Genes and addiction


Drug addiction, like all psychiatric disorders, is defined solely in behavioural terms. For example, addiction can be considered a loss of control over drug-taking, or compulsive drug-seeking and -taking despite horrendous consequences. Abnormal behaviours are a consequence of aberrant brain function, which means that it is a tangible goal to identify the biological underpinnings of addiction. The genetic basis of addiction encompasses two broad areas of enquiry. One of these is the identification of genetic variation in humans that partly determines susceptibility to addiction. The other is the use of animal models to investigate the role of specific genes in mediating the development of addiction. Whereas recent advances in this latter effort are heartening, a major challenge remains: to understand how the many genes implicated in rodent models interact to yield as complex a phenotype as addiction.

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Figure 1: Scheme showing genetic and environmental factors combining to influence the process by which repeated exposure to a drug of abuse causes addiction.

Bob Crimi


  1. 1

    Kendler, K.S. et al. A twin-family study of alcoholism in women. Am. J. Psychiatry 151, 707–715 (1994).

    CAS  Article  Google Scholar 

  2. 2

    Tsuang, M.T. 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).

    CAS  Article  Google Scholar 

  3. 3

    Kendler, K.S., Karkowski, L.M., Neale, M.C. & Prescott, C.A. Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins. Arch. Gen. Psychiatry 57, 261–269 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Reich, T. et al. Genome-wide search for genes affecting the risk for alcohol dependence. Am. J. Med. Genet. 81, 207–215 (1998).

    CAS  Article  Google Scholar 

  5. 5

    Long, J.C. et al. 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 (1998).

    CAS  Article  Google Scholar 

  6. 6

    Thomasson, H.R. et al. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am. J. Hum. Genet. 48, 677–681 (1991).

    CAS  Google Scholar 

  7. 7

    Chen, Y.-C. et al. Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele. Alcohol. Clin. Exp. Res. 23, 1853–1860 (1999).

    CAS  Article  Google Scholar 

  8. 8

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

    CAS  Article  Google Scholar 

  9. 9

    Crawley, J.N. et al. Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132, 107–124 (1997).

    CAS  Article  Google Scholar 

  10. 10

    Brodkin, E.S. et al. Genetic analysis of behavioral, neuroendocrine, and biochemical parameters in inbred rodents: initial studies in Lewis and Fischer 344 rats and in A/J and C57BL/6J mice. Brain Res. 805, 55–68 (1998).

    CAS  Article  Google Scholar 

  11. 11

    Berrettini, W.H., Ferraro, T.N., Alexander, R.C., Buchberg, A.M. & Vogel, W.H. Quantitative trait loci mapping of three loci controlling morphine preference using inbred mouse strains. Nature Genet. 7, 54–58 (1994).

    CAS  Article  Google Scholar 

  12. 12

    McBride, W.J. & Li, T.K. Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. Crit. Rev. Neurobiol. 12, 339–369 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Mogil, J.S. et al. The genetics of pain and pain inhibition. Proc. Natl Acad. Sci. USA 93, 3048–3055 (1996).

    CAS  Article  Google Scholar 

  14. 14

    Weiss, K.M. & Terwilliger, J.D. How many diseases does it take to map a gene with SNPs? Nature Genet. 26, 151–157 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Burmeister, M. Basic concepts in the study of diseases with complex genetics. Biol. Psychiatry 45, 522–532 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Nestler, E.J., Berhow, M.T. & Brodkin, E.S. Molecular mechanisms of drug addiction: adaptations in signal transduction pathways. Mol. Psychiatry 1, 190–199 (1996).

    CAS  Google Scholar 

  17. 17

    Würbel, H. Behaviour and the standardization fallacy. Nature Genet. 26, 263 (2000).

    Article  Google Scholar 

  18. 18

    Gerlai, R. Molecular genetic analysis of mammalian behavior and brain processes: caveats and perspectives. Sem. Neurosci. 8, 153–161 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Berridge, K.C. & Robinson, T.E. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Rev. 28, 309–369 (1998).

    CAS  Article  Google Scholar 

  20. 20

    Wolf, M.E. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog. Neurobiol. 54, 679–720 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Kalivas, P.W. & Nakamura, M. Neural systems for behavioral activation and reward. Curr. Opin. Neurobiol. 9, 223–227 (1999).

    CAS  Article  Google Scholar 

  22. 22

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

    CAS  Article  Google Scholar 

  23. 23

    Koob, G.F., Sanna, P.P. & Bloom, F.E. Neuroscience of addiction. Neuron 21, 467–476 (1998).

    CAS  Article  Google Scholar 

  24. 24

    Wise, R.A. Drug-activation of brain reward pathways. Drug Alcohol Depend. 51, 13–22 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Everitt, B.J. et al. Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems. Ann. NY Acad. Sci. 877, 412–438 (1999).

    CAS  Article  Google Scholar 

  26. 26

    Shaham, Y., Erb, S. & Stewart, J. Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res. Rev. 33, 13–33 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Rocha, B.A. et al. Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor. Nature 393, 175–178 (1998).

    CAS  Article  Google Scholar 

  28. 28

    Crabbe, J.C. Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors. Nature Genet. 14, 98–101 (1996).

    CAS  Article  Google Scholar 

  29. 29

    Maldonado, R. et al. Reduction of morphine abstinence in mice with a mutation in the gene encoding CREB. Science 273, 657–659 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Bohn, L.M. et al. Enhanced morphine analgesia in mice lacking b-arrestin 2. Science 286, 2495–2498 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Zhu, Y. et al. Retention of supraspinal d-like analgesia and loss of morphinemtolerance in d opioid receptor knockout mice. Neuron 24, 243–252 (1999).

    CAS  Article  Google Scholar 

  32. 32

    Matthes, H.W. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the m-opioid receptor gene. Nature 383, 819–823 (1996).

    CAS  Article  Google Scholar 

  33. 33

    Giros, B., Jaber, M., Jones, S.R., Wightman, R.M. & Caron, M.G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379, 606–612 (1996).

    CAS  Article  Google Scholar 

  34. 34

    Ledent, C. et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404 (1999).

    CAS  Article  Google Scholar 

  35. 35

    Rocha, B.A. et al. Cocaine self-administration in dopamine-transporter knockout mice. Nature Neurosci. 1, 132–137 (1998).

    CAS  Article  Google Scholar 

  36. 36

    Maldonado, R. et al. Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 388, 586–589 (1997).

    CAS  Article  Google Scholar 

  37. 37

    Zachariou, V., Caldarone, B.J., Weathers-Lowin, A. & Picciotto, M.R. Nicotine receptor inactivation decreases sensitivity to cocaine. Neuropsychopharmacology (in press).

  38. 38

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

    CAS  Article  Google Scholar 

  39. 39

    Murtra, P., Sheasby, A.M., Hunt, S.P. & De Felipe, C. Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature 405, 180–183 (2000).

    CAS  Article  Google Scholar 

  40. 40

    Horger, B.A. et al. Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J. Neurosci. 19, 4110–4122 (1999).

    CAS  Article  Google Scholar 

  41. 41

    Messer, C.J. et al. Role of GDNF in biochemical and behavioral adaptations to drugs of abuse. Neuron 26, 247–257 (2000).

    CAS  Article  Google Scholar 

  42. 42

    Bainton, R.J. et al. Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila. Curr. Biol. 10, 187–194 (2000).

    CAS  Article  Google Scholar 

  43. 43

    McClung, C. & Hirsch, J. The trace amine tyramine is essential for normal sensitization to cocaine in Drosophila. Curr. Biol. 9, 853–860 (1999).

    CAS  Article  Google Scholar 

  44. 44

    Andretic, R., Chaney, S. & Hirsh, J. A role for circadian genes in cocaine sensitization in Drosophila melanogaster. Science 285, 1066–1068 (1999).

    CAS  Article  Google Scholar 

  45. 45

    Nestler, E.J. & Aghajanian, G.K. Molecular and cellular basis of addiction. Science 278, 58–63 (1997).

    CAS  Article  Google Scholar 

  46. 46

    Kelz, M.B. et al. Expression of the transcription factor DFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).

    CAS  Article  Google Scholar 

  47. 47

    Kelz, M.B. & Nestler, E.J. DFosB: A mediator of long-term neural plasticity. Curr. Opin. Neurol. (in press).

  48. 48

    Whisler, K. et al. Effects of conditional over-expression of DFosB in nucleus accumbens on cocaine-seeking behavior. Soc. Neurosci. Abs. 25, 811 (1999).

    Google Scholar 

  49. 49

    Lane-Ladd, S.B. et al. CREB (cAMP response element-binding protein) in the locus coeruleus: biochemical, physiological, and behavioral evidence for a role in opiate dependence. J. Neurosci. 17, 7890–7901 (1997).

    CAS  Article  Google Scholar 

  50. 50

    Carlezon, W.A. Jr et al. Regulation of cocaine reward by CREB. Science 282, 2272–2275 (1998).

    CAS  Article  Google Scholar 

  51. 51

    Barrot, M., Neve, R.L & Nestler, E.J. Influence of CREB activity in nucleus accumbens shell on psychomotor and rewarding properties of morphine. Soc. Neurosci. Abs. 25, 35 (1999).

    Google Scholar 

  52. 52

    Kalivas, P.W., Duffy, P. & Mackler, S.A. Interrupted expression of NAC-1 augments the behavioral responses to cocaine. Synapse 33, 153–159 (1999).

    CAS  Article  Google Scholar 

  53. 53

    Kuhar, M.J. & Dall Vechia, S.E. CART peptides: novel addiction- and feeding-related neuropeptides. Trends Neurosci. 22, 316–320 (1999).

    CAS  Article  Google Scholar 

  54. 54

    Chen, J.S. et al. Induction of cyclin-dependent kinase 5 in hippocampus by chronic electroconvulsive seizures: role of DFosB. J. Neurosci. (in press).

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Nestler, E. Genes and addiction. Nat Genet 26, 277–281 (2000).

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