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Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction

Nature Neuroscience volume 8, pages 14501457 (2005) | Download Citation

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Abstract

Genetic variation may partially underlie complex personality and physiological traits—such as impulsivity, risk taking and stress responsivity—as well as a substantial proportion of vulnerability to addictive diseases. Furthermore, personality and physiological traits themselves may differentially affect the various stages of addiction, defined chronologically as initiation of drug use, regular drug use, addiction/dependence and potentially relapse. Here we focus on recent approaches to the study of genetic variation in these personality and physiological traits, and their influence on and interaction with addictive diseases.

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References

  1. 1.

    , & Pharmacotherapy of addictions. Nat. Rev. Drug Discov. 1, 710–726 (2002).

  2. 2.

    , , , & Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol. Rev. 57, 1–26 (2005).

  3. 3.

    et al. & , , , Acquisition and maintenance of intravenous cocaine self-administration in Lewis and Fischer inbred rat strains. Brain Res. 778, 418–429 (1997).

  4. 4.

    et al. Co-occurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities. Arch. Gen. Psychiatry 55, 967–972 (1998).

  5. 5.

    , , & 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 (2003).

  6. 6.

    et al. Genetic and environmental influences on transitions in drug use. Behav. Genet. 29, 473–479 (1999).

  7. 7.

    et al. Alcoholism susceptibility loci: Confirmation studies in a replicate sample and further mapping. Alcohol. Clin. Exp. Res. 24, 933–945 (2000).

  8. 8.

    et al. Variations in GABRA2, encoding the α2 subunit of the GABAA receptor, are associated with alcohol dependence and with brain oscillations in the beta frequency. Am. J. Hum. Genet. 74, 705–714 (2004).

  9. 9.

    et al. Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. Hum. Mol. Genet. 13, 1903–1911 (2004).

  10. 10.

    Issues in association analysis: error control in case-control association studies for disease gene discovery. Hum. Hered. 58, 171–174 (2004).

  11. 11.

    , & Genes associated with addiction: alcoholism, opiate and cocaine addiction. Neuromolecular Med. 5, 85–108 (2004).

  12. 12.

    et al. A tryptophan hydroxylase gene marker for suicidality and alcoholism. Arch. Gen. Psychiatry 55, 593–602 (1998).

  13. 13.

    et al. Familial correlates of reduced central serotonergic system function in patients with personality disorders. Arch. Gen. Psychiatry 51, 318–324 (1994).

  14. 14.

    et al. Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch. Gen. Psychiatry 51, 34–38 (1994).

  15. 15.

    et al. Association between dopamine receptor D3 gene BalI polymorphism and cognitive impulsiveness in alcohol-dependent men. Eur. Psychiatry 20, 304–306 (2005).

  16. 16.

    , & Dopamine D4 receptor gene (DRD4) is associated with novelty seeking (NS) and substance abuse: the saga continues. Mol. Psychiatry 6, 497–499 (2001).

  17. 17.

    , & DRD4 and novelty seeking: results of meta-analyses. Am. J. Med. Genet. B Neuropsychiatr. For. Genet. 114, 643–648 (2002).

  18. 18.

    et al. II. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94–1. J. Pharmacol. Exp. Ther. 282, 1020–1027 (1997).

  19. 19.

    , , & Substance abuse vulnerability and D2 receptor genes. Trends Neurosci. 16, 83–88 (1993).

  20. 20.

    , & The A1 allele at the D2 dopamine receptor gene and alcoholism: a reappraisal. J. Am. Med. Assoc. 269, 1673–1677 (1993).

  21. 21.

    , & Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum. Mutat. 23, 540–545 (2004).

  22. 22.

    , , , & Diagnosis and symptoms of depression in opiate addicts. Course and relationship to treatment outcome. Arch. Gen. Psychiatry 39, 151–156 (1982).

  23. 23.

    & Attention deficit hyperactivity disorder and substance abuse: relationships and implications for treatment. Harv. Rev. Psychiatry 2, 246–258 (1995).

  24. 24.

    Medical safety, side effects and toxicity of methadone. Proceedings of the Fourth National Conference on Methadone Treatment, National Association for the Prevention of Addiction to Narcotics (NAPAN)-NIMH, 171–174 (1972).

  25. 25.

    Opiates, opioids and addiction. Mol. Psychiatry 1, 232–254 (1996).

  26. 26.

    , , & Altered HPA axis responsivity to metyrapone testing in methadone maintained former heroin addicts with ongoing cocaine addiction. Neuropsychopharmacology 24, 568–575 (2001).

  27. 27.

    , , , & Naltrexone decreases craving and alcohol self-administration in alcohol dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacology (Berl.) 160, 19–29 (2002).

  28. 28.

    et al. Corticotropin-releasing factor and type 1 corticotropin-releasing factor receptor messenger RNAs in rat brain and pituitary during 'binge'-pattern cocaine administration and chronic withdrawal. J. Pharmacol. Exp. Ther. 279, 351–358 (1996).

  29. 29.

    et al. Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states. Psychopharmacology (Berl.) 170, 62–72 (2003).

  30. 30.

    et al. 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 (1998).

  31. 31.

    , & Opioid receptor and peptide gene polymorphisms: potential implications for addictions. Eur. J. Pharmacol. 410, 249–268 (2000).

  32. 32.

    et al. Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden. Mol. Psychiatry 9, 547–549 (2004).

  33. 33.

    et al. Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden. Neuropsychopharmacology 30, 417–422 (2005).

  34. 34.

    et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6, 243–250 (1996).

  35. 35.

    , , , & Catechol-O-methyltransferase polymorphism alters hypothalamic-pituitary-adrenal axis responses to naloxone: a preliminary report. Biol. Psychiatry 55, 102–105 (2004).

  36. 36.

    et al. Role of genotype in the cycle of violence in maltreated children. Science 297, 851–854 (2002).

  37. 37.

    , & Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003).

  38. 38.

    et al. An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol. Clin. Exp. Res. 29, 8–16 (2005).

  39. 39.

    et al. Genomewide linkage scan for cocaine dependence and related traits: significant linkages for a cocaine-related trait and cocaine-induced paranoia. Am. J. Med. Genet. B Neuropsychiatr. For. Genet. 136, 45–52 (2005).

  40. 40.

    , & Substance abuse vulnerability loci: converging genome scanning data. Trends Genet. 18, 420–425 (2002).

  41. 41.

    Molecular genetics of substance abuse vulnerability: remarkable recent convergence of genome scan results. Ann. NY Acad. Sci. 1025, 1–13 (2004).

  42. 42.

    et al. Redefinition of the human kappa opioid receptor (OPRK1) structure and association of haplotypes with opiate addiction. Pharmacogenetics 14, 793–804 (2004).

  43. 43.

    , , , & High-activity catechol-O-methyltransferase allele is more prevalent in polysubstance abusers. Am. J. Med. Genet. 74, 439–442 (1997).

  44. 44.

    et al. Confirmation of an excess of the high enzyme activity COMT val allele in heroin addicts in a family-based haplotype relative risk study. Am. J. Med. Genet. 96, 599–603 (2000).

  45. 45.

    et al. Association analysis of the DRD4 and COMT genes in methamphetamine abuse. Am. J. Med. Genet. B Neuropsychiatr. For. Genet. 129, 120–124 (2004).

  46. 46.

    et al. A haplotype at DBH, associated with low plasma dopamine-β-hydroxylase activity, also associates with cocaine-induced paranoia. Mol. Psychiatry 5, 56–63 (2000).

  47. 47.

    et al. Cannabinoid receptor gene (CNR1): Association with IV drug use. Mol. Psychiatry 2, 161–168 (1997).

  48. 48.

    et al. Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug Alcohol Depend. 65, 221–224 (2002).

  49. 49.

    et al. Human cannabinoid receptor 1: 5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol. Psychiatry 9, 916–931 (2004).

  50. 50.

    , , , & A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc. Natl. Acad. Sci. USA 99, 8394–8399 (2002).

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Acknowledgements

This work was supported in part by US National Institutes of Health-National Institute on Drug Abuse (NIH-NIDA) Research Scientist Award Grant K05-DA00049; NIH-NIDA Research Center Grant P60-DA05130; NIH-GCRC General Research Center Grant MOI-RR00102; and the New York State Office of Alcoholism and Substance Abuse (OASAS). Thanks to K. Lavoie for assistance in the preparation of this manuscript.

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  1. Mary Jeanne Kreek, David A. Nielsen, Eduardo R. Butelman & K. Steven LaForge are in the Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York, USA. kreek@rockefeller.edu

    • Mary Jeanne Kreek
    • , David A Nielsen
    • , Eduardo R Butelman
    •  & K Steven LaForge

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The authors declare no competing financial interests.

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https://doi.org/10.1038/nn1583

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