasuda R, Pankratz DG, Carter TA, Del Rio JA, Wodicka L, Mayford M, Lockhart DJ, Barlow C (2000) Regional and strain-specific gene expression mapping in the adult mouse brain. Proc Natl Acad Sci USA 97:11038–11043PubMedGoogle Scholar
  114. Schuckit MA (2000) Biological phenotypes associated with individuals at high risk for developing alcohol-related disorder. Part 2. Addict Biol 5:23–36PubMedGoogle Scholar
  115. Schuckit MA, Smith TL (1996) An 8-year follow-up of 450 sons of alcoholic and control subjects. Archiv Gen Psychiat 53:202–210Google Scholar
  116. Sher KJ, Dick DM, Crabbe JC, Hutchison KE, O’Malley S, Heath AC (2010) Consilient research approaches in studying gene x environment interactions in alcohol research. Addict Biol 15:200–216PubMedCentralPubMedGoogle Scholar
  117. Shirley RL, Walter NAR, Reilly MT, Fehr C, Buck KJ (2004) Mpdz is a quantitative trait gene for drug withdrawal seizures. Nat Neurosci 7:699–700PubMedGoogle Scholar
  118. Sikela JM, Maclaren EJ, Kim Y, Karimpour-Fard A, Cai WW, Pollack J, Hitzemann RJ, Belknap JK, McWeeney S, Kerns RT, Downing C, Johnson TE, Grant KJ, Tabakoff B, Hoffman PL, Wu CC, Miles MF (2006) DNA microarray and proteomic strategies for understanding alcohol action. Alcohol Clin Exp Res 30:700–708PubMedCentralPubMedGoogle Scholar
  119. Simms JA, Steensland P, Medina B, Abernathy KE, Chandler LJ, Wise R, Bartlett SE (2008) Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats. Alcohol Clin Exp Res 32:1816–1823PubMedCentralPubMedGoogle Scholar
  120. Sinclair JD, Senter RJ (1967) Increased preference for ethanol in rats following alcohol deprivation. Psychonomic Sci 8:11–12Google Scholar
  121. Sokolov BP, Jiang L, Trivedi NS, Aston C (2003) Transcription profiling reveals mitochondrial, ubiquitin and signaling systems abnormalities in postmortem brains from subjects with a history of alcohol abuse or dependence. J Neurosci Res 72:756–767PubMedGoogle Scholar
  122. Sommer W, Hyytia P, Kiianmaa K (2006) The alcohol-preferring AA and alcohol-avoiding ANA rats: neurobiology of the regulation of alcohol drinking. Addict Biol 11:289–309PubMedGoogle Scholar
  123. Spanagel R (2009) Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev 89:649–705PubMedGoogle Scholar
  124. Stephens DN, Duka T, Crombag HS, Cunningham CL, Heilig M, Crabbe JC (2010) Reward sensitivity: Issues of measurement, and achieving consilience between human and animal phenotypes. Addict Biol 15:145–168PubMedGoogle Scholar
  125. Tabakoff B, Saba L, Kechris K, Hu W, Bhave SV, Finn DA, Grahame NJ, Hoffman PL (2008) The genomic determinants of alcohol preference in mice. Mamm Genome 19:352–365PubMedCentralPubMedGoogle Scholar
  126. Tabakoff B, Saba L, Printz M, Flodman P, Hodgkinson C, Goldman D, Koob GF, Richardson HN, Kechris K, Bell RL, Hubner N, Heinig M, Pravenec M, Mangion J, Legault L, Dongier M, Conigrave KM, Whitfield JB, Saunders J, Grant B, Hoffman PL, WHO/ISBRA study on state, trait markers of alcoholism (2009) Genetical genomic determinants of alcohol consumption in rats and humans. BMC Biol 7:70PubMedCentralPubMedGoogle Scholar
  127. Treutlein J, Rietschel M (2011) Genome-wide association studies of alcohol dependence and substance use disorders. Curr Psychiat Rep 13(2):147–155Google Scholar
  128. Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP, Koob GF (2002) Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: regulation by corticotropin-releasing factor. Alcohol Clin Exp Res 26:1494–1501PubMedGoogle Scholar
  129. Victor M, Adams RD (1953) The effect of alcohol on the nervous system. Assoc Res Nerv Mental Disorders 32:526–573Google Scholar
  130. Volkow ND, Hitzemann RJ, Wang GJ, Fowler JS, Burr G, Pascani K, Dewey SL, Wolf AP (1992) Decreased brain metabolism in neurologically intact healthy alcoholics. Am J Psychiat 149(8):1016–1022PubMedGoogle Scholar
  131. Walter NAR, Bottomly D, Laderas T, Mooney MA, Darakjian P, Searles RP, Harrington CA, McWeeney SK, Hitzemann RJ, Buck KJ (2009) High throughput sequencing in mice: a platform comparison identifies a preponderance of cryptic SNPs. BMC Genomics 10:379PubMedCentralPubMedGoogle Scholar
  132. Walter NAR, McWeeney SK, Peters ST, Belknap JK, Hitzemann RJ, Buck KJ (2007) SNPs matter: impact on detection of differential expression. Nat Methods 4:679–680PubMedCentralPubMedGoogle Scholar
  133. Wills TA, Knapp DJ, Overstreet DH, Breese GR (2009) Sensitization, duration, and pharmacological blockade of anxiety-like behavior following repeated ethanol withdrawal in adolescent and adult rats. Alcohol Clin Exp Res 33:455–463PubMedCentralPubMedGoogle Scholar
  134. Wilson JR, Erwin VG, DeFries JC, Petersen DR, Cole-Harding S (1984) Ethanol dependence in mice: Direct and correlated responses to ten generations of selective breeding. Behav Genet 14:235–256PubMedGoogle Scholar
  135. Wise RA (1973) Voluntary ethanol intake in rats following exposure to ethanol on various schedules. Psychopharmacologia 29:203–210PubMedGoogle Scholar
  136. Zhang B, Hovarth S (2005) A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 4:Article17Google Scholar
  137. Zhao W, Langfelder P, Fuller T, Dong J, Li A, Hovarth S (2010) Weighted gene coexpression network analysis: state of the art. J Biopharm Stat 20:281–300PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • John C. Crabbe
    • 1
    • 3
    Email author
  • Kenneth S. Kendler
    • 2
  • Robert J. Hitzemann
    • 1
    • 3
  1. 1.Portland Alcohol Research Center, Department of Behavioral NeuroscienceOregon Health & Science UniversityPortlandUSA
  2. 2.Virginia Institute for Psychiatric and Behavioral GeneticsVirginia Commonwealth UniversityRichmondUSA
  3. 3.VA Medical CenterPortlandUSA

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