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  • Review Article
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Pharmacogenetic approaches to the treatment of alcohol addiction

Nature Reviews Neuroscience volume 12, pages 670–684 (2011)Cite this article

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Key Points

  • Addictive disorders are common, account for a tremendous disease burden and are in need of improved medical treatments. Alcohol use accounts for more disease burden than any other addictive drug with the exception of nicotine.

  • The discovery of naltrexone as a medication for alcoholism was conceptually groundbreaking, because it demonstrated the feasibility of pharmacotherapy for an addictive disorder using a mechanism other than replacement therapy. Overall, however, the effect size of naltrexone turned out to be small, and despite its evidence base, this medication has not gained widespread clinical use.

  • Clinical experience and meta-analyses have long indicated that clinical response to naltrexone is remarkably variable. Over a decade ago, functional genetic variation was discovered at the locus encoding the target for naltrexone, the mu-opioid receptor (MOR), and this was shortly followed by the suggestion that efficacy of naltrexone may be restricted to carriers of the minor allele at this locus.

  • Recently, a series of translational studies in humans, non-human primates and humanized mice has provided consistent support for the notion that alcohol reward is in part mediated by an alcohol–endogenous opioid–dopamine cascade, that this cascade is more vigorously activated by alcohol in carriers of the minor allele at the OPRM1 gene locus that encodes the MOR, and that these subjects are thereby rendered particularly or maybe selectively sensitive to naltrexone.

  • Alcohol reinforcement is mediated by multiple systems, among which opioids and dopamine are but two, and are mostly involved in pleasurable, positively reinforcing alcohol effects experienced mostly in earlier stages of the addictive process. As patients continue heavy alcohol use, a pathological activation of brain stress systems occurs, and sets the scene for negatively reinforced alcohol use — that is, alcohol use aimed at eliminating anxiety and dysphoria that emerges during abstinence.

  • Corticotropin-releasing factor (CRF), the hypothalamic release factor for pituitary adrenocorticotropic hormone (ACTH), is also widely expressed in extrahypothalamic networks that mediate behavioural and emotional stress responses. Recent work has shown that the CRF system becomes activated following a prolonged history of brain alcohol exposure, and its activity is key to negatively reinforced alcohol seeking and use.

  • Genetic variation that influences the functional activity of the CRF system has been found in rats, non-human primates and humans, and has been shown to be associated with various alcohol use phenotypes in all three species. This suggests that pharmacogenetic effects may need to be considered when CRF receptor 1 (CRF1) antagonists are developed for the treatment of alcoholism.

  • GABAergic and serotonergic transmission are also involved in the pathophysiology of alcoholism, and pharmacogenetic effects of variants within both these systems have also been suggested. A potential implication of these findings is that pharmacogenetic effects may turn out to be the rule rather than the exception, and that much more attention will have to be paid to personalizing pharmacotherapy of addictive disorders.

Abstract

Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments.

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Figure 1: An alcohol–endogenous opioid–dopamine cascade is the target of naltrexone.
Figure 2: Efficacy of naltrexone is moderated by OPRM1 variation in rhesus macaques and humans.
Figure 3: Dopamine release in the ventral striatum in response to alcohol is restricted to OPRM1 118G carriers.
Figure 4: Innate or acquired hyperactivity of extrahypothalamic CRF systems is associated with high alcohol preference.
Figure 5: CRF1 antagonism suppresses stress-induced relapse-like behaviour in msP rats.

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References

  1. Rehm, J. et al. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 373, 2223–2233 (2009).

    Article  PubMed  Google Scholar 

  2. Nutt, D. J., King, L. A. & Phillips, L. D. Drug harms in the UK: a multicriteria decision analysis. Lancet 376, 1558–1565 (2010).

    Article  PubMed  Google Scholar 

  3. Hasin, D. S., Stinson, F. S., Ogburn, E. & Grant, B. F. Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch. Gen. Psychiatry 64, 830–842 (2007).

    Article  PubMed  Google Scholar 

  4. McLellan, A. T., Lewis, D. C., O'Brien, C. P. & Kleber, H. D. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284, 1689–1695 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Goldman, D., Oroszi, G. & Ducci, F. The genetics of addictions: uncovering the genes. Nature Rev. Genet. 6, 521–532 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Bouza, C., Angeles, M., Munoz, A. & Amate, J. M. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 99, 811–828 (2004).

    Article  PubMed  Google Scholar 

  7. Amato, L. et al. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J. Subst. Abuse Treat. 28, 321–329 (2005).

    Article  PubMed  Google Scholar 

  8. Wu, P., Wilson, K., Dimoulas, P. & Mills, E. Effectiveness of smoking cessation therapies: a systematic review and meta-analysis. BMC Public Health 6, 300 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Willenbring, M. L., Massey, S. H. & Gardner, M. B. Helping patients who drink too much: an evidence-based guide for primary care physicians. Am. Fam. Physician 80, 44–50 (2009).

    PubMed  Google Scholar 

  10. Mark, T. L., Kranzler, H. R. & Song, X. Understanding US addiction physicians' low rate of naltrexone prescription. Drug Alcohol Depend. 71, 219–228 (2003).

    Article  PubMed  Google Scholar 

  11. American Psychiatric Association. Diagnostics and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Press, Washington, District of Columbia, 2000).

  12. Cloninger, C. R. Neurogenetic adaptive mechanisms in alcoholism. Science 236, 410–416 (1987).

    Article  CAS  PubMed  Google Scholar 

  13. Vaillant, G. E. A long-term follow-up of male alcohol abuse. Arch. Gen. Psychiatry 53, 243–249 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Vaillant, G. E. The Natural History of Alcoholism: Causes, Patterns, and Paths to Recovery (Harvard Univ. Press, Cambridge, USA, 1983).

    Google Scholar 

  15. Fein, G. & Landman, B. Treated and treatment-naive alcoholics come from different populations. Alcohol 36, 19–26 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kendler, K. S., Thornton, L. M. & Gardner, C. O. Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am. J. Psychiatry 158, 582–586 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Ballenger, J. C. & Post, R. M. Kindling as a model for alcohol withdrawal syndromes. Br. J. Psychiatry 133, 1–14 (1978).

    Article  CAS  PubMed  Google Scholar 

  18. Heilig, M. & Koob, G. F. A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci. 30, 399–406 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Heilig, M. & Egli, M. Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol. Ther. 111, 855–876 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Koob, G. F. & Volkow, N. D. Neurocircuitry of addiction. Neuropsychopharmacology 35, 217–238 (2010).

    Article  PubMed  Google Scholar 

  21. Heinz, A. et al. Reward craving and withdrawal relief craving: assessment of different motivational pathways to alcohol intake. Alcohol Alcohol. 38, 35–39 (2003).

    Article  PubMed  Google Scholar 

  22. Robinson, T. E. & Berridge, K. C. Addiction. Annu. Rev. Psychol. 54, 25–53 (2003).

    Article  PubMed  Google Scholar 

  23. Wise, R. A. Dopamine, learning and motivation. Nature Rev. Neurosci. 5, 483–494 (2004).

    Article  CAS  Google Scholar 

  24. Di Chiara, G. et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47, 227–241 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Di Chiara, G. & Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl Acad. Sci. USA 85, 5274–5278 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Spanagel, R. Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol. Rev. 89, 649–705 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Boileau, I. et al. Alcohol promotes dopamine release in the human nucleus accumbens. Synapse 49, 226–231 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Gilman, J. M., Ramchandani, V. A., Davis, M. B., Bjork, J. M. & Hommer, D. W. Why we like to drink: a functional magnetic resonance imaging study of the rewarding and anxiolytic effects of alcohol. J. Neurosci. 28, 4583–4591 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Spanagel, R., Herz, A. & Shippenberg, T. S. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc. Natl Acad. Sci. USA 89, 2046–2050 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Johnson, S. W. & North, R. A. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J. Neurosci. 12, 483–488 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tanda, G. L. & Di Chiara, G. A dopamine-μ1 opioid link in the rat ventral tegmentum shared by palatable food (Fonzies) and non-psychostimulant drugs of abuse. Eur. J. Neurosci. 10, 1179–1187 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Rubio, G. et al. Clinical predictors of response to naltrexone in alcoholic patients: who benefits most from treatment with naltrexone? Alcohol Alcohol. 40, 227–233 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. King, A. C., Volpicelli, J. R., Frazer, A. & O'Brien, C. P. Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence. Psychopharmacology 129, 15–22 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Krishnan-Sarin, S., Krystal, J. H., Shi, J., Pittman, B. & O'Malley, S. S. Family history of alcoholism influences naltrexone-induced reduction in alcohol drinking. Biol. Psychiatry 62, 694–697 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Bergen, A. W. et al. Mu opioid receptor gene variants: lack of association with alcohol dependence. Mol. Psychiatry 2, 490–494 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Bond, C. et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters β-endorphin binding and activity: possible implications for opiate addiction. Proc. Natl Acad. Sci. USA 95, 9608–9613 (1998). This paper identified the functional N40D variation in the MOR (the target for naltrexone).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bart, G. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Bart, G. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kroslak, T. The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor. J. Neurochem. 103, 177–187 (2007).

    Google Scholar 

  40. Zhang, Y., Wang, D. X., Johnson, A. D., Papp, A. C. & Sadee, W. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J. Biol. Chem. 280, 32618–32624 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Arias, A., Feinn, R. & Kranzler, H. R. Association of an Asn40Asp (A118G) polymorphism in the μ-opioid receptor gene with substance dependence: a meta-analysis. Drug Alcohol Depend. 83, 262–268 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Oslin, D. W. et al. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28, 1546–1552 (2003). This paper was the first to propose that therapeutic efficacy of naltrexone might be restricted to carriers of the OPRM1 118G allele.

    Article  CAS  PubMed  Google Scholar 

  43. Anton, R. F. et al. An evaluation of μ-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch. Gen. Psychiatry 65, 135–144 (2008). This paper provided an independent clinical replication of the finding that naltrexone is primarily effective in carriers of the OPRM1 118G allele.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gelernter, J. et al. Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: results from the VA cooperative study. Alcohol. Clin. Exp. Res. 31, 555–563 (2007).

    CAS  PubMed  Google Scholar 

  45. Ray, L. A. & Hutchison, K. E. Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response — a double-blind placebo-controlled study. Arch. Gen. Psychiatry 64, 1069–1077 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Ray, L. A. & Hutchison, K. E. A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcohol. Clin. Exp. Res. 28, 1789–1795 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Barr, C. S. & Goldman, D. Non-human primate models of inheritance vulnerability to alcohol use disorders. Addict. Biol. 11, 374–385 (2006).

    Article  PubMed  Google Scholar 

  48. Miller, G. M. et al. A mu-opioid receptor single nucleotide polymorphism in rhesus monkey: association with stress response and aggression. Mol. Psychiatry 9, 99–108 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Barr, C. S. et al. Association of a functional polymorphism in the mu-opioid receptor gene with alcohol response and consumption in male rhesus macaques. Arch. Gen. Psychiatry 64, 369–376 (2007). A demonstration that the psychomotor response to alcohol and alcohol preference are markedly enhanced in rhesus macaques that carry an OPRM1 77G allele that is functionally equivalent to the human 118G allele, pointing to the possibility that mesolimbic dopamine circuitry is preferentially activated by alcohol in these subjects.

    Article  CAS  PubMed  Google Scholar 

  50. Barr, C. S. et al. Suppression of alcohol preference by naltrexone in the rhesus macaque: a critical role of genetic variation at the μ-opioid receptor gene locus. Biol. Psychiatry 67, 78–80 (2010). This study demonstrated in a closely controlled experimental system that alcohol preference is selectively suppressed by naltrexone in rhesus carriers of the OPRM1 77G allele.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Vallender, E. J., Ruedi-Bettschen, D., Miller, G. M. & Platt, D. M. A pharmacogenetic model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys. Drug Alcohol Depend. 109, 252–256 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, H. P. et al. Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum. Mol. Genet. 15, 807–819 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Oroszi, G. et al. OPRM1 Asn40Asp predicts response to naltrexone treatment: a haplotype-based approach. Alcohol. Clin. Exp. Res. 33, 383–393 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Shabalina, S. A. et al. Expansion of the human mu-opioid receptor gene architecture: novel functional variants. Hum. Mol. Genet. 18, 1037–1051 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Ramchandani, V. A. et al. A genetic determinant of the striatal dopamine response to alcohol in men. Mol. Psychiatry 16, 809–817 (2011). This study showed that, as predicted by reference 49, alcohol-induced mesolimbic dopamine-release measured using PET is markedly greater in social drinkers carrying the OPRM1 118G allele than in those homozygous for the major 118A allele. It also showed that insertion of the 118G SNP into a humanized mouse is sufficient to confer increased mesolimbic dopamine release in response to alcohol, as measured directly by microdialysis.

    Article  CAS  PubMed  Google Scholar 

  56. Mague, S. D. et al. Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior. Proc. Natl Acad. Sci. USA 106, 10847–10852 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mahmoud, S. et al. Pharmacological consequence of the A118G μ opioid receptor polymorphism on morphine- and fentanyl-mediated modulation of Ca2+ channels in humanized mouse sensory neurons. Anesthesiology 14 Sep 2011 (doi:10.1097/ALN.0b013e318231fc11).

    Article  CAS  PubMed  Google Scholar 

  58. Lotsch, J. & Geisslinger, G. Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics J. 6, 200–210 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Pang, G. S. Y., Wang, J. B., Wang, Z. H., Goh, C. & Lee, C. G. L. The G allele of SNP E1/A118G at the mu-opioid receptor gene locus shows genomic evidence of recent positive selection. Pharmacogenomics 10, 1101–1109 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Wand, G. S., Mangold, D., El Deiry, S., McCaul, M. E. & Hoover, D. Family history of alcoholism and hypothalamic opioidergic activity. Arch. Gen. Psychiatry 55, 1114–1119 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Wand, G. S. et al. The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology 26, 106–114 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Hernandez-Avila, C. A. et al. Population-specific effects of the Asn40Asp polymorphism at the mu-opioid receptor gene (OPRM1) on HPA-axis activation. Pharmacogenet. Genomics 17, 1031–1038 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Kiefer, F., Jahn, H., Otte, C., Naber, D. & Wiedemann, K. Hypothalamic-pituitary-adrenocortical axis activity: a target of pharmacological anticraving treatment? Biol. Psychiatry 60, 74–76 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Kim, S.-G. et al. A mu opioid receptor gene polymorphism (A118G) and naltrexone treatment response in adherent Korean alcohol-dependent patients. Psychopharmacology 201, 611–618 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Heilig, M., Egli, M., Crabbe, J. C. & Becker, H. C. Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addict. Biol. 15, 169–184 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Solomon, R. L. & Corbit, J. D. An opponent-process theory of motivation. I. Temporal dynamics of affect. Psychol. Rev. 81, 119–145 (1974).

    Article  CAS  PubMed  Google Scholar 

  67. Koob, G. F., Vaccarino, F., Amalric, M. & Bloom, F. E. Brain Reward Systems and Abuse (eds Engel, J. & Oreland, L.) 35–50 (Raven Press, New York, 1987).

    Google Scholar 

  68. Koob, G. F. & Le Moal, M. Addiction and the brain antireward system. Annu. Rev. Psychol. 59, 29–53 (2008).

    Article  PubMed  Google Scholar 

  69. Koob, G. F. & Le Moal, M. Plasticity of reward neurocircuitry and the 'dark side' of drug addiction. Nature Neurosci. 8, 1442–1444 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Vale, W., Spiess, J., Rivier, C. & Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and β-endorphin. Science 213, 1394–1397 (1981).

    Article  CAS  PubMed  Google Scholar 

  71. Swanson, L. W., Sawchenko, P. E., Rivier, J. & Vale, W. W. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology 36, 165–186 (1983).

    Article  CAS  PubMed  Google Scholar 

  72. Heinrichs, S. C. & Koob, G. F. Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J. Pharmacol. Exp. Ther. 311, 427–440 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Muller, M. B. & Wurst, W. Getting closer to affective disorders: the role of CRH receptor systems. Trends Mol. Med. 10, 409–415 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Griebel, G. et al. 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor1 receptor antagonist. II. Characterization in rodent models of stress-related disorders. J. Pharmacol. Exp. Ther. 301, 333–345 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Gully, D. et al. 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): a potent and selective corticotrophin-releasing factor1 receptor antagonist. I. Biochemical and pharmacological characterization. J. Pharmacol. Exp. Ther. 301, 322–332 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Hokfelt, T., Johansson, O. & Goldstein, M. Chemical anatomy of the brain. Science 225, 1326–1334 (1984).

    Article  CAS  PubMed  Google Scholar 

  77. Gehlert, D. R. et al. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl- imidazo[1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism. J. Neurosci. 27, 2718–2726 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Baldwin, H. A., Rassnick, S., Rivier, J., Koob, G. F. & Britton, T. K. CRF antagonist reverses the “anxiogenic” response to ethanol withdrawal in the rat. Psychopharmacology 103, 227–232 (1991).

    Article  CAS  PubMed  Google Scholar 

  79. Rassnick, S., Heinrichs, S. C., Britton, K. T. & Koob, G. F. Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal. Brain Res. 605, 25–32 (1993).

    Article  CAS  PubMed  Google Scholar 

  80. Merlo, P. E. et al. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J. Neurosci. 15, 5439–5447 (1995).

    Article  Google Scholar 

  81. Valdez, G. R., Zorrilla, E. P., Roberts, A. J. & Koob, G. F. Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence. Alcohol 29, 55–60 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Sommer, W. H. et al. Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala Crhr1 expression following a history of dependence. Biol. Psychiatry 63, 139–145 (2008).

    Article  PubMed  Google Scholar 

  83. Overstreet, D. H., Knapp, D. J. & Breese, G. R. Accentuated decrease in social interaction in rats subjected to repeated ethanol withdrawals. Alcohol. Clin. Exp. Res. 26, 1259–1268 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Knapp, D. J., Overstreet, D. H., Moy, S. S. & Breese, G. R. SB242084, flumazenil, and CRA1000 block ethanol withdrawal-induced anxiety in rats. Alcohol 32, 101–111 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Overstreet, D. H., Knapp, D. J. & Breese, G. R. Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors. Pharmacol. Biochem. Behav. 77, 405–413 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Breese, G. R., Overstreet, D. H., Knapp, D. J. & Navarro, M. Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior: inhibition by CRF1- and benzodiazepine-receptor antagonists and a 5-HT1a-receptor agonist. Neuropsychopharmacology 30, 1662–1669 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Gilman, J. M. & Hommer, D. W. Modulation of brain response to emotional images by alcohol cues in alcohol-dependent patients. Addict. Biol. 13, 423–434 (2008).

    Article  PubMed  Google Scholar 

  88. Breese, G. R., Overstreet, D. H. & Knapp, D. J. Conceptual framework for the etiology of alcoholism: a “kindling”/stress hypothesis. Psychopharmacology 178, 367–380 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Epstein, D. H., Preston, K. L., Stewart, J. & Shaham, Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology 189, 1–16 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Le, A. & Shaham, Y. Neurobiology of relapse to alcohol in rats. Pharmacol. Ther. 94, 137–156 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Le, A. D. et al. The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology 150, 317–324 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Liu, X. & Weiss, F. Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J. Neurosci. 22, 7856–7861 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hansson, A. C. et al. Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc. Natl Acad. Sci. USA 103, 15236–15241 (2006). Using a genetically selected alcohol preferring rat line, the authors demonstrated for the first time that genetic variation affecting the CRF system influences stress-induced relapse to alcohol seeking and escalation of alcohol consumption. They showed that the potency of a CRF 1 antagonist was enhanced in animals with innate overexpression of CRF 1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kalivas, P. W. & McFarland, K. Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology 168, 44–56 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Le, A. D., Harding, S., Juzytsch, W., Fletcher, P. J. & Shaham, Y. The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. J. Neurosci. 22, 7844–7849 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vertes, R. P., Fortin, W. J. & Crane, A. M. Projections of the median raphe nucleus in the rat. J. Comp. Neurol. 407, 555–582 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Le, A. D. et al. Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress. Neuropsychopharmacology 21, 435–444 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Marinelli, P. W. et al. The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology 195, 345–355 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Funk, C. K., Zorrilla, E. P., Lee, M. J., Rice, K. C. & Koob, G. F. Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biol. Psychiatry 61, 78–86 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Funk, C. K., O'Dell, L. E., Crawford, E. F. & Koob, G. F. Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J. Neurosci. 26, 11324–11332 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sparta, D. R. et al. Blockade of the corticotropin releasing factor type 1 receptor attenuates elevated ethanol drinking associated with drinking in the dark procedures. Alcohol. Clin. Exp. Res. 32, 259–265 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Lowery, E. G. et al. CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/56J mice independent of the HPA axis. Neuropsychopharmacology 35, 1241–1252 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hansson, A. C., Cippitelli, A., Sommer, W., Ciccocioppo, R. & Heilig, M. Region-specific down regulation of Crhr1 gene expression in alcohol preferring msP rats following ad lib access to alcohol. Addict. Biol. 12, 30–34 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Makino, S., Hashimoto, K. & Gold, P. W. Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress. Pharmacol. Biochem. Behav. 73, 147–158 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Barr, C. S. et al. Functional CRH variation increases stress-induced alcohol consumption in primates. Proc. Natl Acad. Sci. USA 106, 14593–14598 (2009). This study demonstrated a gene × environment interaction, such that variation at the rhesus CRF gene locus that moderates sensitivity to feedback inhibition by cortisol moderated alcohol preference in adult life if the animals had been reared under conditions of early life adversity, but not otherwise.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Treutlein, J. et al. Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples. Mol. Psychiatry 11, 594–602 (2006). The first indication that genetic variation affecting the CRF system is associated with alcohol-use phenotypes in humans.

    Article  CAS  PubMed  Google Scholar 

  107. Blomeyer, D. et al. Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biol. Psychiatry 63, 146–151 (2008). This study provided data supporting the notion that genetic variation at the CRFR1 locus and exposure to life stressors interact to determine alcohol use phenotypes in humans.

    Article  CAS  PubMed  Google Scholar 

  108. Nelson, E. C. et al. H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence. Addict. Biology 15, 1–11 (2010).

    Article  CAS  Google Scholar 

  109. Kendler, K. S. et al. Childhood sexual abuse and adult psychiatric and substance use disorders in women: an epidemiological and cotwin control analysis. Arch. Gen. Psychiatry 57, 953–959 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Sinha, R., Shaham, Y. & Heilig, M. Translational and reverse translational research on the role of stress in drug craving and relapse. Psychopharmacology 15 Apr 2011 (doi: 10.1007/s00213-011-2263-y).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zobel, A. W. et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 34, 171–181 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Binneman, B. et al. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am. J. Psychiatry 165, 617–620 (2008).

    Article  PubMed  Google Scholar 

  113. Coric, V. et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress. Anxiety 27, 417–425 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Binder, E. B. et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299, 1291–1305 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Heilig, M., Koob, G. F., Ekman, R. & Britton, K. T. Corticotropin-releasing factor and neuropeptide Y: role in emotional integration. Trends Neurosci. 17, 80–85 (1994).

    Article  CAS  PubMed  Google Scholar 

  116. Zhou, Z. et al. Genetic variation in human NPY expression affects stress response and emotion. Nature 452, 997–1001 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Sommer, W. H. et al. Human NPY promoter variation rs16147:T>C as a moderator of prefrontal NPY gene expression and negative affect. Hum. Mutat. 31, e1594–e1608 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  119. Zubieta, J. K. et al. COMT val158met genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 299, 1240–1243 (2003).

    Article  CAS  PubMed  Google Scholar 

  120. Risch, N. et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301, 2462–2471 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Caspi, A., Hariri, A. R., Holmes, A., Uher, R. & Moffitt, T. E. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am. J. Psychiatry 167, 509–527 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. Edenberg, H. J. et al. Variations in GABRA2, encoding the α 2 subunit of the GABAA receptor, are associated with alcohol dependence and with brain oscillations. Am. J. Hum. Genet. 74, 705–714 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Porjesz, B. et al. Linkage disequilibrium between the β frequency of the human EEG and a GABAA receptor gene locus. Proc. Natl Acad. Sci. USA 99, 3729–3733 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lappalainen, J. et al. Association between alcoholism and γ-amino butyric acid α2 receptor subtype in a Russian population. Alcohol. Clin. Exp. Res. 29, 493–498 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M. & Kranzler, H. R. Allelic and haplotypic association of GABRA2 with alcohol dependence. Am. J. Med Genet. B Neuropsychiatr. Genet. 129B, 104–109 (2004).

    Article  PubMed  Google Scholar 

  127. Fehr, C. et al. Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis. Psychiatr. Genet. 16, 9–17 (2006).

    Article  PubMed  Google Scholar 

  128. Morrow, A. L., VanDoren, M. J., Penland, S. N. & Matthews, D. B. The role of GABAergic neuroactive steroids in ethanol action, tolerance and dependence. Brain Res. Brain Res. Rev. 37, 98–109 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Pierucci-Lagha, A. et al. GABRA2 alleles moderate the subjective effects of alcohol, which are attenuated by finasteride. Neuropsychopharmacology 30, 1193–1203 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Roh, S. et al. Role of GABRA2 in moderating subjective responses to alcohol. Alcohol. Clin. Exp. Res. 35, 400–407 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. Villafuerte, S. et al. Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism. Mol. Psychiatry 12 Apr 2011 (doi: 10.1038/mp.2011.33).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Knutson, B., Fong, G. W., Bennett, S. M., Adams, C. M. & Hommer, D. A region of mesial prefrontal cortex tracks monetarily rewarding outcomes: characterization with rapid event-related fMRI. Neuroimage 18, 263–272 (2003).

    Article  PubMed  Google Scholar 

  133. Knutson, B., Adams, C. M., Fong, G. W. & Hommer, D. Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J. Neurosci. 21, RC159 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Torrens, M., Fonseca, F., Mateu, G. & Farre, M. Efficacy of antidepressants in substance use disorders with and without comorbid depression. A systematic review and meta-analysis. Drug Alcohol Depend. 78, 1–22 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Johnson, B. A., Ait-Daoud, N., Ma, J. Z. & Wang, Y. Ondansetron reduces mood disturbance among biologically predisposed, alcohol-dependent individuals. Alcohol. Clin. Exp. Res. 27, 1773–1779 (2003).

    Article  CAS  PubMed  Google Scholar 

  136. Johnson, B. A., Roache, J. D., Ait-Daoud, N., Zanca, N. A. & Velazquez, M. Ondansetron reduces the craving of biologically predisposed alcoholics. Psychopharmacology 160, 408–413 (2002).

    Article  CAS  PubMed  Google Scholar 

  137. Johnson, B. A. et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients - a randomized controlled trial. JAMA 284, 963–971 (2000).

    Article  CAS  PubMed  Google Scholar 

  138. Dremencov, E., Weizmann, Y., Kinor, N., Gispan-Herman, I. & Yadid, G. Modulation of dopamine transmission by 5HT2C and 5HT3 receptors: a role in the antidepressant response. Curr. Drug Targets 7, 165–175 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Lesch, K. P. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531 (1996).

    Article  CAS  PubMed  Google Scholar 

  140. Johnson, B. A. et al. Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am. J. Psychiatry 168, 265–275 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Kenna, G. A. et al. A within group design of nontreatment seeking 5-HTTLPR genotyped alcohol dependent subjects receiving ondansetron and sertraline. Alcohol. Clin. Exp. Res. 33, 315–323 (2009).

    Article  CAS  PubMed  Google Scholar 

  142. Seneviratne, C., Huang, W., Ait-Daoud, N., Li, M. D. & Johnson, B. A. Characterization of a functional polymorphism in the 3′ UTR of SLC6A4 and its association with drinking intensity. Alcohol. Clin. Exp. Res. 33, 332–339 (2009).

    Article  CAS  PubMed  Google Scholar 

  143. Miller, G. Is pharma running out of brainy ideas? Science 329, 502–504 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Koob, G. F., Lloyd, G. K. & Mason, B. J. Development of pharmacotherapies for drug addiction: a Rosetta Stone approach. Nature Rev. Drug Discov. 8, 500–515 (2009).

    Article  CAS  Google Scholar 

  145. Johnson, B. A., Ait-Daoud, N., Akhtar, F. Z. & Ma, J. Z. Oral topiramate reduces the consequences of drinking and improves the quality of life of alcohol-dependent individuals: a randomized controlled trial. Arch. Gen. Psychiatry 61, 905–912 (2004).

    Article  CAS  PubMed  Google Scholar 

  146. Akil, H. et al. Endogenous opioids — biology and function. Annu. Rev. Neurosci. 7, 223–255 (1984).

    Article  CAS  PubMed  Google Scholar 

  147. Snyder, S. H. & Pasternak, G. W. Historical review: opioid receptors. Trends Pharmacol. Sci. 24, 198–205 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Altshuler, H. L., Phillips, P. E. & Feinhandler, D. A. Alteration of ethanol self-administration by naltrexone. Life Sci. 26, 679–688 (1980).

    Article  CAS  PubMed  Google Scholar 

  149. Egli, M. Can. experimental paradigms and animal models be used to discover clinically effective medications for alcoholism? Addict. Biology 10, 309–319 (2005).

    Article  CAS  Google Scholar 

  150. Volpicelli, J. R., Alterman, A. I., Hayashida, M. & O'Brien, C. P. Naltrexone in the treatment of alcohol dependence. Arch. Gen. Psychiatry 49, 876–880 (1992).

    Article  CAS  PubMed  Google Scholar 

  151. Hunt, W. A., Barnett, L. W. & Branch, L. G. Relapse rates in addiction programs. J. Clin. Psychol. 27, 455–456 (1971).

    Article  CAS  PubMed  Google Scholar 

  152. O'Malley, S. S. et al. Naltrexone and coping skills therapy for alcohol dependence. A controlled study. Arch. Gen. Psychiatry 49, 881–887 (1992).

    Article  CAS  PubMed  Google Scholar 

  153. Monterosso, J. R. et al. Predicting treatment response to naltrexone: the influence of craving and family history. Am. J. Addict. 10, 258–268 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Gianoulakis, C. et al. Different pituitary β-endorphin and adrenal cortisol response to ethanol in individuals with high and low risk for future development of alcoholism. Life Sci. 45, 1097–1109 (1989).

    Article  CAS  PubMed  Google Scholar 

  155. Waldhoer, M., Bartlett, S. E. & Whistler, J. L. Opioid receptors. Annu. Rev. Biochem. 73, 953–990 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Di Chiara, G., Acquas, E. & Tanda, G. Ethanol as a neurochemical surrogate of conventional reinforcers: the dopamine-opioid link. Alcohol 13, 13–17 (1996).

    Article  CAS  PubMed  Google Scholar 

  157. Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates (Elsevier Academic Press, Amsterdam, 2005).

    Google Scholar 

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Acknowledgements

The authors want to acknowledge many co-workers in their respective laboratories who over the years have contributed to work reviewed here; C.P.O. particularly wishes to acknowledge contributions by D. Oslin. The laboratories of M.H. and D.G. are supported by the intramural programme of the US National Institute on Alcohol Abuse and Alcoholism. W.H.B. is supported by US National Institutes of Health (NIH) grants P20-DA-025995, R01-DA-025201 and P60-DA 05186. C.P.O. is supported by NIH grants P60-DA-005186-23, 5-P50-DA-012756-11, R01-DA-024553 and R01-AA017164-2.

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Authors and Affiliations

  1. Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Markus Heilig

  2. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, 20892, Maryland, USA

    David Goldman

  3. Department of Psychiatry, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Wade Berrettini & Charles P. O'Brien

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Correspondence to Markus Heilig.

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Competing interests

M.H., D.G. and W.H.B. have no competing interests to declare. C.P.O. has been a paid consultant for Alkermes, a company that markets an injectable depot formulation of naltrexone.

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Glossary

Disability-adjusted life years

Also known as DALY. A measure of disease burden, expressed as the number of years lost owing to ill-health, disability or early death.

Phenocopy

An environmentally determined observable trait (phenotype) that mimics one that is genetic in nature. Frequently, the use of intermediate phenotypes can help to distinguish between phenocopies.

Kindling

Originally, the act of setting something on fire. In neurology, a process by which repeated electrical or chemical stimulation, initially of insufficient intensity to initiate a seizure, ultimately leads to a lowering of the seizure threshold and spontaneous seizures.

Withdrawal

Sudden and complete cessation of drug taking. The term is also used to denote the syndrome that results when drug is withdrawn after dependence, including tolerance to drug effects, has developed.

Cohen's D

A measure of standardized effect size, most commonly used in treatment studies, and defined as the difference between group means divided by the pooled variance. By convention, 0.2, 0.4 and 0.8 or greater are considered to be small, medium and large effect sizes, respectively.

Pharmacogenetics

The study of inherited variation in the pharmacokinetic or pharmacodynamic effects of drugs. In addictive disorders, the term is used both for the genetic modulation of psychotropic effects produced by the addictive substance and the modulation of therapeutic effects produced by medications used for treatment.

Non-synonymous

A non-synonymous polymorphism is a coding DNA variation that results in altered amino acid sequence.

Single nucleotide polymorphism

(SNP). A one-letter exchange of the genetic code, the most common class of genetic polymorphism between individuals.

Allele

A specific sequence variant encountered at a given position within the genome.

Polymorphism

A common genetic variation (typically considered to be with a frequency >1.0%) within a species.

Linkage disequilibrium

The degree with which a certain combination of alleles at different chromosomal locations is encountered together in a population, in excess of what would be expected by chance alone.

Haplotype block

A block or stretch of DNA that encompasses polymorphisms that are in linkage disequilibrium.

Haplotype

A combination of alleles at different loci on the same chromosome.

Isoform

In relation to proteins, isoforms are different forms of a protein that arise from the same gene.

Reverse translational strategy

Applying findings from humans to model organisms. For example, human genetic variants are inserted into a model organism, allowing their functional role to be studied under better controlled conditions.

Haplotype tagging

The concept that most of the alleles and haplotypes (allele combinations) in a particular chromosomal region can be captured by genotyping a small number of markers.

Chromosomal inversion

A chromosome rearrangement in which a segment of a chromosome is reversed from end to end. An inversion occurs when a single chromosome undergoes breakage and rearrangement within itself.

Intronic

Located in a stretch of DNA between exons; although regulatory elements can reside within introns, genetic variation within introns is often without functional consequences.

Intermediate phenotypes

A genetically influenced trait that is less complex and more proximal to the genetic information than the actual behavioural trait of interest, and is informative of the more distal complex trait while being possible to measure with less variance.

Exon

A stretch of DNA that will be represented in the mature, spliced messenger RNA (mRNA).

Synonymous

A coding sequence variant that, owing to the redundancy of the genetic code, does not result in an amino acid substitution.

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Heilig, M., Goldman, D., Berrettini, W. et al. Pharmacogenetic approaches to the treatment of alcohol addiction. Nat Rev Neurosci 12, 670–684 (2011). https://doi.org/10.1038/nrn3110

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