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Influence of dopamine-related genes on craving, impulsivity, and aggressiveness in Korean males with alcohol use disorder

Abstract

Dopamine is a major neuromodulator that is acutely involved in various cognitive processes, reward-motivated behaviors, and impulsivity. Abnormality in dopaminergic neurotransmission is implicated in the pathophysiology of alcohol use disorder (AUD). The present study examined the genetic influence of dopamine system on problematic drinking, impulsivity, and aggressiveness in a Korean male population with AUD. Five single nucleotide polymorphisms (SNPs) (rs4532 in DRD1, rs2283265 in DRD2, rs6280 in DRD3, rs1800497 in ANKK1, and rs4680 in COMT) and a variable number of tandem repeats (VNTRs) in DAT1 in 295 male patients with AUD were genotyped. For AUD-related clinical characteristics, the Alcohol Use Disorders Identification Test and the Obsessive–Compulsive Drinking Scale (OCDS) were used to assess the severity of hazardous drinking and craving symptoms, respectively. Participants also completed the UPPS-P Impulsive Behavior Scale (UPPS-P) and Buss-Perry Aggression Questionnaire (BPAQ). Analyses were performed using R package SNPassoc; statistical significance was set as p < 0.0083 after Bonferroni correction. A significant association was detected between DRD3 SNP rs6280 and OCDS scores. In regard to impulsivity and aggressiveness, rs4532 of DRD1 was significantly associated with UPPS-P score. Also, rs4532 demonstrated a nominally significant association with BPAQ score, although it did not reach statistical significance after correction for multiple comparisons. Results of this study support the idea that genetic variations in the dopamine system may contribute to alcohol cravings and impulsivity in patients with AUD.

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References

  1. 1.

    Addolorato G, Leggio L, Abenavoli L, Gasbarrini G, Alcoholism Treatment Study G (2005) Neurobiochemical and clinical aspects of craving in alcohol addiction: a review. Addict Behav 30:1209–1224

    PubMed  Google Scholar 

  2. 2.

    Agrawal A, Wetherill L, Bucholz KK, Kramer J, Kuperman S, Lynskey MT, Nurnberger JI Jr, Schuckit M, Tischfield JA, Edenberg HJ, Foroud T, Bierut LJ (2013) Genetic influences on craving for alcohol. Addict Behav 38:1501–1508

    PubMed  Google Scholar 

  3. 3.

    Alcohol GBD, Drug Use C (2018) The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Psychiatry 5:987–1012

    Google Scholar 

  4. 4.

    Anton RF, Moak DH, Latham P (1995) The obsessive compulsive drinking scale: a self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res 19:92–99

    CAS  PubMed  Google Scholar 

  5. 5.

    Arinami T, Itokawa M, Komiyama T, Mitsushio H, Mori H, Mifune H, Hamaguchi H, Toru M (1993) Association between severity of alcoholism and the a1 allele of the dopamine d2 receptor gene taqi a rflp in Japanese. Biol Psychiatry 33:108–114

    CAS  PubMed  Google Scholar 

  6. 6.

    Ashby CR Jr, Rice OV, Heidbreder CA, Gardner EL (2015) The selective dopamine d3 receptor antagonist sb-277011a significantly accelerates extinction to environmental cues associated with cocaine-induced place preference in male sprague-dawley rats. Synapse 69:512–514

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Bahi A, Dreyer JL (2014) Lentiviral vector-mediated dopamine d3 receptor modulation in the rat brain impairs alcohol intake and ethanol-induced conditioned place preference. Alcohol Clin Exp Res 38:2369–2376

    CAS  PubMed  Google Scholar 

  8. 8.

    Beck AT, Steer RA, Carbin MG (1988) Psychometric properties of the beck depression inventory: twenty-five years of evaluation. Clin Psychol Rev 8:77–100

    Google Scholar 

  9. 9.

    Bernhardt N, Nebe S, Pooseh S, Sebold M, Sommer C, Birkenstock J, Zimmermann US, Heinz A, Smolka MN (2017) Impulsive decision making in young adult social drinkers and detoxified alcohol-dependent patients: a cross-sectional and longitudinal study. Alcohol Clin Exp Res 41:1794–1807

    CAS  PubMed  Google Scholar 

  10. 10.

    Bhaskar LV, Kumar SA (2014) Polymorphisms in genes encoding dopamine signalling pathway and risk of alcohol dependence: a systematic review. Acta Neuropsychiatr 26:69–80

    PubMed  Google Scholar 

  11. 11.

    Buss AH, Perry M (1992) The aggression questionnaire. J Pers Soc Psychol 63:452

    CAS  Google Scholar 

  12. 12.

    Chen C, Chen C, Moyzis R, He Q, Li H, Li J, Zhu B, Lessard J, Stern H, Dong Q (2012) Genetic variations in the dopaminergic system and alcohol use: a system-level analysis. Addict Biol 17:479–489

    CAS  PubMed  Google Scholar 

  13. 13.

    Cheon KA, Ryu YH, Kim JW, Cho DY (2005) The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate. Eur Neuropsychopharmacol 15:95–101

    CAS  PubMed  Google Scholar 

  14. 14.

    Choi MJ, Lee E, Lee BO, Lee PG, Oh BH, Lee CH, Namkoong K (2002) The study on reliability and validity of korean versions of obsessive compulsive drinking scale for outpatient of alcohol dependence. J Korean Neuropsychiatr Assoc 41(1):98–109

    Google Scholar 

  15. 15.

    Cools R (2008) Role of dopamine in the motivational and cognitive control of behavior. Neuroscientist 14:381–395

    CAS  PubMed  Google Scholar 

  16. 16.

    Cui C, Noronha A, Morikawa H, Alvarez VA, Stuber GD, Szumlinski KK, Kash TL, Roberto M, Wilcox MV (2013) New insights on neurobiological mechanisms underlying alcohol addiction. Neuropharmacology 67:223–232

    CAS  PubMed  Google Scholar 

  17. 17.

    Diana M (2011) The dopamine hypothesis of drug addiction and its potential therapeutic value. Front Psychiatry 2:64

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Engel J, Jerlhag E (2014) Alcohol: mechanisms along the mesolimbic dopamine system. Prog Brain Res 211:201–233

    CAS  PubMed  Google Scholar 

  19. 19.

    Forbes E, Brown S, Kimak M, Ferrell R, Manuck S, Hariri A (2009) Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity. Mol Psychiatry 14:60

    CAS  PubMed  Google Scholar 

  20. 20.

    Gauderman A (2006) Quanto 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies. http://www.hydra.usc.edu/gxe. Accessed 16 July 2019

  21. 21.

    Gelernter J, Kranzler H (1999) D2 dopamine receptor gene (drd2) allele and haplotype frequencies in alcohol dependent and control subjects: no association with phenotype or severity of phenotype. Neuropsychopharmacology 20:640–649

    CAS  PubMed  Google Scholar 

  22. 22.

    González JR, Armengol L, Solé X, Guinó E, Mercader JM, Estivill X, Moreno V (2007) Snpassoc: an r package to perform whole genome association studies. Bioinformatics 23:654–655

    Google Scholar 

  23. 23.

    Hack LM, Kalsi G, Aliev F, Kuo PH, Prescott CA, Patterson DG, Walsh D, Dick DM, Riley BP, Kendler KS (2011) Limited associations of dopamine system genes with alcohol dependence and related traits in the irish affected sib pair study of alcohol dependence (iaspsad). Alcohol Clin Exp Res 35:376–385

    PubMed  Google Scholar 

  24. 24.

    Hahn HM, Yum TH, Shin YW, Kim KH, Yoon DJ, Chung KJ (1986) A standardization study of beck depression inventory in Korea. J Korean Neuropsychiatr Assoc 25:487–502

    Google Scholar 

  25. 25.

    Heidbreder CA, Newman AH (2010) Current perspectives on selective dopamine d(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders. Ann NY Acad Sci 1187:4–34

    CAS  PubMed  Google Scholar 

  26. 26.

    Heinz A, Siessmeier T, Wrase J, Buchholz HG, Grunder G, Kumakura Y, Cumming P, Schreckenberger M, Smolka MN, Rosch F, Mann K, Bartenstein P (2005) Correlation of alcohol craving with striatal dopamine synthesis capacity and d2/3 receptor availability: a combined [18f]dopa and [18f]dmfp pet study in detoxified alcoholic patients. Am J Psychiatry 162:1515–1520

    PubMed  Google Scholar 

  27. 27.

    Kang S-G, Lee B-H, Lee J-S, Chai YG, Ko K-P, Lee H-J, Ji H, Jang G-H, Shin HE (2014) Drd3 gene rs6280 polymorphism may be associated with alcohol dependence overall and with lesch type 1 alcohol dependence in koreans. Neuropsychobiology 69:140–146

    CAS  PubMed  Google Scholar 

  28. 28.

    Kim D-J, Park BL, Yoon S, Lee H-K, Joe K-H, Cheon Y-H, Gwon D-H, Cho S-N, Lee HW, NamGung S (2007) 5′ utr polymorphism of dopamine receptor d1 (drd1) associated with severity and temperament of alcoholism. Biochem Biophys Res Commun 357:1135–1141

    CAS  PubMed  Google Scholar 

  29. 29.

    Kohno M, Ghahremani DG, Morales AM, Robertson CL, Ishibashi K, Morgan AT, Mandelkern MA, London ED (2015) Risk-taking behavior: dopamine d2/d3 receptors, feedback, and frontolimbic activity. Cereb Cortex 25:236–245

    PubMed  Google Scholar 

  30. 30.

    Koob GF (2013) Theoretical frameworks and mechanistic aspects of alcohol addiction: alcohol addiction as a reward deficit disorder. Curr Top Behav Neurosci 13:3–30

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Kreek MJ, Nielsen DA, Butelman ER, LaForge KS (2005) Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 8:1450

    CAS  PubMed  Google Scholar 

  32. 32.

    Kwon SM, Seo SG (2002) Validation study of the korean version of the aggression questionnaire. Kor J Clin Psychol 21:487–501

    Google Scholar 

  33. 33.

    Le Foll B, Goldberg SR, Sokoloff P (2005) The dopamine d3 receptor and drug dependence: effects on reward or beyond? Neuropharmacology 49:525–541

    PubMed  Google Scholar 

  34. 34.

    Lee BO, Lee CH, Lee PG, Choi MJ, Namkoong K (2000) Development of korean version of alcohol use disorders identification test(audit-k):its reliability and validity. J Korean Acad Addict Psychiatry 4:83–92

    Google Scholar 

  35. 35.

    Lee J-K, Kim H-T, Cho S-M, Kim K-H, Jin H-J, Ryu G-M, Oh B, Park C, Kimm K, Jo SA (2003) Characterization of 458 single nucleotide polymorphisms of disease candidate genes in the korean population. J Hum Genet 48:213

    CAS  PubMed  Google Scholar 

  36. 36.

    Lim SY, Lee YH (2014) A korean validation of the upps-p impulsive behavior scale in college students. Korea J Clin Psychol 33:51–71

    Google Scholar 

  37. 37.

    Linsenbardt DN, Smoker MP, Janetsian-Fritz SS, Lapish CC (2017) Impulsivity in rodents with a genetic predisposition for excessive alcohol consumption is associated with a lack of a prospective strategy. Cogn Affect Behav Neurosci 17:235–251

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Lynam DR, Smith GT, Whiteside SP, Cyders MA (2006) The upps-p: assessing five personality pathways to impulsive behavior. Unpublished technical report

  39. 39.

    Martinez D, Gil R, Slifstein M, Hwang DR, Huang Y, Perez A, Kegeles L, Talbot P, Evans S, Krystal J, Laruelle M, Abi-Dargham A (2005) Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 58:779–786

    CAS  PubMed  Google Scholar 

  40. 40.

    Mayfield RD, Harris RA, Schuckit MA (2008) Genetic factors influencing alcohol dependence. Br J Pharmacol 154:275–287

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Morikawa H, Morrisett RA (2010) Ethanol action on dopaminergic neurons in the ventral tegmental area: interaction with intrinsic ion channels and neurotransmitter inputs. Int Rev Neurobiol 91:235–288

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Mota NR, Bau CH, Banaschewski T, Buitelaar JK, Ebstein RP, Franke B, Gill M, Kuntsi J, Manor I, Miranda A (2013) Association between drd2/drd4 interaction and conduct disorder: a potential developmental pathway to alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 162:546–549

    CAS  Google Scholar 

  43. 43.

    Munafo M, Johnstone E, Welsh K, Walton R (2005) Association between the drd2 gene taq1a (c32806t) polymorphism and alcohol consumption in social drinkers. Pharmacogenomics J 5:96

    CAS  PubMed  Google Scholar 

  44. 44.

    Narendran R, Mason NS, Paris J, Himes ML, Douaihy AB, Frankle WG (2014) Decreased prefrontal cortical dopamine transmission in alcoholism. Am J Psychiatry 171:881–888

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    O’brien C (2011) Addiction and dependence in dsm-v. Addiction 106:866–867

    PubMed  Google Scholar 

  46. 46.

    O’Brien CP (2005) Anticraving medications for relapse prevention: a possible new class of psychoactive medications. Am J Psychiatry 162:1423–1431

    PubMed  Google Scholar 

  47. 47.

    Pattij T, De Vries TJ (2013) The role of impulsivity in relapse vulnerability. Curr Opin Neurobiol 23:700–705

    CAS  PubMed  Google Scholar 

  48. 48.

    Pearson-Fuhrhop KM, Dunn EC, Mortero S, Devan WJ, Falcone GJ, Lee P, Holmes AJ, Hollinshead MO, Roffman JL, Smoller JW (2014) Dopamine genetic risk score predicts depressive symptoms in healthy adults and adults with depression. PLoS One 9:e93772

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Reyes-Huerta HE, Dos Santos C, Martinez K (2018) Impulsive mechanisms influencing relapse in alcohol drinking. Med Hypotheses 112:27–29

    PubMed  Google Scholar 

  50. 50.

    Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M (1993) Development of the alcohol use disorders identification test (audit): who collaborative project on early detection of persons with harmful alcohol consumption–ii. Addiction 88:791–804

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Savitz J, Hodgkinson CA, Martin-Soelch C, Shen PH, Szczepanik J, Nugent A, Herscovitch P, Grace AA, Goldman D, Drevets WC (2013) The functional drd3 ser9gly polymorphism (rs6280) is pleiotropic, affecting reward as well as movement. PLoS One 8:e54108

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Schulte MT, Ramo D, Brown SA (2009) Gender differences in factors influencing alcohol use and drinking progression among adolescents. Clin Psychol Rev 29:535–547

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Sullivan PF (2007) Spurious genetic associations. Biol Psychiatry 61:1121–1126

    CAS  PubMed  Google Scholar 

  54. 54.

    Sun Y, Zhang Y, Wang F, Sun Y, Shi J, Lu L (2016) From genetic studies to precision medicine in alcohol dependence. Behav Pharmacol 27:87–99

    CAS  PubMed  Google Scholar 

  55. 55.

    Taber KH, Black DN, Porrino LJ, Hurley RA (2012) Neuroanatomy of dopamine: reward and addiction. J Neuropsychiatry Clin Neurosci 24:1–4

    PubMed  Google Scholar 

  56. 56.

    Tiihonen J, Hallikainen T, Lachman H, Saito T, Volavka J, Kauhanen J, Salonen J, Ryynänen O, Koulu M, Karvonen M (1999) Association between the functional variant of the catechol-o-methyltransferase (comt) gene and type 1 alcoholism. Mol Psychiatry 4:286

    CAS  PubMed  Google Scholar 

  57. 57.

    Ueno S, Nakamura M, Mikami M, Kondoh K, Ishiguro H, Arinami T, Komiyama T, Mitsushio H, Sano A, Tanabe H (1999) Identification of a novel polymorphism of the human dopamine transporter (dat1) gene and the significant association with alcoholism. Mol Psychiatry 4:552

    CAS  PubMed  Google Scholar 

  58. 58.

    Verdejo-García A, Lawrence AJ, Clark L (2008) Impulsivity as a vulnerability marker for substance-use disorders: review of findings from high-risk research, problem gamblers and genetic association studies. Neurosci Biobehav Rev 32:777–810

    PubMed  Google Scholar 

  59. 59.

    Volkow ND, Wang GJ, Fowler JS, Tomasi D, Telang F (2011) Addiction: beyond dopamine reward circuitry. Proc Natl Acad Sci USA 108:15037–15042

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Wong MM, Nigg JT, Zucker RA, Puttler LI, Fitzgerald HE, Jester JM, Glass JM, Adams K (2006) Behavioral control and resiliency in the onset of alcohol and illicit drug use: a prospective study from preschool to adolescence. Child Dev 77:1016–1033

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Xi ZX, Gardner EL (2007) Pharmacological actions of ngb 2904, a selective dopamine d3 receptor antagonist, in animal models of drug addiction. CNS Drug Rev 13:240–259

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Zhu F, Yan CX, Wen YC, Wang J, Bi J, Zhao YL, Wei L, Gao CG, Jia W, Li SB (2013) Dopamine d1 receptor gene variation modulates opioid dependence risk by affecting transition to addiction. PLoS One 8:e70805

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2018R1A2B2007714). The funding source did not give any influences on the study design, data collection, analysis and interpretation of data, the writing of the report, and the decision to submit the paper for publication.

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SK and JK conceived and planned the study. SK contributed to data collection and management. CP, HK, and JK performed statistical analyses and interpreted the findings. CP, JK, SH and SK wrote the manuscript. SH and HK provided scientific input and helped edit the manuscript. All authors contributed to and have approved the final manuscript.

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Correspondence to Jee In Kang or Se Joo Kim.

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Park, C.I., Kim, H.W., Hwang, S.S. et al. Influence of dopamine-related genes on craving, impulsivity, and aggressiveness in Korean males with alcohol use disorder. Eur Arch Psychiatry Clin Neurosci 271, 865–872 (2021). https://doi.org/10.1007/s00406-019-01072-3

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Keywords

  • Alcohol use disorder
  • Dopamine-related genes
  • Craving
  • Impulsivity
  • Endophenotype
  • Genetic association study