NeuroMolecular Medicine

, Volume 5, Issue 1, pp 85–108 | Cite as

Genes associated with addiction

Alcoholism, opiate, and cocaine addiction
  • Mary Jeanne Kreek
  • David A. Nielsen
  • K. Steven LaForge


Drug addiction is a complex disorder that has a large spectrum of causes. Vulnerability to addiction has been shown in twin studies to have a robust genetic component. This genetic basis for addiction has general and specific components for each drug abused. Although many genes have been implicated in drug addiction, only a handful have either been replicated to have an association or to have an identified functional mechanism related to specific effects of abused drugs. A few selected genetic variants that currently look promising for the study of alcohol, opiate, and cocaine addiction are discussed in this article.

Index Entries

Addiction alcohol cocaine genetics genotype opiate physiogenetics physiogenomics polymorphism single nucleotide polymorphism 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alexander, R. C., Heydt, D., Ferraro, T. N., Vogel, W., Berrettini, W. H. (1996) Further evidence for a quantitative trait locus on murine chromosome 10 controlling morphine preference in inbred mice. Psychiatr. Genet. 6, 29–31.PubMedGoogle Scholar
  2. Alván, G., Bechtel, P., Iselius, L., Gundert-Remy, U. (1990) Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur. J. Clin. Pharmacol. 39, 533–537.PubMedGoogle Scholar
  3. Asghari, V., Sanyal, S., Buchwaldt, S., Paterson, A., Jovanovic, V., Van Tol, H. H. (1995) Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J. Neurochem. 65, 1157–1165.PubMedGoogle Scholar
  4. Aubert, R., Betoulle, D., Herbeth, B., Siest, G., Fumeron, F. (2000) 5-HT2A receptor gene polymorphism is associated with food and alcohol intake in obese people. Int. J. Obes. Relat. Metab. Disord. 24, 920–924.PubMedGoogle Scholar
  5. Barnard, E. A., Skolnick, P., Olsen, R. W., et al. (1998) International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acid A receptors: classification on the basis of subunit structure and receptor function. Pharmacol. Rev. 50, 291–313.PubMedGoogle Scholar
  6. Becker, A., Grecksch, G., Brodemann, R., et al. (2000) Morphine self-administration in mu-opioid receptor-deficient mice. Naunyn-Schmiedebergs Arch. Pharmacol. 361, 584–589.PubMedGoogle Scholar
  7. Becker, A., Grecksch, G., Kraus, J., Loh, H. H., Schroeder, H., Hollt, V. (2002) Rewarding effects of ethanol and cocaine in mu opioid receptor-deficient mice. Naunyn-Schmiedebergs Arch. Pharmacol. 365, 296–302.PubMedGoogle Scholar
  8. Befort, K., Filliol, D., Decaillot, F. M., Gaveriaux-Ruff, C., Hoehe, M. R., Kieffer, B. L. (2001) A single nucleotide polymorphic mutation in the human mu opioid receptor severely impairs receptor signaling. J. Biol. Chem. 276, 3130–3137.PubMedGoogle Scholar
  9. Belknap, J. K., and Crabbe, J. C. (1992) Chromosome mapping of gene loci affecting morphine and amphetamine responses in BXB recombinant inbred mice. Ann. NY. Acad. Sci. 654, 311–323.PubMedGoogle Scholar
  10. Bergen, A. W., Kokoszka, J., Peterson, R., et al. (1997) Mu opioid receptor gene variants: lack of association with alcohol dependence. Mol. Psychiatry 2, 490–494.PubMedGoogle Scholar
  11. Berrettini, W. H., Ferraro, T. N., Alexander, A. C., Buchberg, A. M., Vogel, W. H. (1994) Quantitative trait loci mapping of three loci controlling morphine preference using inbred mouse strains. Nat. Genet. 7, 54–58.PubMedGoogle Scholar
  12. Berrettini, W. H., Hoehe, M. R., Ferrada, T. N., Gottheil, E. (1997) Human mu opioid receptor gene polymorphisms and vulnerability to substance abuse. Addict. Biol. 2, 303–308.Google Scholar
  13. Bierut, L. J., Dinwiddie, S. H., Begleiter, H., et al. (1998) Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. Arch. Gen. Psychiatry 55, 982–988.PubMedGoogle Scholar
  14. Bond, C., LaForge, K. S., Tian, M., et al. (1998) Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc. Natl. Acad. Sci. USA. 95, 9608–9613.PubMedGoogle Scholar
  15. Bosron, W. F., Ehrig, T., Li, T. K. (1993) Genetic factors in alcohol metabolism and alcoholism. Semin. Liver Dis. 13, 126–135.PubMedGoogle Scholar
  16. Boyle, A. E., Segal, R., Smith, B. R., Amit, Z. (1993) Bidirectional effects of GABAergic agonists and antagonists on maintenance of voluntary ethanol intake in rats. Pharmacol. Biochem. Behav. 46, 179–182.PubMedGoogle Scholar
  17. Brunner, H. G., Nelen, M., Breakefield, X. O., Ropers, H. H., van Oost, B. A. (1993) Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262, 578–580.PubMedGoogle Scholar
  18. Carr, L. G., Foroud, T., Stewart, T., Castelluccio, P., Edenberg, H. J., Li, T. K. (2002) Influence of ADH1B polymorphism on alcohol use and its subjective effects in a Jewish population. Am. J. Med. Genet. 112, 138–143.PubMedGoogle Scholar
  19. Cases, O., Seif, I., Grimsby, J., et al. (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268, 1763–1766.PubMedGoogle Scholar
  20. Chang, Y. T., Sun, H. S., Fann, C. S., et al. (2002) Association of the gamma-aminobutyric acid A receptor gene cluster with alcohol dependence in Taiwanese Han. Mol. Psychiatry 7, 828–829.PubMedGoogle Scholar
  21. Chen, A. C. H., LaForge, K. S., Ho, A., et al. (2002) Potentially functional polymorphism in the promoter region of prodynorphin gene may be associated with protection against cocaine dependence or abuse. Am. J. Med. Genet. 114, 429–435.PubMedGoogle Scholar
  22. Chen, W. J., Loh, E. W., Hsu, Y. P., Chen, C. C., Yu, J. M., Cheng, A. T. (1996) Alcohol-metabolising genes and alcoholism among Taiwanese Han men: independent effect of ADH2, ADH3 and ALDH2. Br. J. Psychiatry 168, 762–767.PubMedGoogle Scholar
  23. Claye, L. H., Maisonneuve, I. M., Yu, J., Ho, A., Kreek, M. J. (1997) Local perfusion of dynorphin A1–17 reduces extracellular dopamine levels in the nucleus accumbens. In Harris, L. S. (ed.), Problems of Drug Dependence, 1996; Proceedings of the 58th Annual Scientific Meeting of the College on Problems of Drug Dependence. National Institute of Drug Abuse Research Monograph Series, 174 (p. 113). Washington, DC: U.S. Government Printing Office. DHHS Pub. No.: (ADM)97-4236.Google Scholar
  24. Cloninger, R., Bohman, M., Sigvardsson, S. (1981) Inheritance of alcohol abuse: cross-fostering analysis of adopted men. Arch. Gen. Psychiatry 38, 861–868.PubMedGoogle Scholar
  25. Comings, D. E., Gonzalez, N., Wu, S., et al. (1999) Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. Am. J. Med. Genet. 88, 358–368.PubMedGoogle Scholar
  26. Crabb, D. W., Dipple, K. M., 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.PubMedGoogle Scholar
  27. Crabb, D. W., Edenberg, H. J., Bosron, W. F., Li, T. K. (1989) Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. J. Clin. Invest. 83, 314–316.PubMedGoogle Scholar
  28. Crabbe, J. C., Phillips, T. J., Feller, D. J., et al. (1996) Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors. Nat. Genet. 14, 98–101.PubMedGoogle Scholar
  29. Cravatt, B. F., Demarest, K., Patricelli, M. P., et al. (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl. Acad. Sci. USA. 98, 9371–9376.PubMedGoogle Scholar
  30. Cubells, J. F., van Kammen, D. P., Kelley, M. E., et al. (1998) Dopamine β-hydroxylase: two polymorphisms in linkage disequilibrium at the structural gene DBH associate with biochemical phenotypic variation. Hum. Genet. 102, 533–540.PubMedGoogle Scholar
  31. Cubells, J. F., Kranzler, H. R., McCance-Katz, E., et al. (2000) A haplotype at the DBH locus, associated with low plasma dopamine β-hydroxylase activity, also associates with cocaine-induced paranoia. Mol. Psychiatry 5, 56–63.PubMedGoogle Scholar
  32. Dálen, P., Frengell, C., Dahl, M. L., Sjoqvist, F. (1997) Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther. Drug Monit. 19, 543–544.PubMedGoogle Scholar
  33. Daly, A. K., Brockmoller, J., Broly, F., et al. (1996) Nomenclature for human CYP2D6 alleles. Pharmacogenetics 6, 193–201.PubMedGoogle Scholar
  34. Edenberg, H. J. (2002) The collaborative study on the genetics of alcoholism: an update. Alcohol Res. Health 26, 214–218.PubMedGoogle Scholar
  35. Ehlers, C. L., Carr, L., Betancourt, M., Montane-Jaime, K. (2003) Association of the ADH2*3 allele with greater alcohol expectancies in African-American young adults. J. Stud. Alcohol 64, 176–181.PubMedGoogle Scholar
  36. Ehlers, C. L., Gilder, D. A., Harris, L., Carr, L. (2001) Association of the ADH2*3 allele with a negative family history of alcoholism in African American young adults. Alcohol. Clin. Exp. Res. 25, 1773–1777.PubMedGoogle Scholar
  37. Ekelund, J., Lichtermann, D., Jarvelin, M. R., Peltonen, L. (1999). Association between novelty seeking and the type 4 dopamine receptor gene in a large Finnish cohort sample. Am. J. Psychiatry 156, 1453–1455.PubMedGoogle Scholar
  38. Fehr, C., Grintschuk, N., Szegedi, A., et al. (2000) The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy. Psychiatry Res. 97, 1–10.PubMedGoogle Scholar
  39. Fernandes, L. C., Kilicarslan, T., Kaplan, H. L., Tyndale, R. F., Sellers, E.M., Romach, M. K. (2002) Treatment of codeine dependence with inhibitors of cytochrome P450 2D6. J. Clin. Psychopharmacol. 22, 326–329.PubMedGoogle Scholar
  40. Foroud, T., Edenberg, H. J., Goate, A., et al. (2000) Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping. Alcohol. Clin. Exp. Res. 24, 933–945.PubMedGoogle Scholar
  41. Franke, P., Nothen, M. M., Wang, T., et al. (2000) DRD4 exon III VNTR polymorphism-susceptibility factor for heroin dependence? Results of a case-control and a family-based association approach. Mol. Psychiatry 5, 101–104.PubMedGoogle Scholar
  42. Franke, P., Wang, T., Nöthen, M. K., et al. (2001) Non-replication of association between μ-opioid-receptor gene (OPRM1) A118G polymorphism and substance dependence. Am. J. Med. Genet. 105, 114–119.PubMedGoogle Scholar
  43. Fuke, S., Suo, S., Takahashi, N., Koike, H., Sasagawa, N., Ishiura, S. (2001) The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression. Pharmacogenomics J. 1, 152–156.PubMedGoogle Scholar
  44. Gaedigk, A., Blum, M., Gaedigk, R., Eichelbaum, M., Meyer U. A. (1991) Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am. J. Hum. Genet. 48, 943–950.PubMedGoogle Scholar
  45. Gelernter, J., Kranzler, H., Coccaro, E., Siever, L., New, A., Mulgrew, C. L. (1997) D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects. Am. J. Hum. Genet. 61, 1144–1152.PubMedGoogle Scholar
  46. Gelernter, J., Kranzler, H., Cubells, J. (1999) Genetics of two mu opioid receptor gene (OPRM1) exon 1 polymorphisms: population studies, and allele frequencies in alcohol-and drug-dependent subjects. Mol. Psychiatry 4, 476–483.PubMedGoogle Scholar
  47. Genet. Epidemiol. (1999) 17(suppl 1), Google Scholar
  48. George, S. R., Cheng, R., Nguyen, T., Israel, Y., O’Dowd, B. F. (1993) Polymorphisms of the D4 dopamine receptor alleles in chronic alcoholism. Biochem. Biophys. Res. Comm. 196, 107–114.PubMedGoogle Scholar
  49. Glatt, S. J., Faraone, S. V., Tsuang, M. T. (2003) Association between a functional catechol O-methyl-transferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. Am. J. Psychiatry 160, 469–476.PubMedGoogle Scholar
  50. Gough, A. C., Miles, J. S., Spurr, N. K., et al. (1990) Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 347, 773–776.PubMedGoogle Scholar
  51. Grobin, A. C., Matthews, D. B., Devaud, L. L., Morrow, A. L. (1998) The role of GABA(A) receptors in the acute and chronic effects of ethanol. Psychopharmacol. (Berl.) 139, 2–19.Google Scholar
  52. Hall, F. S., Sora, I., Uhl, G.R. (2001) Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice. Psychopharmacology 154, 43–49.PubMedGoogle Scholar
  53. Harada, S., Agarwal, D. P., Goedde, H. W., Tagaki, S., Ishikawa, B. (1982) Possible protective role against alcoholism for aldehyde dehydrogenase isozyme deficiency in Japan. Lancet 2, 827.PubMedGoogle Scholar
  54. Harada, S., Misawa, S., Agarwal, D. P., Goedde, H. W. (1980). Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: isozyme variation and its possible role in alcohol intoxication. Am. J. Hum. Genet. 32, 8–15.PubMedGoogle Scholar
  55. Hernandez-Avila, C. A., Wand, G., Luo, X., Gelernter, J., Kranzler, H. R. (2003) Association between the cortisol response to opioid blockade and the Asn40Asp polymorphism at the mu-opioid receptor locus (OPRM1). Am. J. Med. Genet. 118B, 60–65.Google Scholar
  56. Higuchi, S., Matsushita, S., Muramatsu, T., Murayama, M., Hayashida, M. (1996) Alcohol and aldehyde dehydrogenase genotypes and drinking behavior in Japanese. Alcohol. Clin. Exp. Res. 20, 493–497.PubMedGoogle Scholar
  57. Higuchi, S., Muramatsu, T., Shigemori, K., et al. (1992) The relationship between low Km aldehyde dehydrogenase phenotype and drinking behavior in Japanese. J. Stud. Alcohol 53, 170–175.PubMedGoogle Scholar
  58. Hoehe, M. R., Kopke, K., Wendel, B., et al. (2000) Sequence variability and candidate gene analysis in complex diseases: association of μ opioid receptor gene variation with substance dependence. Hum. Mol. Genet. 9, 2895–2908.PubMedGoogle Scholar
  59. Holmes, A., Murphy, D. L., Crawley, J. N. (2002) Reduced aggression in mice lacking the serotonin transporter. Psychopharmacol. (Berl.) 161, 160–167.Google Scholar
  60. Horikawa, S., Takai, T., Toyosato, M., et al. (1983) Isolation and structural organization of the human preproenkephalin B gene. Nature 306, 611–614.PubMedGoogle Scholar
  61. Hsu, Y. P., Loh, E. W., Chen, W. J., Chen, C. C., Yu, J. M., Cheng, A. T. (1996) Association of monoamine oxidase A alleles with alcoholism among male Chinese in Taiwan. Am. J. Psychiatry 153, 1209–1211.PubMedGoogle Scholar
  62. Hsu, Y. P., Tai, J. J., Seow, S. V., Chen, C. C., Yu, J. M., Cheng, A. T. (1998) Allelic association of tryptophan hydroxylase with alcoholism in five Taiwanese ethnic groups. Mol. Psychiatry 3, 213–214.PubMedGoogle Scholar
  63. Huang, Y. Y., Grailhe, R., Arango, V., Hen, R., Mann, J. J. (1999) Relationship of psychopathology to the human serotonin 1B genotype and receptor binding kinetics in postmortem brain tissue. Neuropsychopharmacology 21, 238–246.PubMedGoogle Scholar
  64. Hutchison, K. E., McGeary, J., Smolen, A., Bryan, A., Swift, R. M. (2002) The DRD4 VNTR polymorphism moderates craving after alcohol consumption. Health Psychol. 21, 139–146.PubMedGoogle Scholar
  65. Ikawa, M., Impraim, C.C., Wang, G., Yoshida, A. (1983). Isolation and characterization of aldehyde dehydrogenase isozymes from usual and atypical human livers. J. Biol. Chem. 258, 6282–6287.PubMedGoogle Scholar
  66. Ilveskoski, E., Kajander, O. A., Lehtimaki, T., et al. (2001) Association of neuropeptide y polymorphism with the occurrence of type 1 and type 2 alcoholism. Alcohol Clin. Exp. Res. 25, 1420–1422.PubMedGoogle Scholar
  67. Ishiguro, H., Saito, T., Shibuya, H., Toru, M., Arinami, T. (1999) The 5′ region of the tryptophan hydroxylase gene: mutation search and association study with alcoholism. J. Neural. Transm. 106, 1017–1025.PubMedGoogle Scholar
  68. Johansson, I., Lundqvist, E., Bertilsson, L., Dahl, M. L., Sjoqvist, F., Ingelman-Sundberg, M. (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc. Natl. Acad. Sci. USA. 90, 11825–11829.PubMedGoogle Scholar
  69. Jonsson, E. G., Goldman, D., Spurlock, G., et al. (1997) Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers. Eur. Arch. Psychiatry Clin. Neurosci. 247, 297–302.PubMedGoogle Scholar
  70. Joober, R., Gauthier, J., Lal, S., et al. (2002) Catechol-O-methyltransferase Val-108/158-Met gene variants associated with performance on the Wisconsin Card Sorting Test. Arch. Gen. Psychiatry 59, 662–663.PubMedGoogle Scholar
  71. Kagimoto, M., Heim, M., Kagimoto, K., Zeugin, T., Meyer, U. A. (1990) Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J. Biol. Chem. 265, 17209–17214.PubMedGoogle Scholar
  72. Kaij, L. (1960) Alcoholism in Twins: Studies on the Etiology and Sequels of Abuse and Alcohol., Almqvist & Wiksell, Stockholm.Google Scholar
  73. Karvonen, M. K., Pesonen, U., Koulu, M., et al. (1998) Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels. Nat. Med. 4, 1434–1437.PubMedGoogle Scholar
  74. Kathiramalainathan, K., Kaplan, H. L., Romach, M. K., et al. (2000) Inhibition of cytochrome P450 2D6 modifies codeine abuse liability. J. Clin. Psychopharmacol. 20, 435–444.PubMedGoogle Scholar
  75. Kauhanen, J., Hallikainen, T., Tuomainen, T. P., et al. (2000a) Association between the functional polymorphism of catechol-O-methyltransferase gene and alcohol consumption among social drinkers. Alcohol. Clin. Exp. Res. 24, 135–139.PubMedGoogle Scholar
  76. Kauhanen, J., Karvonen, M. K., Pesonen, U., et al. (2000b) Neuropeptide Y polymorphism and alcohol consumption in middle-aged men. Am. J. Med. Genet. 93, 117–121.PubMedGoogle Scholar
  77. Kendler, K. S., Jacobson, K. C., Prescott, C. A., Neale, M. C. (2003) Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am. J. Psychiatry 160, 687–695.PubMedGoogle Scholar
  78. Kitanaka, N., Sora, I., Kinsey, S., Zeng, Z., Uhl, G. R. (1998) No heroin or morphine 6 beta-glucuronide analgesia in mu-opioid receptor knockout mice. Eur. J. Pharmacol. 355, R1-R3.PubMedGoogle Scholar
  79. Koch, T., Kroslak, T., Averbeck, M., et al. (2000). Allelic variation S268P of the human mu-opioid receptor affects both desensitization and G protein coupling. Mol. Pharmacol. 58, 328–334.PubMedGoogle Scholar
  80. Kotler, M., Cohen, H., Segman, R., et al. (1997) Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects. Mol. Psychiatry 2, 251–254.PubMedGoogle Scholar
  81. Kozak, C. A., Fillie, J., Adamson, M. C., Chen, Y., Yu, L. (1994) Murine chromosomal location of the mu and kappa opioid receptor genes. Genomics 21, 659–661.PubMedGoogle Scholar
  82. Kranzler, H., Lappalainen, J., Nellissery, M., Gelernter, J. (2002) Association study of alcoholism subtypes with a functional promoter polymorphism in the serotonin transporter protein gene. Alcohol. Clin. Exp. Res. 26, 1330–1335.PubMedGoogle Scholar
  83. Kreek, M. J. (1996) Opioid receptors: some perspectives from early studies of their role in normal physiology, stress responsivity, and in specific addictive diseases. Neurochem. Res. 21, 1469–1488.PubMedGoogle Scholar
  84. Kreek, M. J. (2000) Opiates, opioids, SNP’s and the addictions: Nathan B. Eddy Memorial Award for lifetime excellence in drug abuse research lecture. In Harris, L. S. (ed.), Problems of Drug Dependence, 1999; Proceedings of the 61st Annual Scientific Meeting of the College on Problems of Drug Dependence. National Institute of Drug Abuse Research Monograph Series, 180 (pp. 3–22). Washington, DC: U.S. Government Printing Office. DHHS Pub. No. (ADM)00-4737.Google Scholar
  85. Kreek, M. J., LaForge, K. S., Butelman, E. (2002a) Pharmacotherapy of addictions. Nat. Rev. Drug Discov. 1, 710–726.PubMedGoogle Scholar
  86. Kreek, M. J. (2002b) Gene diversity in the endorphin system: SNPs, chips and possible implications. In Yudell, M., and DeSalle, R. (eds.) (pp. 97–108), The Genomic Revolution: Unveiling the Unity of Life. National Academy Press/Joseph Henry Press, Washington, DC.Google Scholar
  87. LaForge, K.S., Yuferov, V., Kreek, M. J. (2000) Opioid receptor and peptide gene polymorphisms: potential implications for addictions. Eur. J. Pharmacol. 410, 249–268.PubMedGoogle Scholar
  88. Lappalainen, J., Kranzler, H. R., Malison, R., et al. (2002) A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. Arch. Gen. Psychiatry 59, 825–831.PubMedGoogle Scholar
  89. Lappalainen, J., Long, J. C., Eggert, M., et al. (1998) Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch. Gen. Psychiatry 55, 989–994.PubMedGoogle Scholar
  90. Lesch, K. P., Bengel, D., Heils, A., et al. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531.PubMedGoogle Scholar
  91. Li, T., Liu, X., Zhu, Z. H., et al. (2000) Association analysis of polymorphisms in the mu opioid gene and heroin abuse in Chinese subjects. Addict. Biol. 5, 181–186.Google Scholar
  92. Li, T., Xu, K., Deng, H., et al. (1997) Association analysis of the dopamine D4 gene exon III VNTR and heroin abuse in Chinese subjects. Mol. Psychiatry 2, 413–416.PubMedGoogle Scholar
  93. Long, J. C., Knowler, W. C., Hanson, R. L., et al. (1998) Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population. Am. J. Med. Genet. 81, 216–221.PubMedGoogle Scholar
  94. Lötsch, J., Sharke, C., Grösch, S., Darimont, J., Schmidt, H., Geisslinger, G. (2002) The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 4, 3–9.Google Scholar
  95. Mattay, V. S., Goldberg, T. E., Fera, F., et al. (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc. Natl. Acad. Sci. USA. 100, 6186–6191.PubMedGoogle Scholar
  96. Matthes, H. W. D., Maldonado, R., Simonin, F., et al. (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the μ opioid receptor gene. Nature 383, 819–823.PubMedGoogle Scholar
  97. McCreadie, R. G. (2002) Use of drugs, alcohol and tobacco by people with schizophrenia: case-control study. Br. J. Psychiatry 181, 321–325.PubMedGoogle Scholar
  98. Merikangas, K. R., Stolar, M., Stevens, D. E., et al. (1998) Familial transmission of substance use disorders. Arch. Gen. Psychiatry 55, 973–979.PubMedGoogle Scholar
  99. Meroz, Y., Davidson, E. M., Shir, Y., Caraco, Y. (2001) Variable response to alfentanil due to genetic polymorphism. Anesthesiology 95, A1358.Google Scholar
  100. Mizoi, Y., Tatsuno, Y., Adachi, J., et al. (1983) Alcohol sensitivity related to polymorphism of alcohol-metabolizing enzymes in Japanese. Pharmacol. Biochem. Behav. 18(Suppl 1), 127–133.PubMedGoogle Scholar
  101. Muramatsu, T., Higuchi, S. (1995) Dopamine transporter gene polymorphism and alcoholism. Biochem. Biophys. Res. Comm. 211, 28–32.PubMedGoogle Scholar
  102. Muramatsu, T., Higuchi, S., Murayama, M., Matsushita, S., Hayashida, M. (1996) Association between alcoholism and the dopamine D4 receptor gene. J. Med. Genet. 33, 113–115.PubMedGoogle Scholar
  103. Nakamura, K., Iwahashi, K., Matsuo, Y., Miyatake, R., Ichikawa, Y., Suwaki, H. (1996) Characteristics of Japanese alcoholics with the atypical aldehyde dehydrogenase 2*2. I. A comparison of the genotypes of ALDH2, ADH2, ADH3, and cytochrome P-4502E1 between alcoholics and nonalcoholics. Alcohol. Clin. Exp. Res. 20, 52–55.PubMedGoogle Scholar
  104. Nestler, E. J. (2000) Genes and addiction. Nat. Genet. 26, 277–281.PubMedGoogle Scholar
  105. Nielsen, D. A., Dean, M., Goldman, D. (1992) Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. Am. J. Hum. Genet. 51, 1366–1371.PubMedGoogle Scholar
  106. Nielsen, D. A., Goldman, D., Virkkunen, M., Tokola, R., Rawlings, R., Linnoila, M. (1994) Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch. Gen. Psychiatry 51, 34–38.PubMedGoogle Scholar
  107. Nielsen, D. A., Virkkunen, M., Lappalainen, J., et al. (1998) A tryptophan hydroxylase gene marker for suicidality and alcoholism. Arch. Gen. Psychiatry 55, 593–602.PubMedGoogle Scholar
  108. O’Malley, S. S., Krishnan-Sarin, S., Farren, C., Sinha, R., Kreek, M. J. (2002) Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacol. (Berl.) 160, 19–29.Google Scholar
  109. Ono, H., Shirakawa, O., Kitamura, N., et al. (2002) Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls. Mol. Psychiatry 7, 1127–1132.PubMedGoogle Scholar
  110. Oscarson, M., Hidestrand, M., Johansson, I., Ingelman-Sundberg, M. (1997) A combination of mutations in the CYP2D6*17 (CYP2D6Z) allele causes alterations in enzyme function. Mol. Pharmacol. 52, 1034–1040.PubMedGoogle Scholar
  111. Osier, M., Pakstis, A. J., Kidd, J. R., et al. K. (1999) Linkage disequilibrium at the ADH2 and ADH3 loci and risk of alcoholism. Am. J. Hum. Genet. 64, 1147–1157.PubMedGoogle Scholar
  112. Oslin, D. W., Berrettini, W., Kranzler, H. R., et al. (2003) A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28, 1546–1552.PubMedGoogle Scholar
  113. Oxenstierna, G., Edman, G., Iselius, L., Oreland, L., Ross, S. B., Sedvall, G. (1986) Concentrations of monoamine metabolites in the cerebrospinal fluid of twins and unrelated individuals—a genetic study. J. Psychiat. Res. 20, 19–29.PubMedGoogle Scholar
  114. Palmatier, M. A., Kang, A. M., Kidd, K. K. (1999) Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol. Psychiatry 46, 557–567.PubMedGoogle Scholar
  115. Parsian, A., Cloninger, C. R., Sinha, R., Shang, S. H. (2003) Functional variation in promoter region of monoamine oxidase A and subtypes of alcoholism: haplotype analysis. Am. J. Med. Genet. 117B, 46–50.Google Scholar
  116. Parsian, A., Zhang, Z. H. (1999) Human chromosomes 11p15 and 4p12 and alcohol dependence: possible association with the GABRB1 gene. Am. J. Med. Genet. 88, 533–538.PubMedGoogle Scholar
  117. Partanen, J., Bruun, K., Markkanen, T. (1966) Inheritance of Drinking Behavior: A Study on Intelligence, Personality, and Use of Alcohol of Adult Twins. The Finnish Foundation for Alcohol Studies, Helsinki.Google Scholar
  118. Poulsen, L., Brøsen, K., Arendt-Nielsen, L., Gram, L. F., Elbæk, K., Sindrup, S. H. (1996) Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur. J. Clin. Pharmacol. 51, 289–295.PubMedGoogle Scholar
  119. Reich, T., Edenberg, H. J., Goate, A., et al. (1998) Genome-wide search for genes affecting the risk for alcohol dependence. Am. J. Med. Genet. 81, 207–215.PubMedGoogle Scholar
  120. Roberts, A. J., McDonald, J. S., Heyser, C. J., et al. (2000) mu-opioid receptor knockout mice do not self-administer alcohol. J. Pharmacol. Exp. Ther. 293, 1002–1008.PubMedGoogle Scholar
  121. Romach, M. K., Otton, S. V., Somer, G., Tyndale, R. F., Sellers, E. M. (2000) Cytochrome P450 2D6 and treatment of codeine dependence. J. Clin. Psychopharmacol. 20, 43–45.PubMedGoogle Scholar
  122. Sabol, S. Z., Hu, S., Hamer, D. (1998) A functional polymorphism in the monoamine oxidase A gene promoter. Hum. Genet. 103, 273–279.PubMedGoogle Scholar
  123. Samochowiec, J., Lesch, K. P., Rottmann, M., et al. (1999) Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism. Psychiatry Res. 86, 67–72.PubMedGoogle Scholar
  124. Sander, T., Samochowiec, J., Ladehoff, M., et al. (1999) Association analysis of exonic variants of the gene encoding the GABAB receptor and alcohol dependence. Psychiatr. Genet. 9, 69#-373.PubMedGoogle Scholar
  125. Schinka, J. A., Town, T., Abdullah, L., et al. (2002) A functional polymorphism within the mu-opioid receptor gene and risk for abuse of alcohol and other substances. Mol. Psychiatry 7, 224–228.PubMedGoogle Scholar
  126. Schluger, J. H., Ho, A., Borg, L., et al. (1998) Nalmefene causes greater hypothalamic-pituitary-adrenal axis activation than naloxone in normal volunteers: implications for the treatment of alcoholism. Alcohol. Clin. Exp. Res. 22, 1430–1436.PubMedGoogle Scholar
  127. Shea, S. H., Wall, T. L., Carr, L. G., Li, T. K. (2001) ADH2 and alcohol-related phenotypes in Ashkenazic Jewish American college students. Behav. Genet. 31, 231–239.PubMedGoogle Scholar
  128. Shen, Y. C., Fan, J. H., Edenberg, H. J., et al. (1997) Polymorphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism. Alcohol. Clin. Exp. Res. 21, 1272–1277.PubMedGoogle Scholar
  129. Shi, J., Jui, L., Xu, Y., Wang, F., Huang, W., Hu, G. (2002) Sequence variation in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Human Mut. 19, 459–460.Google Scholar
  130. Silva, A. P., Cavadas, C., Grouzmann, E. (2002) Neuropeptide Y and its receptors as potential therapeutic drug targets. Clin. Chim. Acta 326, 3–25.PubMedGoogle Scholar
  131. Sindrup, S. H., Brosen, K., Bjerring, P., et al. (1990) Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin. Pharmacol. Ther. 48, 686–693.PubMedGoogle Scholar
  132. Sipe, J. C., Chiang, K., Gerber, A. L., Beutler, E., Cravatt, B. F. (2002) A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc. Natl. Acad. Sci. USA. 99, 8394–8399.PubMedGoogle Scholar
  133. Skarke, C., Darimont, J., Schmidt, H., Geisslinger, G., Lötsch, J. (2003) Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin. Pharmacol. Ther. 73, 107–121.PubMedGoogle Scholar
  134. Sora, I., Takahashi, N., Funada, M., et al. (1997) Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc. Natl. Acad. Sci. USA. 94, 1544–1549.PubMedGoogle Scholar
  135. Spielman, R. S., and Weinshilboum, R. M. (1981) Genetics of red cell COMT activity: analysis of thermal stability and family data. Am. J. Med. Genet. 10, 279–290.PubMedGoogle Scholar
  136. Stallings, M. C., Corley, R. P., Hewitt, J. K., et al. (2003) A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence. Drug Alcohol Depend. 70, 295–307.PubMedGoogle Scholar
  137. Szeto, C. Y., Tang, N. L., Lee, D. T., Stadlin, A. (2001) Association between mu opioid receptor gene polymorphisms and Chinese heroin addicts. Neuroreport 12, 1103–1106.PubMedGoogle Scholar
  138. Takeshita, T., Morimoto, K., Mao, X., Hashimoto, T., Furuyama, J. (1994) Characterization of the three genotypes of low Km aldehyde dehydrogenase in a Japanese population. Hum. Genet. 94, 217–223.PubMedGoogle Scholar
  139. Tan, E.-C., Tan, C.-H., Karupathivan, U., Yap, E. P. H. (2003) Mu opioid receptor gene polymorphisms and heroin dependence in Asian populations. Neuroreport 14, 569–572.PubMedGoogle Scholar
  140. Thiele, T. E., Marsh, D. J., Ste Marie, L., Bernstein, I. L., Palmiter, R. D. (1998) Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 396, 366–369.PubMedGoogle Scholar
  141. Thomasson, H. R., Crabb, D. W., Edenberg, H. J., Li, T. K. (1993) Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism. Behav. Genet. 23, 131–136.PubMedGoogle Scholar
  142. Thomasson, H. R., Crabb, D. W., Edenberg, H. J., et al. (1994) Low frequency of the ADH2*2 allele among Atayal natives of Taiwan with alcohol use disorders. Alcohol. Clin. Exp. Res. 18, 640–643.PubMedGoogle Scholar
  143. Thomasson, H. R., Edenberg, H. J., Crabb, D. W., et al. (1991) Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am. J. Hum. Genet. 48, 677–681.PubMedGoogle Scholar
  144. Thorsell, A., Rimondi, R., Heilig, M. (2002) Blockade of central neuropeptide Y (NPY) Y2 receptors reduces ethanol self-administration in rats. Neurosci. Lett. 332, 1–4.PubMedGoogle Scholar
  145. Tiihonen, J., Hallikainen, T., Lachman, H., et al. (1999) Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism. Mol. Psychiatry 4, 286–289.PubMedGoogle Scholar
  146. Town, T., Abdullah, L., Crawford, F., et al. (1999) Association of a functional mu-opioid receptor allele (+118A) with alcohol dependency. Am. J. Med. Genet. 88, 458–461.PubMedGoogle Scholar
  147. Tsuang, M. T., Lyons, M. J., Meyer, J. M., et al. (1998) Co-occurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities. Arch. Gen. Psychiatry 55, 967–972.PubMedGoogle Scholar
  148. Tyndale, R.F. (2003) Genetics of alcohol and tobacco use in humans. Ann. Med. 35, 94–121.PubMedGoogle Scholar
  149. Tyndale, R. F., Droll, K. P., Sellers, E. M. (1997) Genetically deficient CYP2D6 metabolism provides protection against oral opiate dependence. Pharmacogenetics 7, 375–379.PubMedGoogle Scholar
  150. Ueno, S., Nakamura, M., Mikami, M., et al. (1999) Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism. Mol. Psychiatry 4, 552–557.PubMedGoogle Scholar
  151. Uhl, G. R., Liu, Q. R., Walther, D., Hess, J., Naiman, D. (2001) Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am. J. Hum. Genet. 69, 1290–1300.PubMedGoogle Scholar
  152. Vandenbergh, D. J., Rodriguez, L. A., Hivert, E., et al. (2000) Long forms of the dopamine receptor (DRD4) gene VNTR are more prevalent in substance abusers: no interaction with functional/alleles of the catechol-o-methyltransferase (COMT) gene. Am. J. Med. Genet. 96, 678–683.PubMedGoogle Scholar
  153. Van Tol, H. H., Wu, C. M., Guan, H. C., et al. (1992) Multiple dopamine D4 receptor variants in the human population. Nature 358, 149–152.PubMedGoogle Scholar
  154. Vanyukov, M. M., Moss, H. B., Yu, L. M., Tarter, R. E., Deka, R. (1995) Preliminary evidence for an association of a dinucleotide repeat polymorphism at the MAOA gene with early onset alcoholism/substance abuse. Am. J. Med. Genet. 60, 122–126.PubMedGoogle Scholar
  155. Wall, T. L., Carr, L. G., Ehlers, C. L. (2003) Protective association of genetic variation in alcohol dehydrogenase with alcohol dependence in Native American Mission Indians. Am. J. Psychiatry 160, 41–46.PubMedGoogle Scholar
  156. Wall, T. L., Garcia-Andrade, C., Thomasson, H. R., Cole, M., Ehlers, C. L. (1996) Alcohol elimination in Native American Mission Indians: an investigation of interindividual variation. Alcohol. Clin. Exp. Res. 20, 1159–1164.PubMedGoogle Scholar
  157. Wand, G. S., McCaul, M., Yang, X., et al. (2002) The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology 26, 106–114.PubMedGoogle Scholar
  158. Wang, D., Quillan, J. M., Winas, K., Lucan, J. L., Sadee, W. (2001a) Single nucleotide polymorphisms in the human mu opioid receptor alter basal G protein coupling and calmodulin binding. J. Biol. Chem. 276, 34624–34630.PubMedGoogle Scholar
  159. Wang, T., Franke, P., Neidt, H., et al. (2001b) Association study of the low-activity allele of catechol-O-methyltransferase and alcoholism using a family-based approach. Mol. Psychiatry 6, 109–111.PubMedGoogle Scholar
  160. Wei, J., Ramchand, C. N., Hemmings, G. P. (1997) Possible control of dopamine β-hydroxylase via a codominant mechanism associated with the polymorphic (GT)n repeat at its gene locus in healthy individuals. Hum.Genet. 99, 52–55.PubMedGoogle Scholar
  161. Weinshilboum, R. M. (1974) Serum dopamine β-hydroxylase. Pharmacol. Rev. 30, 133–166.Google Scholar
  162. Weinshilboum, R. M., and Raymond, F. A. (1977) Inheritance of low erythrocyte catechol-o-methyltransferase activity in man. Am. J. Hum. Genet. 29, 125–135.PubMedGoogle Scholar
  163. Wendel, B., and Hoehe, M. R. (1998) The human mu opioid receptor gene 5′ regulatory and intronic sequences J. Mol. Med. 76, 525–532.PubMedGoogle Scholar
  164. Whitfield, J. B. (1997) Meta-analysis of the effects of alcohol dehydrogenase genotype on alcohol dependence and alcoholic liver disease. Alcohol Alcohol. 32, 613–619.PubMedGoogle Scholar
  165. Wilson, A. F., Elston, R. C., Siervogel, R. M., Tran, L. D. (1988) Linkage of a gene regulating dopamine β-hydroxylase activity and the ABO blood group locus. Am. J. Hum. Genet. 42, 160–166.PubMedGoogle Scholar
  166. Yasunami, M., Kikuchi, I., Sarapata, D., Yoshida, A. (1990) The human class I alcohol dehydrogenase gene cluster: three genes are tandemly organized in an 80-kb-long segment of the genome. Genomics 7, 152–158.PubMedGoogle Scholar
  167. Yoshida, A., Hsu, L. C., Yasunami, M. (1991) Genetics of human alcohol-metabolizing enzymes. Prog. Nucleic Acid Res. Mol. Biol. 40, 255–287.PubMedGoogle Scholar
  168. Yoshida, A., Huang, I. Y., Ikawa, M. (1984) Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals. Proc. Natl. Acad. Sci. USA. 81, 258–261.PubMedGoogle Scholar
  169. Zabetian, C. P., Anderson, G. M., Buxbaum, S. G., et al. (2001) A quantitative-trait analysis of human plasma-dopamine β-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. Am. J. Hum. Genet. 68, 515–522.PubMedGoogle Scholar
  170. Zhang, Y., Schlussmen, S. D., Ho, A., Kreek, M. J. (2003) Effect of chronic “binge cocaine” on basal levels and cocaine-induced increases of dopamine in caudate putamen and nucleus accumbens of C57BL/6J and 129/J mice. Synapse 50, 191–199.PubMedGoogle Scholar
  171. Zhu, G., Pollak, L., Mottagui-Tabar, S., et al. (2003) NPY leu7pro and alcohol dependence in Finnish and Swedish populations. Alcohol. Clin. Exp. Res. 27, 19–24.PubMedGoogle Scholar
  172. Zimprich, A., Kraus, J., Wöltje M., Mayer, P., Rauch, E., Höllt V. (2000) An allelic variation in the human prodynorphin gene promoter alters stimulus-induced expression. J. Neurochem. 74, 472–477.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Mary Jeanne Kreek
    • 1
  • David A. Nielsen
    • 1
  • K. Steven LaForge
    • 1
  1. 1.Laboratory of the Biology of Addictive DiseasesThe Rockefeller UniversityNew York

Personalised recommendations