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Genetic Basis of Ethanol Reward

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Molecular Biology of Drug Addiction

Abstract

Substantial evidence supports the suggestion that development of alcoholism is strongly influenced by family history and that genes underlie a significant portion of that influence (1). Despite recognition of a genetic influence for many decades, it is only within the last 10 years that scientists have had the sophisticated research tools needed to begin the task of identifying specific genes involved in alcoholism. These tools have been provided by advances in molecular biology and by improvements in the animal genetic models and behavioral models used to study the processes that contribute to excessive ethanol consumption.

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References

  1. NIAAA. (2000) 10th Special Report to the U.S. Congress on Alcohol and Health. Public Health Service, U.S. Department of Health and Human Services, Washington, DC.

    Google Scholar 

  2. Tabakoff, B. and Hoffman, P. L. (1988) A neurobiological theory of alcoholism, in Theories on Alcoholism (Chaudron, C. D. and Wilkinson, D. A., eds.), Addiction Research Foundation, Toronto, Canada, pp. 29–72.

    Google Scholar 

  3. Crabbe, J. C. and Cunningham, C. L. (1999) Drug and alcohol dependence-related behaviors, in Handbook of Molecular Techniques for Brain and Behavior Reasearch (Technique in the Behavioral and Neutral Sciences), vol. 13, (Crusio, W. E. and Gerlai, R. T., eds.), Elsevier, Amsterdam, pp. 652–666.

    Google Scholar 

  4. Cunningham, C. L., Fidler, T. L., and Hill, K. G. (2000) Animal models of alcohol’s motivational effects. Alcohol Res. Health 24, 85–92.

    PubMed  CAS  Google Scholar 

  5. Heyman, G. M. (2000) An economic approach to animal models of alcoholism. Alcohol Res. Health 24, 132–139.

    PubMed  CAS  Google Scholar 

  6. Spanagel, R. (2000). Recent animal models of alcoholism. Alcohol Res. Health 24, 124–131.

    PubMed  CAS  Google Scholar 

  7. McClearn, G. E. and Rodgers, D. A. (1959) Differences in alcohol preference among inbred strains of mice. Quart. J. Stud. Alcohol 20, 691–695.

    Google Scholar 

  8. Dole, V. P., Ho, A., and Gentry, T. (1983) An improved technique for monitoring the drinking behavior of mice. Physiol. Behay. 30, 971–974.

    CAS  Google Scholar 

  9. Gill, K., Mundl, W. J., Cabilio, S., and Amit, Z. (1989) A microcomputer controlled data acquisition system for research on feeding and drinking behavior in rats. Physiol. Behay. 45, 741–746.

    CAS  Google Scholar 

  10. Stromberg, M. F., Mackler, S. A., Volpicelli, J. R., O’Brien, C. P., and Dewey, S. L. (2001) The effect of gamma-vinyl-GABA on the consumption of concurrently available oral cocaine and ethanol in the rat. Pharmacol. Biochem. Behay. 68, 291–299.

    CAS  Google Scholar 

  11. Le, A. D., Corrigall, W. A., Harding, J. W., Juzytsch, W., and Li, T. K. (2000) Involvement of nicotinic receptors in alcohol self-administration. Alcohol. Clin. Exp. Res. 24, 155–163.

    PubMed  CAS  Google Scholar 

  12. Marcucella, H. (1989) Predicting the amount of ethanol consumed per bout from schedule of access to ethanol. Animal Learn. Behay. 17, 101–112.

    Google Scholar 

  13. Meisch, R. A. (1977) Ethanol self-administration: infrahuman studies, in Advances in Behavioral Pharmacology, Vol. 1, (Thompson, T and Dews, P., eds.), Academic Press, New York, pp. 35–84.

    Google Scholar 

  14. Samson, H. H. and Hodge, C. W. (1996) Neurobehavioral regulation of ethanol intake, in Pharmacological Effects of Ethanol on the Nervous System (Deitrich, R. A. and Erwin, V. G., eds.). CRC Press, Boca Raton, FL, pp. 203–226.

    Google Scholar 

  15. Rodd-Henricks, Z. A., McKinzie, D. L., Crile, R. S., Murphy, J. M., and McBride, W. J. (2000) Regional heterogeneity for the intracranial self-administration of ethanol within the ventral tegmental area of female Wistar rats. Psychopharmacology 149, 217–224.

    PubMed  CAS  Google Scholar 

  16. Grahame, N. J., and Cunningham, C. L. (1997) Intravenous ethanol self-administration in C57BL/6J and DBA/2J mice. Alcohol. Clin. Exp. Res. 21, 56–62.

    PubMed  CAS  Google Scholar 

  17. Belknap, J. K., Belknap, N. D., Berg, J. H., and Coleman, R. (1977) Preabsorptive vs postabsorptive control of ethanol intake in C57BL/6J and DBA/2J mice. Behay. Genet. 7, 413–425.

    CAS  Google Scholar 

  18. Samson, H. H. (1986) Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol. Clin. Exp. Res. 10, 436–442.

    PubMed  CAS  Google Scholar 

  19. Richter, C. P., and Campbell, K. H. (1940) Alcohol taste thresholds and concentrations of solution preferred by rats. Science 91, 507–509.

    PubMed  CAS  Google Scholar 

  20. Meisch, R. A., and Thompson, T. (1974) Ethanol intake as a function of concentration during food deprivation and satiation. Pharmacol. Biochem. Behay. 2, 589–596.

    CAS  Google Scholar 

  21. Cunningham, C. L., Howard, M. A., Gill, S. J., Rubinstein, M., Low, M. J., and Grandy, D. K. (2000) Ethanol-conditioned place preference is reduced in dopamine D2 receptor-deficient mice. Pharmacol. Biochem. Behay. 67, 693–699.

    CAS  Google Scholar 

  22. Phillips, T. J., Belknap, J. K., Buck, K. J., and Cunningham, C. L. (1998) Genes on mouse chromosomes 2 and 9 determine variation in ethanol consumption. Mammal. Genome 9, 936–941.

    CAS  Google Scholar 

  23. Risinger, F. O., Freeman, P. A., Rubinstein, M., Low, M. J., and Grandy, D. K. (2000) Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice. Psychopharmacology 152, 343–350.

    PubMed  CAS  Google Scholar 

  24. Samson, H. H, Slawecki, C. J., Sharpe, A. L., and Chappell, A. (1998) Appetitive and consummatory behaviors in the control of ethanol consumption: a measure of ethanol seeking behavior. Alcohol. Clin. Exp. Res. 22, 1783–1787.

    PubMed  CAS  Google Scholar 

  25. Samson, H. H., Sharpe, A. L., and Denning, C. (1999) Initiation of ethanol self-administration in the rat using sucrose substitution in a sipper-tube procedure. Psychopharmacology 147, 274–279.

    PubMed  CAS  Google Scholar 

  26. Cunningham, C. L. (1993) Pavlovian drug conditioning, in Methods in Behavioral Pharmacology (van Haaren, F., ed.), Elsevier, Amsterdam, pp. 349–381.

    Google Scholar 

  27. Cunningham, C. L. (1998) Drug conditioning and drug-seeking behavior, in Learning and Behavior Therapy (O’Donohue, W., ed.), Allyn and Bacon, Boston, pp. 518–544.

    Google Scholar 

  28. Katz, R. J. and Gormezano, G. (1979) A rapid and inexpensive technique for assessing the reinforcing effects of opiate drugs. Pharmacol. Biochem. Behay. 11, 231–233.

    CAS  Google Scholar 

  29. Bardo, M. T. and Bevins, R. A. (2000) Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology 153, 31–43.

    PubMed  CAS  Google Scholar 

  30. Tzschentke, T. M. (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog. Neurobiol. 56, 613–672.

    PubMed  CAS  Google Scholar 

  31. Goudie, A. J. (1987). Aversive stimulus properties of drugs: the conditioned taste aversion paradigm, in Experimental Psychopharmacology: Concepts and Methods (Greenshaw, A. J. and Dourish, C. T., eds.), Humana Press, Clifton, NJ, pp. 341–391.

    Google Scholar 

  32. Sherman, J. E., Jorenby, D. E., and Baker, T. B. (1988) Classical conditioning with alcohol: acquired preferences and aversions, tolerance, and urges/cravings, in Theories on Alcoholism (Chaudron, C. D. and Wilkinson, D. A., eds.), Toronto: Addiction Research Foundation, Canada, pp. 173–237.

    Google Scholar 

  33. Cappell, H., LeBlanc, A. E., and Endrenyi, L. (1973) Aversive conditioning by psychoactive drugs: effects of morphine, alcohol and chlordiazepoxide. Psychopharmacologia 29, 239–246

    PubMed  CAS  Google Scholar 

  34. Reicher, M. A. and Holman, E. W. (1977) Location preference and flavor aversion reinforced by amphetamine in rats. Animal Learn. Behay. 5, 343–346.

    Google Scholar 

  35. Grigson, P. S. (1997) Conditioned taste aversions and drugs of abuse: a reinterpretation. Behay. Neurosci. 111, 129–136.

    CAS  Google Scholar 

  36. Hunt, T. and Amit, Z. (1987). Conditioned taste aversion induced by self-administered drugs: paradox revisited. Neurosci. Biobehay. Rev. 11, 107–130.

    CAS  Google Scholar 

  37. Broadbent, J., Muccino, K. J., and Cunningham, C. L. (2002) Ethanol-induced conditioned taste aversion in fifteen inbred mouse strains. Behay. Neurosci., in press.

    Google Scholar 

  38. Holloway, F. A., King, D. A., Bedingfield, J. B., and Gauvin, D. V. (1992) Role of context in ethanol tolerance and subsequent hedonic effects. Alcohol 9, 109–116.

    PubMed  CAS  Google Scholar 

  39. Cunningham, C. L., Niehus, J. S., and Noble, D. (1993) Species difference in sensitivity to ethanol’s hedonic effects. Alcohol 10, 97–102.

    PubMed  CAS  Google Scholar 

  40. Cunningham, C. L., Okorn, D. M., and Howard, C. E. (1997) Interstimulus interval determines whether ethanol produces conditioned place preference or aversion in mice. Animal Learn. Behay. 25, 31–42.

    Google Scholar 

  41. Risinger, F. O. and Cunningham, C. L. (1998) Ethanol-induced conditioned taste aversion in BXD recombinant inbred mice. Alcohol. Clin. Exp. Res. 22, 1234–1244.

    PubMed  CAS  Google Scholar 

  42. Cunningham, C. L. (1995) Localization of genes influencing ethanol-induced conditioned place preference and locomotor activity in BXD recombinant inbred mice. Psychopharmacology 120, 28–41.

    PubMed  CAS  Google Scholar 

  43. Belknap, J. K., Crabbe, J. C., and Young, E. R. (1993) Voluntary consumption of ethanol in 15 inbred mouse strains. Psychopharmacology 112, 503–510.

    PubMed  CAS  Google Scholar 

  44. Cunningham, C. L., Okorn, D. M., and Howard, C. E. (1996) Ethanol-induced conditioned place preference and activation in 15 inbred mouse strains. Alcohol. Clin. Exp. Res. 20, 59A.

    Google Scholar 

  45. Grupe, A., Germer, S., Usuka, J., Aud, D., Belknap, J. K., Klein, R. F., Ahluwalia, M. K., Higuchi, R., and Peltz, G. (2001) In silico mapping of complex disease-related traits in mice. Science 292, 1915–1918.

    PubMed  CAS  Google Scholar 

  46. Paigen, K. and Eppig, J. T. (2000) A mouse phenome project. Mammal. Genome 11, 715–717.

    CAS  Google Scholar 

  47. Crusio, W. E. (1996) Gene-targeting studies: new methods, old problems. Trends Neurosci. 19, 186–187.

    PubMed  CAS  Google Scholar 

  48. Lathe, R. (1996) Mice, gene targeting and behaviour: more than just genetic background. Trends Neurosci. 19, 183–186.

    PubMed  CAS  Google Scholar 

  49. Gerlai, R. (1996) Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? Trends Neurosci. 19, 177–181.

    PubMed  CAS  Google Scholar 

  50. Banbury Conference on Genetic Background in Mice. (1997) Mutant mice and neuroscience: recommendations concerning genetic background. Neuron 19, 755–759.

    Google Scholar 

  51. Kelly, M. A., Rubinstein, M., Phillips, T. J., Lessov, C. N., Burkhart-Kasch, S., Zhang, G., Bunzow, J. R., Fang, Y., Gerhardt, G. A., Grandy, D. K., and Low, M. J. (1998) Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. J. Neurosci. 18, 3470–3479.

    PubMed  CAS  Google Scholar 

  52. Low, M. J., Kelly, M. A., Rubinstein, M., and Grandy, D. K. (1998) Single genes and complex phenotypes. Mol. Pharmacol. 3, 375–377.

    CAS  Google Scholar 

  53. Phillips, T. J., Hen, R., and Crabbe, J. C. (1999) Complications associated with genetic background effects in research using knockout mice. Psychopharmacology 147, 5–7.

    PubMed  CAS  Google Scholar 

  54. Gingrich, J. A. and Hen, R. (2000) The broken mouse: the role of development, plasticity and environment in the interpretation of phenotypic changes in knockout mice. Curr. Opin. Neurobiol. 10, 146–152.

    PubMed  CAS  Google Scholar 

  55. Crabbe, J. C., Belknap, J. K., and Buck, K. J. (1994) Genetic animal models of alcohol and drug abuse. Science 264, 1715–1723.

    PubMed  CAS  Google Scholar 

  56. Lumeng, L., Murphy, J. M., McBride, W. J., and Li, T. K. (1995) Genetic influences on alcohol preference in animals, in The Genetics of Alcoholism (Begleiter, H. and Kissin, B., eds.), Oxford University Press, New York, pp. 165–201.

    Google Scholar 

  57. Phillips, T. J. and Crabbe, J. C. (1991) Behavioral studies of genetic differences in alcohol action, in The Genetic Basis of Alcohol and Drug Actions (Crabbe, J. C. and Harris, R. A., eds.), Plenum Press, New York, pp. 25–104.

    Google Scholar 

  58. Grahame, N. J. (2000) Selected lines and inbred strains. Tools in the hunt for the genes involved in alcoholism. Alcohol Res. Health 24, 159–163.

    PubMed  CAS  Google Scholar 

  59. Phillips, T. J., Belknap, J. K., Hitzemann, R., Buck, K. J., Cunningham, C. L., and Crabbe, J. C. (2002) Harnessing the mouse to unravel the genetics of human disease. Genes Brain Behay. 1, 14–26.

    CAS  Google Scholar 

  60. Metten, P., Phillips, T. J., Crabbe, J. C., Tarantino, L. M., McClearn, G. E., Plomin, R., Erwin, V. G., and Belknap, J. K. (1998) High genetic susceptibility to ethanol withdrawal predicts low ethanol consumption. Mammal. Genome 9, 983–990.

    CAS  Google Scholar 

  61. Belknap, J. K., Richards, S. P., O’Toole, L. A., Helms, M. L., and Phillips, T. J. (1997) Shortterm selective breeding as a tool for QTL mapping: Ethanol preference drinking in mice. Behay. Genet. 27, 55–66.

    CAS  Google Scholar 

  62. Carr, L. G., Foroud, T., Bice, P., Gobbett, T., Ivashina, J., Edenberg, H., Lumeng, L., and Li, T. K. (1998) A quantitative trait locus for alcohol consumption in selectively bred rat lines. Alcohol. Clin. Exp. Res. 22, 884–887.

    PubMed  CAS  Google Scholar 

  63. Bice, P., Foroud, T., Bo, R., Castelluccio, P., Lumeng, L., Li, T. K., and Carr, L. G. (1998) Genomic screen for QTLs underlying alcohol consumption in the P and NP rat lines. Mammal. Genome 9, 949–955.

    CAS  Google Scholar 

  64. Foroud, T., Bice, P., Castelluccio, P., Bo, R., Miller, L., Ritchotte, A., Lumeng, L., Li, T. K., and Carr, L. G. (2000) Identification of quantitative trait loci influencing alcohol consumption in the high alcohol drinking and low alcohol drinking rat lines. Behay. Genet. 30, 131–140.

    CAS  Google Scholar 

  65. McClearn, G. E., Tarantino, L. M., Rodriguez, L. A., Jones, B. C., Blizard, D. A., and Plomin, R. (1997) Genotypic selection provides experimental confirmation for an alcohol consumption quantitative trait locus in mouse. Mol. Psychiatr. 2, 486–489.

    CAS  Google Scholar 

  66. Sugano, M., Tsuchida, K., Sawada, S., and Makino, N. (2000) Reduction of plasma angiotensin II to normal levels by antisense oligodeoxynucleotides against liver angiotensinogen cannot completely attenuate vascular remodeling in spontaneously hypertensive rats. J. Hypertens. 18, 725–731.

    PubMed  CAS  Google Scholar 

  67. Palmer, A. A. and Phillips, T. J. (2002) Quantitative trait locus mapping in mice, in Methods for Alcohol Related Neuroscience Research. (Liu, Y. and Lovinger, D., eds.), CRC Press, Boca Raton, FL, pp. 1–30.

    Google Scholar 

  68. Rikke, B. A. and Johnson, T. E. (1998) Towards the cloning of genes underlying murine QTLs. Mammal. Genome 9, 963–968.

    CAS  Google Scholar 

  69. Zeng, Z. B., Kao, C. H., and Basten, C. J. (1999) Estimating the genetic architecture of quantitative traits. Genet. Res. 74, 279–289.

    PubMed  CAS  Google Scholar 

  70. Crabbe, J. C., Phillips, T. J., Buck, K. J., Cunningham, C. L., and Belknap, J. K. (1999) Identifying genes for alcohol and drug sensitivity: recent progress and future directions. Trends Neurosci. 22, 173–179.

    PubMed  CAS  Google Scholar 

  71. Grisel, J. E. (2000) Quantitative trait locus analysis. Alcohol. Res. Health 24, 169–174.

    PubMed  CAS  Google Scholar 

  72. Flint, J. and Mott, R. (2001) Finding the molecular basis of quantitative traits: successes and pitfalls. Nat. Rev. Genet. 2, 427–445.

    Google Scholar 

  73. Phillips, T. J., Crabbe, J. C., Metten, P., and Belknap, J. K. (1994) Localization of genes affecting alcohol drinking in mice. Alcohol. Clin. Exp. Res. 18, 931–941.

    PubMed  CAS  Google Scholar 

  74. Rodriguez, L. A., Plomin, R., Blizard, D. A., Jones, B. C., and McClearn, G. E. (1995) Alcohol acceptance, preference, and sensitivity in mice. II. Quantitative trait loci mapping analysis using BXD recombinant inbred strains. Alcohol. Clin. Exp. Res. 19, 367–373.

    PubMed  CAS  Google Scholar 

  75. Tarantino, L. M., McClearn, G. E., Rodriguez, L. A., and Plomin, R. (1998).Confirmation of quantitative trait loci for alcohol preference in mice. Alcohol. Clin. Exp. Res. 22, 1099–1105.

    PubMed  CAS  Google Scholar 

  76. Melo, J. A., Shendure, J., Pociask, K., and Silver, L. M. (1996) Identification of sex-specific quantitative trait loci controlling alcohol preference in C57BL/ 6 mice. Nat. Genet. 13, 147–153.

    PubMed  CAS  Google Scholar 

  77. Peirce, J. L., Derr, R., Shendure, J., Kolata, T., and Silver, L. M. (1998) A major influence of sex-specific loci on alcohol preference in C57BL/6 and DBA/2 inbred mice. Mammal. Genome 9, 942–948.

    CAS  Google Scholar 

  78. Dudek, B. C. and Tritto, T. (1995) Classical and neoclassical approaches to the genetic analysis of alcohol-related phenotypes. Alcohol. Clin. Exp. Res. 19, 802–810.

    PubMed  CAS  Google Scholar 

  79. Whatley, V. J., Johnson, T. E., and Erwin, V. G. (1999) Identification and confirmation of quantitative trait loci regulating alcohol consumption in congenic strains of mice. Alcohol. Clin. Exp. Res. 23, 1262–1271.

    PubMed  CAS  Google Scholar 

  80. Gill, K., Desauiniers, N., Desjardins, P., and Lake, K. (1998) Alcohol preference in AXB/ BXA recombinant inbred mice: gender differences and gender-specific quantitative trait loci. Mammal. Genome 9, 929–935.

    CAS  Google Scholar 

  81. Vadasz, C., Saito, M., Balla, A., Kiraly, I., Vadasz, C., 2nd, Gyetvai, B., Mikics, E., Pierson, D., Brown, D., and Nelson, J. C. (2000) Mapping of quantitative trait loci for ethanol preference in quasi- congenic strains. Alcohol 20, 161–171.

    PubMed  CAS  Google Scholar 

  82. Vadasz, C., Saito, M., Gyetvai, B., Mikics, E., and Vadasz, C., II. (2000) Scanning of five chromosomes for alcohol consumption loci. Alcohol 22, 25–34.

    PubMed  CAS  Google Scholar 

  83. Gehle, V. M. and Erwin, V. G. (1998) Common quantitative trait loci for alcohol-related behaviors and CNS neurotensin measures: voluntary ethanol consumption. Alcohol. Clin. Exp. Res. 22, 401–408.

    PubMed  CAS  Google Scholar 

  84. Phillips, T. J., Brown, K. J., Burkhart-Kasch, S., Wenger, C. D., Kelly, M. A., Rubinstein, M., Grandy, D. K., and Low, M. J. (1998) Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors. Nat. Neurosci. 1, 610–615.

    PubMed  CAS  Google Scholar 

  85. Belknap, J. K. and Atkins, A. L. (2001). The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies. Mammal. Genome, 12, 893–899.

    CAS  Google Scholar 

  86. Lander, E. and Kruglyak, L. (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247.

    PubMed  CAS  Google Scholar 

  87. Cunningham, C. L. and Prather, L. K. (1992) Conditioning trial duration affects ethanolinduced conditioned place preference in mice. Animal Learn. Behay. 20, 187–194.

    Google Scholar 

  88. Risinger, F. O. and Oakes, R. A. (1996) Dose- and conditioning-trial dependent ethanolinduced conditioned place preference in Swiss-Webster mice. Pharmacol. Biochem. Behay. 55, 117–123.

    CAS  Google Scholar 

  89. Fernandez, J. R., Tarantino, L. M., Hofer, S. M., Vogler, G. P., and McClearn, G. E. (2000) Epistatic quantitative trait loci for alcohol preference in mice. Behay. Genet. 30, 431–437.

    CAS  Google Scholar 

  90. Hood, H. M., Belknap, J. K., Crabbe, J. C., and Buck, K. J. (2001) Genomewide search for epistasis in a complex trait: pentobarbital withdrawal convulsions in mice. Behay. Genet. 31, 93–100.

    CAS  Google Scholar 

  91. Beal, M. F. (2001) Experimental models of Parkinson’s disease. Nat. Rev. Neurosci. 2, 325–334.

    PubMed  CAS  Google Scholar 

  92. Garver, E., Tu, G. C., Cao, Q. N., Aini, M., Zhou, F., and Israel, Y. (2001) Eliciting the lowactivity aldehyde dehydrogenase asian phenotype by an antisense mechanism results in an aversion to ethanol. J. Exp. Med. 194, 571–580.

    PubMed  CAS  Google Scholar 

  93. Homanics, G. E. and Hiller-Sturmhofel, S. (1997) New genetic technologies in alcohol research. Alcohol Health Res. World 21, 298–309.

    PubMed  CAS  Google Scholar 

  94. Homanics, G. E., Quinlan, J. J., Mihalek, R. M., and Firestone, L. L. (1998) Alcohol and anesthetic mechanisms in genetically engineered mice. Front. Biosci. 3, 548–558.

    Google Scholar 

  95. Landel, C. P. (1991) The production of transgenic mice by embryo microinjection. Genet. Anal. Tech. Appl. 8, 83–94.

    PubMed  CAS  Google Scholar 

  96. Pravenec, M., Landa, V., Zidek, V., Musilova, A., Kren, V., Kazdova, L., Aitman, T. J., Glazier, A. M., Ibrahimi, A., Abumrad, N. A., Qi, N., Wang, J. M., St. Lezin, E. M., and Kurtz, T. W. (2001) Transgenic rescue of defective Cd36 ameliorates insulin resistance in spontaneously hypertensive rats. Nat. Genet. 27, 156–158.

    PubMed  CAS  Google Scholar 

  97. Wehner, J. M. and Bowers, B. J. (1995) Use of transgenics, null mutants, and antisense approaches to study ethanol’s actions. Alcohol. Clin. Exp. Res. 19, 811–820.

    PubMed  CAS  Google Scholar 

  98. LeMarquand, D., Pihl, R. O., and Benkelfat, C. (1994) Serotonin and alcohol intake, abuse, and dependence: findings of animal studies. Biol. Psychiatr. 36, 395–421.

    CAS  Google Scholar 

  99. Crabbe, J. C., Phillips, T. J., Feller, D. J., Hen, R., Wenger, C. D., Lessov, C. N., and Schafer, G. L. (1996) Elevated alcohol consumption in null mutant mice lacking 5-HT 1 B serotonin receptors. Nat. Genet. 14, 98–101.

    PubMed  CAS  Google Scholar 

  100. Risinger, F. O., Bormann, N. M., and Oakes, R. A. (1996) Reduced sensitivity to ethanol reward, but not ethanol aversion in mice lacking 5-HT1b receptors. Alcohol. Clin. Exp. Res. 20, 1401–1405.

    PubMed  CAS  Google Scholar 

  101. Bouwknecht, J. A., Hijzen, T. H., van der Gugten, J., Maes, R. A., Hen, R., and Olivier, B. (2000) Ethanol intake is not elevated in male 5-HT(1B) receptor knockout mice. Eur. J. Pharmacol. 403, 95–98.

    PubMed  CAS  Google Scholar 

  102. Crabbe, J. C., Wahlsten, D., and Dudek, B. C. (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284, 1670–1672.

    PubMed  CAS  Google Scholar 

  103. Risinger, F. O., Doan, A. M., and Vickrey, A. C. (1999) Oral operant ethanol self-administration in 5-HT lb knockout mice. Behay. Brain Res. 102, 211–215.

    CAS  Google Scholar 

  104. Engel, S. R., Lyons, C. R., and Allan, A.M. (1998) 5-HT3 receptor over-expression decreases ethanol self administration in transgenic mice. Psychopharmacology 140, 243–248.

    PubMed  CAS  Google Scholar 

  105. Cases, O., Seif, I., Grimsby, J., Gaspar, P., Chen, K., Pournin, S., Muller, U., Aguet, M., Babinet, C., Shih, J. C., and et al. (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268, 1763–1766.

    PubMed  CAS  Google Scholar 

  106. Popova, N. K., Vishnivetskaya, G. B., Ivanova, E. A., Skrinskaya, J. A., and Seif, I. (2000) Altered behavior and alcohol tolerance in transgenic mice lacking MAO A: a comparison with effects of MAO A inhibitor clorgyline. Pharmacol. Biochem. Behay. 67, 719–727.

    CAS  Google Scholar 

  107. Di Chiara, G. (1998) A motivational learning hypothesis of the role of mesolimbic dopamine in compulsive drug use. J. Psychopharmacol. 12, 54–67.

    PubMed  Google Scholar 

  108. Spanagel, R. and Weiss, F. (1999) The dopamine hypothesis of reward: past and current status. Trends Neurosci. 22, 521–527.

    PubMed  CAS  Google Scholar 

  109. Koob, G. F., Roberts, A. J., Schulteis, G., Parsons, L. H., Heyser, C. J., Hyytiä, P., Merlo-Pich, E., and Weiss, F. (1998) Neurocircuitry targets in ethanol reward and dependence. Alcohol. Clin. Exp. Res. 22, 3–9.

    PubMed  CAS  Google Scholar 

  110. El-Ghundi, M., George, S. R., Drago, J., Fletcher, P. J., Fan, T., Nguyen, T., Liu, C., Sibley, D. R., Westphal, H., and O’Dowd, B. F. (1998) Disruption of dopamine D1 receptor gene expression attenuates alcohol-seeking behavior. Eur. J. Pharmacol. 353, 149–158.

    PubMed  CAS  Google Scholar 

  111. Drago, J., Gerfen, C. R., Lachowicz, J. E., Steiner, H., Hollon, T. R., Love, P. E., Ooi, G. T., Grinberg, A., Lee, E. J., Huang, S. P., and et al. (1994) Altered striatal function in a mutant mouse lacking D 1 A dopamine receptors. Proc. Natl. Acad. Sci. USA 91, 12,564–12,568.

    Google Scholar 

  112. Robinson, S. W., Dinulescu, D. M., and Cone, R. D. (2000) Genetic models of obesity and energy balance in the mouse. Ann. Rev. Genet. 34, 687–745.

    PubMed  CAS  Google Scholar 

  113. Thanos, P. K., Volkow, N. D., Freimuth, P., Umegaki, H., Ikari, H., Roth, G., Ingram, D. K., and Hitzemann, R. (2001) Overexpression of dopamine D2 receptors reduces alcohol selfadministration. J. Neurochem. 78, 1094–1103.

    PubMed  CAS  Google Scholar 

  114. Risinger, F. O., Freeman, P. A., Greengard, P., and Fienberg, A. A. (2001) Motivational effects of ethanol in DARPP-32 knock-out mice. J. Neurosci. 21, 340–348.

    PubMed  CAS  Google Scholar 

  115. Herz, A. (1997) Endogenous opioid systems and alcohol addiction. Psychopharmacology 129, 99–111.

    PubMed  CAS  Google Scholar 

  116. Roberts, A. J., McDonald, J. S., Heyser, C. J., Kieffer, B. L., Matthes, H. W., Koob, G. F., and Gold, L. H. (2000) Mu-Opioid receptor knockout mice do not self-administer alcohol. J. Pharmacol. Exp. Ther. 293, 1002–1008.

    PubMed  CAS  Google Scholar 

  117. Hall, F. S., Sora, I., and Uhl, G. R. (2001) Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice. Psychopharmacology 154, 43–49.

    PubMed  CAS  Google Scholar 

  118. Grisel, J. E., Mogil, J. S., Grahame, N. J., Rubinstein, M., Belknap, J. K., Crabbe, J. C., and Low, M. J. (1999) Ethanol oral self-administration is increased in mutant mice with decreased beta-endorphin expression. Brain Res. 835, 62–67.

    PubMed  CAS  Google Scholar 

  119. Grahame, N. J., Low, M. J., and Cunningham, C. L. (1998) Intravenous self-administration of ethanol in beta-endorphin-deficient mice. Alcohol. Clin. Exp. Res. 22, 1093–1098.

    PubMed  CAS  Google Scholar 

  120. Hodge, C. W., Mehmert, K. K., Kelley, S. P., McMahon, T., Haywood, A., Olive, M. F., Wang, D., Sanchez-Perez, A. M., and Messing, R. O. (1999) Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKCepsilon. Nat. Neurosci. 2, 997–1002.

    PubMed  CAS  Google Scholar 

  121. Olive, M. F., Mehmert, K. K., Messing, R. O., and Hodge, C. W. (2000) Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol in PKCedeficient mice. Eur. J. Neurosci. 12, 4131–4140.

    PubMed  CAS  Google Scholar 

  122. Thiele, T. E., Willis, B., Stadler, J., Reynolds, J. G., Bernstein, I. L., and McKnight, G. S. (2000) High ethanol consupmtion and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice. J. Neurosci. 20, RC75.

    Google Scholar 

  123. Wand, G., Levine, M., Zweifel, L., Schwindinger, W., and Abel, T. (2001) The cAMP-protein kinase A signal transduction pathway modulates ethanol consumption and sedative effects of ethanol. J. Neurosci. 21, 5297–5303.

    PubMed  CAS  Google Scholar 

  124. Thiele, T. E., Marsh, D. J., Ste Marie, L., Bernstein, I. L., and Palmiter, R. D. (1998) Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 396, 366–369.

    PubMed  CAS  Google Scholar 

  125. Thiele, T. E., Miura, G. I., Marsh, D. J., Bernstein, I. L., and Palmiter, R. D. (2000) Neurobiological responses to ethanol in mutant mice lacking neuropeptide Y or the Y5 receptor. Pharmacol. Biochem. Behay. 67, 683–691.

    CAS  Google Scholar 

  126. Weinshenker, D., Rust, N. C., Miller, N. S., and Palmiter, R. D. (2000) Ethanol-associated behaviors of mice lacking norepinephrine. J. Neurosci. 20, 3157–3164.

    PubMed  CAS  Google Scholar 

  127. Blednov, Y. A., Stoffel, M., Chang, S. R., and Harris, R. A. (2001) Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice. J. Pharmacol. Exp. Ther. 298, 521–530.

    PubMed  CAS  Google Scholar 

  128. Siems, W., Maul, B., Krause, W., Gerard, C., Hauser, K. F., Hersh, L. B., Fischer, H. S., Zernig, G., and Saria, A. (2000) Neutral endopeptidase and alcohol consumption, experiments in neutral endopeptidase-deficient mice. Eur. J. Pharmacol. 397, 327–334.

    PubMed  CAS  Google Scholar 

  129. Maul, B., Siems, W. E., Hoehe, M. R., Grecksch, G., Bader, M., and Walther, T. (2001) Alcohol consumption is controlled by angiotensin II. FASEB J. 15, 1640–1642.

    PubMed  CAS  Google Scholar 

  130. Meliska, C. J., Bartke, A., Vandergriff, J. L., and Jensen, R. A. (1995) Ethanol and nicotine consumption and preference in transgenic mice overexpressing the bovine growth hormone gene. Pharmacol. Biochem. Behay. 50, 563–570.

    CAS  Google Scholar 

  131. Aragon, C. M. and Amit, Z. (1993) Differences in ethanol-induced behaviors in normal and acatalasemic mice: systematic examination using a biobehavioral approach. Pharmacol. Biochem. Behay. 44, 547–554.

    CAS  Google Scholar 

  132. Lariviere, W. R., Chesler, E. J., and Mogil, J. S. (2001) Transgenic studies of pain and analgesia: mutation or background genotype? J. Pharmacol. Exp. Ther. 297, 467–473.

    PubMed  CAS  Google Scholar 

  133. Wang, Q., Hummler, E., Maillard, M., Nussberger, J., Rossier, B. C. K. I., Brunner, H. R., and Burnier, M. (2001) Compensatory up-regulation of angiotensin II subtype 1 receptors in alpha ENaC knockout heterozygous mice. Kidney Int. 59, 2216–2221.

    PubMed  CAS  Google Scholar 

  134. Miles, M. F., Barhite, S., Sganga, M., and Elliott, M. (1993) Phosducin-like protein: an ethanol-responsive potential modulator of guanine nucleotide-binding protein function. Proc. Natl. Acad. Sci. USA 90, 10,831–10,835.

    Google Scholar 

  135. Miles, M. F., Diaz, J. E., and DeGuzman, V. (1992) Ethanol-responsive gene expression in neural cell cultures. Biochim. Biophys. Acta 1138, 268–274.

    PubMed  CAS  Google Scholar 

  136. Lander, E. S. (1999) Array of hope. Nat. Genet. 21(Suppl. I), 3–4.

    PubMed  CAS  Google Scholar 

  137. Lewohl, J. M., Wang, L., Miles, M. F., Zhang, L., Dodd, P. R., and Harris, R. A. (2000). Gene expression in human alcoholism: microarray analysis of frontal cortex. Alcohol. Clin. Exp. Res. 24, 1873–1882.

    PubMed  CAS  Google Scholar 

  138. Thibault, C., Lai, C., Wilke, N., Duong, B., Olive, M. F., Rahman, S., Dong, H., Hodge, C. W., Lockhart, D. J., and Miles, M. F. (2000) Expression profiling of neural cells reveals specific patterns of ethanol-responsive gene expression. Mol. Pharmacol. 58, 1593–1600.

    PubMed  CAS  Google Scholar 

  139. Xu, Y., Ehringer, M., Yang, F., and Sikela, J. M. (2001) Comparison of global brain gene expression profiles between inbred long-sleep and inbred short-sleep mice by high-density gene array hybridization. Alcohol. Clin. Exp. Res. 25, 810–818.

    PubMed  CAS  Google Scholar 

  140. Topple, A. N., Hunt, G. E., and McGregor, I. S. (1998) Possible neural substrates of beercraving in rats. Neurosci. Lett. 252, 99–102.

    PubMed  CAS  Google Scholar 

  141. Ryabinin, A. E., Wang, Y.-M., Freeman, P., and Risinger, F. O. (1999) Selective effects of alcohol drinking on restraint-induced expression of immediate early genes in mouse brain. Alcohol. Clin. Exp. Res. 23, 1272–1280.

    PubMed  CAS  Google Scholar 

  142. Bachtell, R. K., Wang, Y.-M., Freeman, P., Risinger, F. O., and Ryabinin, A. E. (1999) Alcohol drinking produces brain region-selective changes in expression of inducible transcription factors. Brain Res. 847, 157–165.

    PubMed  CAS  Google Scholar 

  143. Ryabinin, A. E., Bachtell, R. K., Freeman, P., and Risinger, F. O. (2001) ITF expression in mouse brain during acquisition of alcohol self- administration. Brain Res. 890, 192–195.

    PubMed  CAS  Google Scholar 

  144. Weitemier, A., Woerner, A., Bäckström, P., Hyytiá, P., and Ryabinin, A. E. (2001) Expression of c-Fos in Alko Alcohol rats responding for ethanol in an operant paradigm. Alcohol. Clin. Exp. Res. 25, 704–710.

    PubMed  CAS  Google Scholar 

  145. Buttner-Ennever, J. A., Horn, A. K., Scherberger, H., and D’ascanio, P. (2001) Motoneurons of twitch and nontwitch extraocular muscle fibers in the abducens, trochlear, and oculomotor nuclei of monkeys. J. Comp. Neurol. 438, 318–335.

    PubMed  CAS  Google Scholar 

  146. Weninger, S. C., Peters, L. L., and Majzoub, J. A. (2000) Urocortin expression in the EdingerWestphal nucleus is up-regulated by stress and corticotropin-releasing hormone deficiency. Endocrinology 141, 256–263.

    PubMed  CAS  Google Scholar 

  147. Syvalahti, E. K., Pohjalainen, T., Korpi, E. R., Palvimaki, E. P., Ovaska, T., Kuoppamaki, M., and Hietala, J. (1994) Dopamine D2 receptor gene expression in rat lines selected for differences in voluntary alcohol consumption. Alcohol. Clin. Exp. Res. 18, 1029–1031.

    PubMed  CAS  Google Scholar 

  148. Sommer, W., Arlinde, C., Caberlotto, L., Thorsell, A., Hyytia, P., and Heilig, M. (2001) Differential expression of diacylglycerol kinase iota and L 1 8A mRNAs in the brains of alcoholpreferring AA and alcohol-avoiding ANA rats. Mol. Psychiatr. 6, 103–108.

    CAS  Google Scholar 

  149. Eravci, M., Schulz, O., Grospietsch, T., Pinna, G., Brodel, O., Meinhold, H., and Baumgartner, A. (2000) Gene expression of receptors and enzymes involved in GABAergic and glutamatergic neurotransmission in the CNS of rats behaviourally dependent on ethanol. Br. J. Pharmacol. 131, 423–432.

    PubMed  CAS  Google Scholar 

  150. Agarwal, D. P. and Goedde, H. W. (1992) Pharmacogenetics of alcohol metabolism and alcoholism. Pharmacogenetics 2, 48–62.

    PubMed  CAS  Google Scholar 

  151. Crabb, D. W., Dipple, K. M., and Thomasson, H. R. (1993) Alcohol sensitivity, alcohol metabolism, risk of alcoholism, and the role of alcohol and aldehyde dehydrogenase genotypes. J. Lab. Clin. Med. 122, 234–240.

    PubMed  CAS  Google Scholar 

  152. Enomoto, N., Takase, S., Yasuhara, M., and Takada, A. (1991) Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol. Clin. Exp. Res. 15, 141–144.

    PubMed  CAS  Google Scholar 

  153. Higuchi, S. (1994) Polymorphisms of ethanol metabolizing enzyme genes and alcoholism. Alcoh. Alcohol. Suppl. 2, 29–34.

    CAS  Google Scholar 

  154. Tagliabracci, C. E. and Singh, S. M. (1996) Genetic regulation of gene-specific mRNA by ethanol in vivo and its possible role in ethanol preference in a cross with RI lines in mice. Biochem. Genet. 34, 219–238.

    PubMed  CAS  Google Scholar 

  155. Crabbe, J. C., Phillips, T. J., Kosobud, A., and Belknap, J. K. (1990) Estimation of genetic correlation: Interpretation of experiments using selectively bred and inbred animals. Alcohol. Clin. Exp. Res. 14, 141–151.

    PubMed  CAS  Google Scholar 

  156. Belknap, J. K., Hitzemann, R., Crabbe, J. C., Phillips, T. J., Buck, K. J., and Williams, R. W. (2001) QTL analysis and genomewide mutagenesis in mice: complementary genetic approaches to the dissection of complex traits. Behay. Genet. 31, 5–15.

    CAS  Google Scholar 

  157. Nadeau, J. H. and Frankel, W. N. (2000) The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs. Nat. Genet. 25, 381–384.

    PubMed  CAS  Google Scholar 

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Cunningham, C.L., Phillips, T.J. (2003). Genetic Basis of Ethanol Reward. In: Maldonado, R. (eds) Molecular Biology of Drug Addiction. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-343-9_14

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