Abstract
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.
Keywords
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- AA/ANA:
-
Alko Alcohol/Nonalcohol rat selected lines
- AD:
-
Alcohol dependence
- ADH:
-
Alcohol dehydrogenase
- AFT:
-
Acute functional tolerance
- ALDH:
-
Aldehyde dehydrogenase
- BEC:
-
Blood ethanol concentration
- BLA:
-
Basolateral amygdala
- BXD RI:
-
Recombinant inbred strains derived from crossing C57BL/6J and DBA/2J inbreds
- C57BL/6J:
-
A common inbred strain of mice
- CA3:
-
Region of hippocampus
- CeA:
-
Central nucleus of the amygdala
- DBA/2J:
-
A common inbred strain of mice
- DSM-IV-R:
-
Diagnostic and Statistical Manual of the American Psychiatric Association
- FHP/FHN:
-
Family history positive/negative
- GABA:
-
Gamma aminobutyric acid
- GLAST :
-
Gene encoding the glutamate-aspartate transporter
- GLT-1 :
-
Gene encoding a glutamate transporter
- GluR1,2,4 :
-
Genes encoding glutamate receptor subunits
- Gnb1 :
-
Gene encoding the guanine nucleotide binding protein beta 1 subunit
- GO:
-
Gene ontology
- HAFT/LAFT:
-
High/Low Acute Functional Tolerance mouse selected lines
- HAPLAP:
-
High/Low Alcohol Preferring mouse selected lines
- HDID:
-
High Drinking in the Dark mouse selected line
- HIC:
-
Handling-induced convulsion
- HT:
-
Hypothermia
- HRT/LRT:
-
High/Low Rapid Tolerance mouse selected lines
- NAc:
-
Nucleus accumbens
- P/NP:
-
Preferring/Non-preferring rat selected lines
- QTL:
-
Quantitative trait locus/loci
- Scd5 :
-
Gene encoding a stearoyl-CoA desaturase isoform
- Scn4b :
-
Gene encoding the sodium channel 4b subunit
- SNP:
-
Single nucleotide polymorphism
- WDR:
-
Withdrawal
- WGCNA:
-
Weighted gene covariance network analysis
- WSP/WSR:
-
Withdrawal Seizure-Prone/-Resistant mouse selected lines
References
Allison DB, Cui X, Page GP, Sabripour M (2006) Microarray data analysis: from disarray to consolidation and consensus. Nat Rev Genet 7:55--65
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 11:270–288
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):131–147
Belknap JK, Atkins AL (2001) The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies. Mamm Genome 12:893–899
Berta J, Wilson JR (1992) Seven generations of genetic selection for ethanol dependence in mice. Behav Genet 22(3):345–359
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 36:248–260
Bjork K, Hansson AC, Sommer WH (2010) Genetic variation and brain gene expression in rodent models of alcoholism. Int Rev Neurobiol 91:129–171
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 & Wilkins
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 28:9840–9849
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 65:795–807
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 43:411–420
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--1137
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):210–215
Cloninger CR (1987) Neurogenetic adaptive mechanisms in alcoholism. Science 236:410–416
Crabbe JC (1998) Provisional mapping of quantitative trait loci for chronic ethanol withdrawal severity in BXD recombinant inbred mice. J Pharmacol Exp Ther 286:263–271
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 23:798–806
Crabbe JC (2008) Neurogenetic studies of alcohol addiction. Philos Trans R Soc Lond B Biol Sci 363:3201–3211
Crabbe JC (2010) Consilience of rodent and human phenotypes relevant for alcohol dependence: introduction to the special issue. Addict Biol 15:103–108
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):128–133
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):446–458
Crabbe JC, Young ER, Kosobud A (1983) Genetic correlations with ethanol withdrawal severity. Pharmacol Biochem Behav 18(Suppl.1):541–547
Crabbe JC, Kosobud A, Young ER, Tam BR, McSwigan JD (1985) Bidirectional selection for susceptibility to ethanol withdrawal seizures in Mus musculus. Behav Genet 15:521–536
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):141–151
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):663–667
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 269:184–192
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 277:624–632
Crabbe JC, Phillips TJ, Harris RA, Arends MA, Koob GF (2006) Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol 11:195–269
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 65:662–670
Crabbe JC, Bell RL, Ehlers CL (2010a) Human and laboratory rodent low response to alcohol: is better consilience possible? Addict Biol 15:125–144
Crabbe JC, Phillips TJ, Belknap JK (2010b) The complexity of alcohol drinking: studies in rodent genetic models. Behav Genet 40:737–750
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 45:427–440
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 81:943–953
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 32:197–208
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 92:335–342
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 15:217–226
Edenberg HJ, Foroud T (2006) The genetics of alcoholism: identifying specific genes through family studies. Addict Biol 11:386–396
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 15:185–199
Enoch MA, Goldman D (2001) The genetics of alcoholism and alcohol abuse. Curr Psychiatry Rep 3:144–151
Erwin VG, Deitrich RA (1996) Genetic selection and characterization of mouse lines for acute functional tolerance to ethanol. J Pharmacol Exp Ther 279:1310–1317
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 47:345–349
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):264–275
Finn DA, Ford MM, Wiren KM, Roselli CE, Crabbe JC (2004) The role of pregnane neurosteroids in ethanol withdrawal: behavioral genetic approaches. Pharmacol Ther 101:91–112
Finn DA, Belknap JK, Cronise K, Yoneyama N, Murillo A, Crabbe JC (2005) A procedure to produce high alcohol intake in mice. Psychopharmacology 178:471–480
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 93:359–370
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 93–121
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 277:604–612
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 24:579–587
Goldman D, Ducci F (2007) Deconstruction of vulnerability to complex diseases: enhanced effect sizes and power of intermediate phenotypes. Scientific World J 7:124–130
Goldstein DB (1972) Relationship of alcohol dose to intensity of withdrawal signs in mice. J Pharmacol Exp Ther 180:203–215
Goldstein DB, Pal N (1971) Alcohol dependence produced in mice by inhalation of ethanol: grading the withdrawal reaction. Science 172:288–290
Grant BF (2000) Theoretical and observed subtypes of DSM-IV alcohol abuse and dependence in a general population sample. Drug Alcohol Depend 60:287–293
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 66:795–800
Harper CG, Kril JJ (1990) Neuropathology of alcoholism. Alcohol Alcohol 25:207–216
Hashimoto JG, Wiren KM (2008) Neurotoxic consequences of chronic alcohol withdrawal: Expression profiling reveals importance of gender over withdrawal severity. Neuropsychopharmacol 33:1084–1096
Heilig M, Egli M, Crabbe JC, Becker HC (2010) Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addict Biol 15:169–184
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--722
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 27:155–168
Hu W, Saba L, Kechris K, Bhave SV, Hoffman PL, Tabakoff B (2008) Genomic insights into acute alcohol tolerance. J Pharmacol Exp Ther 326:792–800
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 11:585
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 21:1042–1046
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 16:1–33
Kalant H (1998) Research on tolerance: what can we learn from history? Alcohol Clin Exp Res 22:67–76
Kalant H, LeBlanc AE, Gibbins RJ (1971) Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev 23:135–191
Khanna JM, Kalant H, Shah G, Weiner J (1991) Rapid tolerance as an index of chronic tolerance. Pharmacol Biochem Behav 38:427–432
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 302:1238–1245
Kliethermes CL (2005) Anxiety-like behaviors following chronic ethanol exposure. Neurosci Biobehav Rev 28:837–850
Koob GF, Le Moal M (2005) Neurobiology of Addiction. Academic Press, New York
Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35:217–238
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):170–327
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 221–256
Kryger R, Wilce PA (2010) The effects of alcoholism on the human basolateral amygdala. Neuroscience 167:361–371
Lander ES (2011) Initial impact of the sequencing of the human genome. Nature 470:187–197
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 24:1873–1882
Lesscher HM, van Kerkhof LW, Vanderschuren LJ (2010) Inflexible and indifferent alcohol drinking in male mice. Alcohol Clin Exp Res 34:1219–1225
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 15:109–124
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 31:1574–1582
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) 181:688–696
Majchrowicz E (1975) Induction of physical dependence upon ethanol and the associated behavioral changes in rats. Psychopharmacologia 43:245–254
Mardis ER (2011) A decade’s perspective on DNA sequencing technology. Nature 470:198–203
Mardones J, Segovia-Riquelme N (1983) Thirty-two years of selection of rats by ethanol preference: UChA and UChB strains. Neurobehav Toxicol Teratol 5:171–178
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 29:1706–1719
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 81:802–813
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 44:171–183
McClearn GE (1979) Genetics and alcoholism simulacra. Alcohol Clin Exp Res 3:255–258
McClearn GE, Rodgers DA (1959) Differences in alcohol preference among inbred strains of mice. Quart J Studies Alcohol 20:691–695
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):652–835
Melendez RI, Middaugh LD, Kalivas PW (2006) Development of an alcohol deprivation and escalation effect in C57BL/6J mice. Alcohol Clin Exp Res 30:2017–2025
Mellanby E (1919) Alcohol: its absorption into and disappearance from the blood under different conditions. Medical Research Committee, London
Metten P, Crabbe JC (1994) Common genetic determinants of severity of acute withdrawal from ethanol, pentobarbital and diazepam in inbred mice. Behav Pharmacol 5:533–547
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 269–290
Metten P, Crabbe JC (2005) Alcohol withdrawal severity in inbred mouse (Mus musculus) strains. Behav Neurosci 119:911–925
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 95:113–122
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 34:1552–1564
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 760:94–101
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 103:6368–6373
Newlin DB, Thomson JB (1990) Alcohol challenge with sons of alcoholics: a critical review and analysis. Psychol Bull 108(3):383–402
Okamoto M, Boisse NR, Rosenberg HC, Rosen R (1978) Characteristics of functional tolerance during barbiturate physical dependence production. J Pharmacol Exp Ther 207:906–915
Oldham MC, Horvath S, Geschwind DH (2006) Conservation and evolution of gene coexpression networks in human and chimpanzee brains. Proc Natl Acad Sci USA 103:17973–17978
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 11:1271–1282
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 1–30
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 288:866–878
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 17:643–656
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 277:613–623
Ponomarev I, Crabbe JC (2004) Characterization of acute functional tolerance to the hypnotic effects of ethanol in mice. Alcohol Clin Exp Res 28:991–997
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:e28
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 11:603–611
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 1121:54–71
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 623:16–24
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 16:27–35
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 100:2053–2058
Rustay NR, Crabbe JC (2004) Genetic analysis of rapid tolerance to ethanol’s incoordinating effects in mice: inbred strains and artificial selection. Behav Genet 34:441–451
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):1269–1280
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 97:11038–11043
Schuckit MA (2000) Biological phenotypes associated with individuals at high risk for developing alcohol-related disorder. Part 2. Addict Biol 5:23–36
Schuckit MA, Smith TL (1996) An 8-year follow-up of 450 sons of alcoholic and control subjects. Archiv Gen Psychiat 53:202–210
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 15:200–216
Shirley RL, Walter NAR, Reilly MT, Fehr C, Buck KJ (2004) Mpdz is a quantitative trait gene for drug withdrawal seizures. Nat Neurosci 7:699–700
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 30:700–708
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 32:1816–1823
Sinclair JD, Senter RJ (1967) Increased preference for ethanol in rats following alcohol deprivation. Psychonomic Sci 8:11–12
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 72:756–767
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 11:289–309
Spanagel R (2009) Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev 89:649–705
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 15:145–168
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 19:352–365
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 7:70
Treutlein J, Rietschel M (2011) Genome-wide association studies of alcohol dependence and substance use disorders. Curr Psychiat Rep 13(2):147–155
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 26:1494–1501
Victor M, Adams RD (1953) The effect of alcohol on the nervous system. Assoc Res Nerv Mental Disorders 32:526–573
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):1016–1022
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 10:379
Walter NAR, McWeeney SK, Peters ST, Belknap JK, Hitzemann RJ, Buck KJ (2007) SNPs matter: impact on detection of differential expression. Nat Methods 4:679–680
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 33:455–463
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 14:235–256
Wise RA (1973) Voluntary ethanol intake in rats following exposure to ethanol on various schedules. Psychopharmacologia 29:203–210
Zhang B, Hovarth S (2005) A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 4:Article17
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 20:281–300
Acknowledgments
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.
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Appendix
Appendix
Sidebar. Mouse measures of tolerance and withdrawal severity in Tables 1 and 2
Trait | Description | Tabled variables | Reference |
---|---|---|---|
Hypothermic tolerance (standard inbred strains) | Mice were injected daily for 8 days with 3.0 g/kg EtOH. Initial hypothermic sensitivity was indexed as difference scores, each representing the reduction (on day 1) from baseline at 30 or 60 min after injection. Tolerance on days 3, 5, and 8 was indexed as the difference in post-injection change score from day 1 sensitivity score | Table 1, traits 1 and 2 tolerance on day 3 (e.g., HT chronic 30–3 and HT chronic 60–3) Table 1, traits 3 and 4, tolerance on day 5 Table 1, traits 5 and 6, tolerance on day 8 | Crabbe et al. (1982) |
Acute functional tolerance Loss of righting reflex (standard inbred strains) | Mice were injected with 3.0 g/kg EtOH. Blood samples were taken when they lost the righting reflex (i.e., were unable to turn over from a supine position) and when they regained it. The difference in blood EtOH concentrations (recovery minus initial loss) indexed AFT | Table 1, trait 7 AFT LORR | Ponomarev and Crabbe (2004) |
Acute withdrawal (standard inbred strains) | Mice were injected with 4.0 g/kg EtOH and the handling-induced convulsion (HIC) was scored before, and hourly after for 12 h. Withdrawal severity was indexed as the area under the HIC curve corrected for baseline HIC | Table 1, trait 8 Acute WDR | Metten and Crabbe (1994) |
Chronic withdrawal—continuous (standard inbred strains) | Mice were continuously exposed to EtOH vapor for 72 h at an average blood EtOH concentration of 1.6 mg/ml. Withdrawal HIC severity was assessed hourly for 10 h and again at 24 and 25 h. The average area under the 25 h HIC withdrawal curve for each strain was corrected by subtracting the area for HIC scores from a group exposed to air | Table 1, trait 9 Chronic Cont. WDR | Metten and Crabbe (2005) |
Chronic withdrawal—intermittent (Standard inbred strains) | Mice were exposed to EtOH vapor for 16 h/day for 3 days at an average blood EtOH concentration of 1.7 mg/ml. Withdrawal HIC severity was assessed hourly for 10 h and again at 24 and 25 h. The average area under the 25 h HIC withdrawal curve for each strain was corrected by subtracting the area for HIC scores from a group exposed to air | Table 1, trait 10, Chronic Interm. WDR | Metten et al. (2010) |
Hypothermic tolerance (BXD RI recombinant inbred strains) | Mice were injected daily for 3 days with 2.0, 3.0 or 4.0 g/kg EtOH. Initial hypothermic sensitivity was indexed as the average difference from baseline at 30 and 60 min after injection on day 1. Tolerance on days 3, 5, and 8 was indexed as the difference in post-injection change score from day 1 sensitivity scores | Table 2, traits 1–3 HT chronic 2 g/kg, HT chronic 3 g/kg, and HT chronic 4 g/kg | |
Grid test tolerance (BXD RI recombinant inbred strains) | Mice were injected with saline for two days, and EtOH 2.0 g/kg on days 3,5,7,9, and 11. The grid test was used to assess foot fall errors through a wire mesh floor on each EtOH day, corrected for locomotion. Tolerance was indexed as the difference between ataxia ratios (foot falls/activity) on days 11 and 3 | Table 2, trait 4 Grid test | Phillips et al. (1996) |
Acute functional tolerance Dowel test (BXD RI recombinant inbred strains) | Mice were injected with 1.75 g/kg EtOH and placed on a stationary, 1.27 cm dowel, from which they soon fell. A blood sample was collected when they recovered ability to stay on the dowel (BEC1), and they were given a second, 2.0 g/kg injection. Another blood sample (BEC2) was taken when they again regained ability. AFT was indexed as BEC2 minus BEC1 | Table 2, trait 5 AFT Dowel (Kirstein) | Kirstein et al. (2002) |
Acute functional tolerance Dowel test (BXD RI recombinant inbred strains) | Mice were given an injection of 2.0 g/kg EtOH. Brain EtOH levels were taken within 10 s of fall from a rotating, 5 cm dowel to assess initial sensitivity. Separate groups of mice were given the initial 2.0 g/kg injection, and when they recovered ability to stay on the dowel, a blood sample was taken. Mice were then given a “booster” dose of 1.0 g/kg and a second recovery was assessed. Four to five booster doses were given until each RI strain of mice was recovering function at a stable plateau of blood EtOH concentrations. The difference between the final and the initial brain EtOH concentration was taken as the index of tolerance | Table 2, trait 6 AFT Dowel (Gallaher) | Gallaher et al. (1996) |
Acute withdrawal (BXD RI recombinant inbred strains) | Same as for standard inbreds | Table 2, trait 7 Acute WDR | P. Metten and J.K. Belknap, unpublished data, with permission |
Chronic withdrawal—continuous (BXD RI recombinant inbred strains) | Same as for standard inbreds. Average blood EtOH concentration was 1.5 mg/ml | Table 2, trait 8 Chronic cont. WDR | Crabbe (1998) |
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Crabbe, J.C., Kendler, K.S., Hitzemann, R.J. (2011). Modeling the Diagnostic Criteria for Alcohol Dependence with Genetic Animal Models. In: Sommer, W., Spanagel, R. (eds) Behavioral Neurobiology of Alcohol Addiction. Current Topics in Behavioral Neurosciences, vol 13. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28720-6_162
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