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A genetic determinant of the striatal dopamine response to alcohol in men

Molecular Psychiatry volume 16, pages 809–817 (2011)Cite this article

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Abstract

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

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References

  1. Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J . Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 2009; 373: 2223–2233.

    Article  PubMed  Google Scholar 

  2. Bouza C, Angeles M, Munoz A, Amate JM . Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004; 99: 811–828.

    Article  PubMed  Google Scholar 

  3. Heilig M, Egli M . Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther 2006; 111: 855–876.

    Article  CAS  PubMed  Google Scholar 

  4. Spanagel R . Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev 2009; 89: 649–705.

    Article  CAS  PubMed  Google Scholar 

  5. Schuckit MA . Vulnerability factors for alcoholism. In: Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: The Fifth Generation of Progress, 41st ed. Lippincott Williams & Wilkins: Philadelphia, PA, 2002 pp 1399–1412.

    Google Scholar 

  6. Goldman D, Oroszi G, Ducci F . The genetics of addictions: uncovering the genes. Nat Rev Genet 2005; 6: 521–532.

    Article  CAS  PubMed  Google Scholar 

  7. Wise RA . Dopamine, learning and motivation. Nat Rev Neurosci 2004; 5: 483–494.

    Article  CAS  PubMed  Google Scholar 

  8. 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 1988; 85: 5274–5278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Weiss F, Lorang MT, Bloom FE, Koob GF . Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp Ther 1993; 267: 250–258.

    CAS  PubMed  Google Scholar 

  10. Boileau I, Assaad JM, Pihl RO, Benkelfat C, Leyton M, Diksic M et al. Alcohol promotes dopamine release in the human nucleus accumbens. Synapse 2003; 49: 226–231.

    Article  CAS  PubMed  Google Scholar 

  11. Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L 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 1998; 95: 9608–9613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ray LA, Hutchison KE . Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response—a double-blind placebo-controlled study. Arch Gen Psychiatry 2007; 64: 1069–1077.

    Article  CAS  PubMed  Google Scholar 

  13. Miller GM, Bendor J, Tiefenbacher S, Yang H, Novak MA, Madras BK . A mu-opioid receptor single nucleotide polymorphism in rhesus monkey: association with stress response and aggression. Mol Psychiatry 2004; 9: 99–108.

    Article  CAS  PubMed  Google Scholar 

  14. Barr CS, Schwandt M, Lindell SG, Chen SA, Goldman D, Suomi SJ 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 2007; 64: 369–376.

    Article  CAS  PubMed  Google Scholar 

  15. Arias A, Feinn R, Kranzler HR . Association of an Asn40Asp (A118G) polymorphism in the mu-opioid receptor gene with substance dependence: a meta-analysis. Drug Alcohol Depend 2005; 83: 262–268.

    Article  Google Scholar 

  16. Endres CJ, Kolachana BS, Saunders RC, Su T, Weinberger D, Breier A et al. Kinetic modeling of [11C]raclopride: combined PET-microdialysis studies. J Cereb Blood Flow Metab 1997; 17: 932–942.

    Article  CAS  PubMed  Google Scholar 

  17. Gunning-Dixon FM, Head D, McQuain J, Acker JD, Raz N . Differential aging of the human striatum: a prospective MR imaging study. AJNR Am J Neuroradiol 1998; 19: 1501–1507.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Urban N, Slifstein M, Kegeles LS, Martinez D, Xu X, Sakr E et al. In vivo evidence for gender differences in alcohol induced striatal dopamine release: a PET imaging study with [11C]. Personal communication, Paper Presented at the Annual Meeting of the American College of Neuropsychopharmacology 2009.

  19. Arias A, Feinn R, Kranzler HR . Association of an Asn40Asp (A118G) polymorphism in the mu-opioid receptor gene with substance dependence: a meta-analysis. Drug Alcohol Depend 2005; 83: 262–268.

    Article  Google Scholar 

  20. Ramchandani VA, Plawecki M, Li TK, O’Connor S . Intravenous ethanol infusions can mimic the time course of breath alcohol concentrations following oral alcohol administration in healthy volunteers. Alcohol Clin Exp Res 2009; 33: 938–944.

    Article  CAS  PubMed  Google Scholar 

  21. Ramchandani VA, Bolane J, Li TK, O’Connor S . A physiologically-based pharmacokinetic (PBPK) model for alcohol facilitates rapid BrAC clamping. Alcohol Clin Exp Res 1999; 23: 617–623.

    Article  CAS  PubMed  Google Scholar 

  22. Blekher T, Ramchandani VA, Flury L, Foroud T, Kareken D, Yee RD et al. Saccadic eye movements are associated with a family history of alcoholism at baseline and after exposure to alcohol. Alcohol Clin Exp Res 2002; 26: 1568.

    Article  PubMed  Google Scholar 

  23. Kwo PY, Ramchandani VA, O’Connor S, Amann D, Carr LG, Sandrasegaran K et al. Gender differences in alcohol metabolism: relationship to liver volume and effect of adjusting for body mass. Gastroenterology 1998; 115: 1552–1557.

    Article  CAS  PubMed  Google Scholar 

  24. Morzorati SL, Ramchandani VA, Flury L, Li TK, O’Connor S . Self-reported subjective perception of intoxication reflects family history of alcoholism when breath alcohol levels are constant. Alcohol Clin Exp Res 2002; 26: 1299–1306.

    Article  PubMed  Google Scholar 

  25. Ramchandani VA, Flurry L, Morzorati SL, Kareken D, Blekher T, Foroud T et al. Recent drinking history: association with family history of alcoholism and the acute response to alcohol during a 60 Mg% Clamp. J Stud Alcohol 2002; 63: 734–745.

    Article  PubMed  Google Scholar 

  26. Neumark YD, Friedlander Y, Durst R, Leitersdorf E, Jaffe D, Ramchandani VA et al. Alcohol dehydrogenase polymorphisms influence alcohol-elimination rates in a male Jewish population. Alcohol Clin Exp Res 2004; 28: 10–14.

    Article  CAS  PubMed  Google Scholar 

  27. Gilman JM, Ramchandani VA, Davis MB, Bjork JM, Hommer DW . Why we like to drink: a functional magnetic resonance imaging study of the rewarding and anxiolytic effects of alcohol. J Neurosci 2008; 28: 4583–4591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. de Wit H, McCracken SG . Ethanol self-administration in males with and without an alcoholic first-degree relative. Alcohol Clin Exp Res 1990; 14: 63–70.

    Article  CAS  PubMed  Google Scholar 

  29. Lammertsma AA, Hume SP . Simplified reference tissue model for PET receptor studies. Neuroimage 1996; 4: 153–158.

    Article  CAS  PubMed  Google Scholar 

  30. Skinner HA, Sheu WJ . Reliability of alcohol use indices. The lifetime drinking history and the MAST. J Stud Alcohol 1982; 43: 1157.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang HP, Luo XG, Kranzler HR, Lappalainen J, Yang BZ, Krupitsky E et al. Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum Mol Genet 2006; 15: 807–819.

    Article  CAS  PubMed  Google Scholar 

  32. Belknap JK, Crabbe JC, Young ER . Voluntary consumption of ethanol in 15 inbred mouse strains. Psychopharmacology (Berl) 1993; 112: 503–510.

    Article  CAS  Google Scholar 

  33. Crawley JN, Paylor R . A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav 1997; 31: 197–211.

    Article  CAS  PubMed  Google Scholar 

  34. Morris BJ, Millan MJ, Herz A . Antagonist-induced opioid receptor up-regulation. II. Regionally specific modulation of mu, delta and kappa binding sites in rat brain revealed by quantitative autoradiography. J Pharmacol Exp Ther 1988; 247: 729–736.

    CAS  PubMed  Google Scholar 

  35. Sim LJ, Selley DE, Childers SR . In vitro autoradiography of receptor-activated G proteins in rat brain by agonist-stimulated guanylyl 5′-[gamma-[35S]thio]-triphosphate binding. Proc Natl Acad Sci USA 1995; 92: 7242–7246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Paxinos G, Franklin KBJ . The Mouse Brain in Stereotaxic Coordinates, 2nd ed. Academic Press: London, 2001.

    Google Scholar 

  37. Margas W, Mahmoud S, Ruiz-Velasco V . Muscarinic acetylcholine receptor modulation of mu ({mu}) opioid receptors in adult rat sphenopalatine ganglion neurons. J Neurophysiol 2009; 103: 172–182.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Frantz KJ, Hansson KJ, Stouffer DG, Parsons LH . 5-HT6 receptor antagonism potentiates the behavioral and neurochemical effects of amphetamine but not cocaine. Neuropharmacology 2002; 42: 170–180.

    Article  CAS  PubMed  Google Scholar 

  39. Munafo MR, Brown SM, Hariri AR . Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry 2008; 63: 852–857.

    Article  CAS  PubMed  Google Scholar 

  40. Furmark T, Appel L, Michelgard A, Wahlstedt K, Ahs F, Zancan S et al. Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo. Biol Psychiatry 2005; 58: 132–142.

    Article  CAS  PubMed  Google Scholar 

  41. Newlin DB, Thomson JB . Alcohol challenge with sons of alcoholics—a critical-review and analysis. Psychol Bull 1990; 108: 383–402.

    Article  CAS  PubMed  Google Scholar 

  42. Bart G, Kreek MJ, Ott J, LaForge KS, Proudnikov D, Pollak L et al. Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden. Neuropsychopharmacology 2005; 30: 417–422.

    Article  CAS  PubMed  Google Scholar 

  43. Arias A, Feinn R, Kranzler HR . Association of an Asn40Asp (A118G) polymorphism in the [mu]-opioid receptor gene with substance dependence: a meta-analysis. Drug Alcohol Depend 2006; 83: 262–268.

    Article  CAS  PubMed  Google Scholar 

  44. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002; 297: 400–403.

    Article  CAS  PubMed  Google Scholar 

  45. Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, Shoaf SE et al. Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry 2002; 7: 118–122.

    Article  CAS  PubMed  Google Scholar 

  46. Barr CS, Newman TK, Schwandt M, Shannon C, Dvoskin RL, Lindell SG et al. Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques. Proc Natl Acad Sci USA 2004; 101: 12358–12363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386–389.

    Article  CAS  PubMed  Google Scholar 

  48. Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 2009; 301: 2462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kendler KS, Thornton LM, Gardner CO . Genetic risk, number of previous depressive episodes, and stressful life events in predicting onset of major depression. Am J Psychiatry 2001; 158: 582–586.

    Article  CAS  PubMed  Google Scholar 

  50. Oslin DW, Berrettini W, Kranzler HR, Pettinati H, Gelernter J, Volpicelli JR et al. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 2003; 28: 1546–1552.

    Article  CAS  PubMed  Google Scholar 

  51. Anton RF, Oroszi G, O’Malley S, Couper D, Swift R, Pettinati H et al. An evaluation of mu-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 2008; 65: 135–144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gelernter J, Gueorguieva R, Kranzler HR, Zhang HP, Cramer J, Rosenheck R 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 2007; 31: 555–563.

    CAS  PubMed  Google Scholar 

  53. Barr CS, Chen SA, Schwandt ML, Lindell SG, Sun H, Suomi SJ et al. Suppression of alcohol preference by naltrexone in the rhesus macaque: a critical role of genetic variation at the μ-opioid receptor gene (OPRM1) locus. Biol Psychiatry 2009; 67: 78–80.

    Article  Google Scholar 

  54. Schultz W . Behavioral theories and the neurophysiology of reward. Annu Rev Psychol 2006; 57: 87–115.

    Article  PubMed  Google Scholar 

  55. Zhang Y, Wang DX, Johnson AD, Papp AC, Sadee W . Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 2005; 280: 32618–32624.

    Article  CAS  PubMed  Google Scholar 

  56. Mague SD, Isiegas C, Huang P, Liu-Chen LY, Lerman C, Blendy JA . Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior. Proc Natl Acad Sci USA 2009; 106: 10847–10852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. He L, Fong J, von Zastrow M, Whistler JL . Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 2002; 108: 271–282.

    Article  CAS  PubMed  Google Scholar 

  58. Barr CS, Schwandt ML, Lindell SG, Higley JD, Maestripieri D, Goldman D et al. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proc Natl Acad Sci USA 2008; 105: 5277–5281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Way BM, Taylor SE, Eisenberger NI . Variation in the μ-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection. Proc Natl Acad Sci USA 2009; 106: 15079–15084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wand GS, McCaul M, Yang X, Reynolds J, Gotjen D, Lee S et al. The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology 2002; 26: 106–114.

    Article  CAS  PubMed  Google Scholar 

  61. Pang GSY, Wang JB, Wang ZH, Goh C, Lee CGL . The G allele of SNP E1/A118G at the mu-opioid receptor gene locus shows genomic evidence of recent positive selection. Pharmacogenomics 2009; 10: 1101–1109.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the NIAAA Division of Intramural Clinical and Biological Research (Heilig, Hommer, George and Ramchandani), and Grants AA014619 from NIAAA (Parsons) and PAI 433/06 from Consejeria de Innovacion y Ciencia (Pavon). We gratefully acknowledge data analysis by M Kerich and R Momenan, biochemical analysis by E Singley and PET data collection by C Jones, S Kumar, S Eappen, and J Issa.

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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, MD, USA

    V A Ramchandani, J Umhau, H Sun, R Damadzic, R Eskay, A Thorsell, M L Schwandt, W H Sommer, D T George, D Hommer & M Heilig

  2. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA

    F J Pavon & L H Parsons

  3. Department of Anesthesiology, Pennsylvania State University College of Medicine, Hershey, PA, USA

    V Ruiz-Velasco & W Margas

  4. TaconicArtemis GmbH, Koeln, Germany

    M Schoor

  5. Central Institute for Mental Health, Mannheim, Germany

    W H Sommer

  6. PET Department, Mark O. Hatfield Clinical Research Center, National Institutes of Health, Bethesda, MD, USA

    P Herscovitch

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  1. V A Ramchandani
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Ramchandani, V., Umhau, J., Pavon, F. et al. A genetic determinant of the striatal dopamine response to alcohol in men. Mol Psychiatry 16, 809–817 (2011). https://doi.org/10.1038/mp.2010.56

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