Role of Dopamine Receptors in ADHD: A Systematic Meta-analysis

Abstract

The dopaminergic system plays a pivotal role in the central nervous system via its five diverse receptors (D1–D5). Dysfunction of dopaminergic system is implicated in many neuropsychological diseases, including attention deficit hyperactivity disorder (ADHD), a common mental disorder that prevalent in childhood. Understanding the relationship of five different dopamine (DA) receptors with ADHD will help us to elucidate different roles of these receptors and to develop therapeutic approaches of ADHD. This review summarized the ongoing research of DA receptor genes in ADHD pathogenesis and gathered the past published data with meta-analysis and revealed the high risk of DRD5, DRD2, and DRD4 polymorphisms in ADHD.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Tannock R (1998) Attention deficit hyperactivity disorder: advances in cognitive, neurobiological, and genetic research. J Child Psychol Psychiatry 39(1):65–99

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Baumgartel A, Wolraich ML, Dietrich M (1995) Comparison of diagnostic criteria for attention deficit disorders in a German elementary school sample. J Am Acad Child Adolesc Psychiatry 34:629–638

    Article  Google Scholar 

  3. 3.

    Anderson JC, Williams S, McGee R, Silva PA (1987) DSMIII-R disorders in preadolescent children: prevalence in a large sample from the general population. Arch Gen Psychiatry 44:69–76

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Barkley RA, Smith KM, Fischer M, Navia B (2006) An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal children followed to adulthood. Am J Med Genet B Neuropsychiatr Genet 141B(5):487–498

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Biederman J, Newcorn J, Sprich S (1991) Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 148:564–577

    PubMed  CAS  Google Scholar 

  6. 6.

    Gittelman R, Mannuzza S, Shenker R, Bonagura N (1985) Hyperactive boys almost grown up. I. Psychiatric status. Arch Gen Psychiatry 42(10):937–947

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Swanson JM, Sergeant JA, Taylor E, Sonuga-Barke E, Jensen PS, Cantwell DP (1998) Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 351(9100):429–433

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Wilens TE, Biederman J, Spencer TJ (2002) Attention deficit/hyperactivity disorder across the lifespan. Annu Rev Med 53:113–131

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Woodward L, Taylor E, Dowdney L (1998) The parenting and family functioning of children with hyperactivity. J Child Psychol Psychiatry 39:161–169

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Barkley RA (1990) Attention deficit hyperactivity disorder: a handbook for diagnosis and treatment. Guilford, New York

    Google Scholar 

  11. 11.

    Mannuzza S, Klein RG, Bessler A, Malloy P, LaPadula M (1993) Adult outcome of hyperactive boys. Educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry 50(7):565–576

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Lilienfeld SO, Waldman ID (1990) The relation between childhood attention-deficit hyperactivity disorder and adult antisocial behavior reexamined: the problem of heterogeneity. Clin Psychol Rev 10(6):699–725

    Article  Google Scholar 

  13. 13.

    Loeber R, Dishion T (1983) Early predictors of male delinquency: a review. Psychol Bull 94(1):68–99

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366:237–248

    PubMed  Article  Google Scholar 

  15. 15.

    Spencer T, Biederman J, Wilens T (1999) Attention-deficit/hyperactivity disorder and comorbidity. Pediatr Clin N Am 46:915–927

    CAS  Article  Google Scholar 

  16. 16.

    Jensen PS, Martin D, Cantwel LD (1997) Comorbidity in ADHD: implications for research, practice and DSMIV. J Am Acad Child Adolesc Psychiatry 36(7):1065–1079

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Bird HR, Gould MS, Staghezza BM (1993) Patterns of diagnostic comorbidity in a community sample of children aged 9 through 16 years. J Am Acad Child Adolesc Psychiatry 32(2):361–368

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 57(11):1313–1323

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Derks EM, Hudziak JJ, Dolan CV, van Beijsterveldt TC, Verhulst FC, Boomsma DI (2008) Genetic and environmental influences on the relation between attention problems and attention deficit hyperactivity disorder. Behav Genet 38(1):11–23

    PubMed  Article  Google Scholar 

  20. 20.

    Haberstick BC, Timberlake D, Hopfer CJ, Lessem JM, Ehringer MA, Hewitt JK (2008) Genetic and environmental contributions to retrospectively reported DSM-IV childhood attention deficit hyperactivity disorder. Psychol Med 38(7):1057–1066

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Wood AC, Rijsdijk F, Saudino KJ, Asherson P, Kuntsi J (2008) High heritability for a composite index of children's activity level measures. Behav Genet 38(3):266–276

    PubMed  Article  Google Scholar 

  22. 22.

    Bobb AJ, Addington AM, Sidransky E, Gornick MC, Lerch JP, Greenstein DK, Clasen LS, Sharp WS, Inoff-Germain G, Wavrant-De VF, Arcos-Burgos M, Straub RE, Hardy JA, Castellanos FX, Rapoport JL (2005) Support for association between ADHD and two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet 134B(1):67–72

    PubMed  Article  Google Scholar 

  23. 23.

    Banaschewski T, Becker K, Scherag S, Franke B, Coghill D (2010) Molecular genetics of attention-deficit/hyperactivity disorder: an overview. Eur Child Adolesc Psychiatry 19(3):237–257

    PubMed  Article  Google Scholar 

  24. 24.

    Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126(1):51–90

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Sibley DR, Monsma FJ Jr (1992) Molecular biology of dopamine receptors. Trends Pharmacol Sci 13:61–69

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Gingrich JA, Caron MG (1993) Recent advances in the molecular biology of dopamine receptors. Annu Rev Neurosci 16:299–321

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Cichon S, Nöthen MM, Stöber G, Schroers R, Albus M, Maier W, Rietschel M, Körner J, Weigelt B, Franzek E et al (1996) Systematic screening for mutations in the 5′-regulatory region of the human dopamine D1 receptor (DRD1) gene in patients with schizophrenia and bipolar affective disorder. Am J Med Genet 67(4):424–428

    Google Scholar 

  28. 28.

    Pivonello R, Ferone D, Lombardi G, Colao A, Lamberts SW, Hofland LJ (2007) Novel insights in dopamine receptor physiology. Eur J Endocrinol 156(Suppl 1):S13–S21

    PubMed  CAS  Article  Google Scholar 

  29. 29.

    Fukunaga K, Shioda N (2012) Novel dopamine D2 receptor signaling through proteins interacting with the third cytoplasmic loop. Mol Neurobiol 45(1):144–152

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78(1):189–225

    PubMed  CAS  Google Scholar 

  31. 31.

    Vallone D, Picetti R, Borrelli E (2000) Structure and function of dopamine receptors. Neurosci Biobehav Rev 24(1):125–132

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Gloerich M, Bos JL (2010) Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol 50:355–375

    PubMed  CAS  Article  Google Scholar 

  33. 33.

    Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275(5306):1593–1599

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Beninger RJ, Miller R (1998) Dopamine D1-like receptors and reward-related incentive learning. Neurosci Biobehav Rev 22(2):335–345

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Hollerman JR, Schultz W (1998) Dopamine neurons report an error in the temporal prediction of reward during learning. Nat Neurosci 1(4):304–309

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Iversen SD (1995) Interactions between excitatory amino acids and dopamine systems in the forebrain: implications for schizophrenia and Parkinson's disease. Behav Pharmacol 6(5 And 6):478–491

    PubMed  CAS  Google Scholar 

  37. 37.

    Picetti R, Saiardi A, Abdel ST, Bozzi Y, Baik JH, Borrelli E (1997) Dopamine D2 receptors in signal transduction and behavior. Crit Rev Neurobiol 11(2–3):121–142

    PubMed  CAS  Google Scholar 

  38. 38.

    Watanabe M, Kodama T, Hikosaka K (1997) Increase of extracellular dopamine in primate prefrontal cortex during a working memory task. J Neurophysiol 78(5):2795–2798

    PubMed  CAS  Google Scholar 

  39. 39.

    Hietala J, Syvalahti E (1996) Dopamine in schizophrenia. Ann Med 28:557–561

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Baldessarini RJ (1997) Dopamine receptors and clinical medicine. In: Neve KA, Neve RL (eds) The Dopamine Receptors. Humana Press, NJ, pp 457–498

    Google Scholar 

  41. 41.

    Bardo MT (1998) Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. Crit Rev Neurobiol 12(1–2):37–67

    PubMed  CAS  Google Scholar 

  42. 42.

    Nestler EJ (1997) Molecular mechanisms of opiate and cocaine addiction. Curr Opin Neurobiol 7(5):713–719

    PubMed  CAS  Article  Google Scholar 

  43. 43.

    Self DW, Barnhart WJ, Lehman DA, Nestler EJ (1996) Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 271(5255):1586–1589

    PubMed  CAS  Article  Google Scholar 

  44. 44.

    Wise RA (1996) Neurobiology of addiction. Curr Opin Neurobiol 6(2):243–251

    PubMed  CAS  Article  Google Scholar 

  45. 45.

    Donnan GA, Woodhouse DG, Kaczmarczyk SJ, Holder JE, Paxinos G, Chilco PJ, Churchyard AJ, Kalnins RM, Fabinyi GC, Mendelsohn FA (1991) Evidence for plasticity of the dopaminergic system in parkinsonism. Mol Neurobiol 5(2–4):421–433

    PubMed  CAS  Article  Google Scholar 

  46. 46.

    Yu S, Ueda K, Chan P (2005) α-Synuclein and dopamine metabolism. Mol Neurobiol 31(1):243–254

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Seiden LS, Sabol KE, Ricaurte GA (1993) Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 33:639–677

    PubMed  CAS  Article  Google Scholar 

  48. 48.

    Robertson SD, Matthies HJ, Galli A (2009) A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters. Mol Neurobiol 39(2):73–80

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Safer DJ, Krager JM (1988) A survey of medication treatment for hyperactive/inattentive students. JAMA 260(15):2256–2258

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Sidhu A, Niznik HB (2000) Coupling of dopamine receptor subtypes to multiple and diverse G proteins. Int J Dev Neurosci 18(7):669–677

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Grandy DK, Zhou QY, Allen L, Litt R, Magenis RE, Civelli O, Litt M (1990) A human D1 dopamine receptor gene is located on chromosome 5 at q35.1 and identifies an EcoRI RFLP. Am J Hum Genet 47(5):828–834

    PubMed  CAS  Google Scholar 

  52. 52.

    Jin LQ, Wang HY, Friedman E (2001) Stimulated D(1) dopamine receptors couple to multiple Galpha proteins in different brain regions. J Neurochem 78(5):981–990

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Wang HY, Undie AS, Friedman E (1995) Evidence for the coupling of Gq protein to D1-like dopamine sites in rat striatum: possible role in dopamine-mediated inositol phosphate formation. Mol Pharmacol 48(6):988–994

    PubMed  CAS  Google Scholar 

  54. 54.

    Bergson C, Mrzljak L, Smiley JF, Pappy M, Levenson R, Goldman-Rakic PS (1995) Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain. J Neurosci 15(12):7821–7836

    PubMed  CAS  Google Scholar 

  55. 55.

    Paul ML, Graybiel AM, David JC, Robertson HA (1992) D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease. J Neurosci 12(10):3729–3742

    PubMed  CAS  Google Scholar 

  56. 56.

    Drago J, Gerfen CR, Lachowicz JE, Steiner H, Hollon TR, Love PE, Ooi GT, Grinberg A, Lee EJ, Huang SP, Et A (1994) Altered striatal function in a mutant mouse lacking D1A dopamine receptors. Proc Natl Acad Sci USA 91(26):12564–12568

    PubMed  CAS  Article  Google Scholar 

  57. 57.

    Xu M, Moratalla R, Gold LH, Hiroi N, Koob GF, Graybiel AM, Tonegawa S (1994) Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses. Cell 79(4):729–742

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Crawford CA, Drago J, Watson JB, Levine MS (1997) Effects of repeated amphetamine treatment on the locomotor activity of the dopamine D1A-deficient mouse. Neuroreport 8(11):2523–2527

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Moratalla R, Xu M, Tonegawa S, Graybiel AM (1996) Cellular responses to psychomotor stimulant and neuroleptic drugs are abnormal in mice lacking the D1 dopamine receptor. Proc Natl Acad Sci USA 93(25):14928–14933

    PubMed  CAS  Article  Google Scholar 

  60. 60.

    Drago J, Padungchaichot P, Accili D, Fuchs S (1998) Dopamine receptors and dopamine transporter in brain function and addictive behaviors: insights from targeted mouse mutants. Dev Neurosci 20(2–3):188–203

    PubMed  CAS  Article  Google Scholar 

  61. 61.

    Ariano MA, Drago J, Sibley DR, Levine MS (1998) Striatal excitatory amino acid receptor subunit expression in the D1A-dopamine receptor-deficient mouse. Dev Neurosci 20(2–3):237–241

    PubMed  CAS  Article  Google Scholar 

  62. 62.

    Levine MS, Altemus KL, Cepeda C, Cromwell HC, Crawford C, Ariano MA, Drago J, Sibley DR, Westphal H (1996) Modulatory actions of dopamine on NMDA receptor-mediated responses are reduced in D1A-deficient mutant mice. J Neurosci 16(18):5870–5882

    PubMed  CAS  Google Scholar 

  63. 63.

    Smith DR, Striplin CD, Geller AM, Mailman RB, Drago J, Lawler CP, Gallagher M (1998) Behavioural assessment of mice lacking D1A dopamine receptors. Neuroscience 86(1):135–146

    PubMed  CAS  Article  Google Scholar 

  64. 64.

    Arnsten AF, Steere JC, Hunt RD (1996) The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry 53(5):448–455

    PubMed  CAS  Article  Google Scholar 

  65. 65.

    Arnsten A (2001) Dopaminergic and noradrenergic influences on cognitive functions mediated by prefrontal cortex. In: Solanto MV, Arnsten A, Castellanos FX (eds) Stimulant drugs and ADHD. basic and clinical neuroscience. Oxford University Press, New York, NY, pp 185–208

    Google Scholar 

  66. 66.

    Goldman-Rakic PS, Muly ER, Williams GV (2000) D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev 31(2–3):295–301

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Denney CB, Rapport MD (2001) Cognitive pharmacology of stimulants in children with ADHD. Oxford University Press, Inc, New York, NY, pp 283–302

    Google Scholar 

  68. 68.

    Castellanos FX, Tannock R (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 3(8):617–628

    PubMed  CAS  Google Scholar 

  69. 69.

    Cao Y, Cui Q (2010) Association between the polymorphisms dopamine D1 receptor gene and attention deficit hyperactivity disorder. Progress in Modern Biomedicine 10(21):4039–4041

    Google Scholar 

  70. 70.

    Misener VL, Luca P, Azeke O, Crosbie J, Waldman I, Tannock R, Roberts W, Malone M, Schachar R, Ickowicz A, Kennedy JL, Barr CL (2004) Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder. Mol Psychiatry 9(5):500–509

    PubMed  CAS  Article  Google Scholar 

  71. 71.

    Cichon S, Nothen MM, Erdmann J, Propping P (1994) Detection of four polymorphic sites in the human dopamine D1 receptor gene (DRD1). Hum Mol Genet 3(1):209

    PubMed  CAS  Article  Google Scholar 

  72. 72.

    Sherrington R, Mankoo B, Attwood J, Kalsi G, Curtis D, Buetow K, Povey S, Gurling H (1993) Cloning of the human dopamine D5 receptor gene and identification of a highly polymorphic microsatellite for the DRD5 locus that shows tight linkage to the chromosome 4p reference marker RAF1P1. Genomics 18(2):423–425

    PubMed  CAS  Article  Google Scholar 

  73. 73.

    Sunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HH, Niznik HB (1991) Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature 350(6319):614–619

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Beischlag TV, Marchese A, Meador-Woodruff JH, Damask SP, O'Dowd BF, Tyndale RF, van Tol HH, Seeman P, Niznik HB (1995) The human dopamine D5 receptor gene: cloning and characterization of the 5′-flanking and promoter region. Biochemistry 34(17):5960–5970

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Ciliax BJ, Nash N, Heilman C, Sunahara R, Hartney A, Tiberi M, Rye DB, Caron MG, Niznik HB, Levey AI (2000) Dopamine D(5) receptor immunolocalization in rat and monkey brain. Synapse 37(2):125–145

    PubMed  CAS  Article  Google Scholar 

  76. 76.

    Liu F, Wan Q, Pristupa ZB, Yu XM, Wang YT, Niznik HB (2000) Direct protein–protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors. Nature 403(6767):274–280

    PubMed  CAS  Article  Google Scholar 

  77. 77.

    Karlsson RM, Hefner KR, Sibley DR, Holmes A (2008) Comparison of dopamine D1 and D5 receptor knockout mice for cocaine locomotor sensitization. Psychopharmacology (Berl) 200(1):117–127

    CAS  Article  Google Scholar 

  78. 78.

    Rivkees SA, Lachowicz JE (1997) Functional D1 and D5 dopamine receptors are expressed in the suprachiasmatic, supraoptic, and paraventricular nuclei of primates. Synapse 26(1):1–10

    PubMed  CAS  Article  Google Scholar 

  79. 79.

    Apostolakis EM, Garai J, Clark JH, O'Malley BW (1996) In vivo regulation of central nervous system progesterone receptors: cocaine induces steroid-dependent behavior through dopamine transporter modulation of D5 receptors in rats. Mol Endocrinol 10(12):1595–1604

    PubMed  CAS  Article  Google Scholar 

  80. 80.

    Niznik HBSK (2000) D1-like dopamine receptors: molecular biology and pharmacolgy. Springer Verlag, Di Chiara

    Google Scholar 

  81. 81.

    Sibley DR (1999) New insights into dopaminergic receptor function using antisense and genetically altered animals. Annu Rev Pharmacol Toxicol 39:313–341

    PubMed  CAS  Article  Google Scholar 

  82. 82.

    Kirley A, Hawi Z, Daly G, McCarron M, Mullins C, Millar N, Waldman I, Fitzgerald M, Gill M (2002) Dopaminergic system genes in ADHD: toward a biological hypothesis. Neuropsychopharmacology 27(4):607–619

    PubMed  CAS  Google Scholar 

  83. 83.

    Bakker SC, van der Meulen EM, Oteman N, Schelleman H, Pearson PL, Buitelaar JK, Sinke RJ (2005) DAT1, DRD4, and DRD5 polymorphisms are not associated with ADHD in Dutch families. Am J Med Genet B Neuropsychiatr Genet 132B(1):50–52

    PubMed  Article  Google Scholar 

  84. 84.

    Barr CL, Wigg KG, Feng Y, Zai G, Malone M, Roberts W, Schachar R, Tannock R, Kennedy JL et al (2000) Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor. Mol Psychiatry 5(5):548

    PubMed  CAS  Article  Google Scholar 

  85. 85.

    Hawi Z, Lowe N, Kirley A, Gruenhage F, Nothen M, Greenwood T, Kelsoe J, Fitzgerald M, Gill M (2003) Linkage disequilibrium mapping at DAT1, DRD5 and DBH narrows the search for ADHD susceptibility alleles at these loci. Mol Psychiatry 8(3):299–308

    PubMed  CAS  Article  Google Scholar 

  86. 86.

    Hawi Z, Segurado R, Conroy J, Sheehan K, Lowe N, Kirley A, Shields D, Fitzgerald M, Gallagher L, Gill M (2005) Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder. Am J Hum Genet 77(6):958–965

    PubMed  CAS  Article  Google Scholar 

  87. 87.

    Manor I, Corbex M, Eisenberg J, Gritsenkso I, Bachner-Melman R, Tyano S, Ebstein RP (2004) Association of the dopamine D5 receptor with attention deficit hyperactivity disorder (ADHD) and scores on a continuous performance test (TOVA). Am J Med Genet B Neuropsychiatr Genet 127B(1):73–77

    PubMed  Article  Google Scholar 

  88. 88.

    Mill J, Curran S, Richards S, Taylor E, Asherson P (2004) Polymorphisms in the dopamine D5 receptor (DRD5) gene and ADHD. Am J Med Genet B Neuropsychiatr Genet 125B(1):38–42

    PubMed  Article  Google Scholar 

  89. 89.

    Payton A, Holmes J, Barrett JH, Hever T, Fitzpatrick H, Trumper AL, Harrington R, McGuffin P, O'Donovan M, Owen M, Ollier W, Worthington J, Thapar A (2001) Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family-based study. Am J Med Genet 105(5):464–470

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    Langley K, Fowler TA, Grady DL, Moyzis RK, Holmans PA, van den Bree MB, Owen MJ, O'Donovan MC, Thapar A (2009) Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder. Eur Child Adolesc Psychiatry 18(1):26–32

    PubMed  Article  Google Scholar 

  91. 91.

    Kim BN, Kang D, Cho SC, Park TW, Lim MH, Chung YC, Kim JW, Hwang JW, Yoo HJ, Chung US, Son JW, Yang JC, Chung SK, Lee JY, Jung YW (2009) Shorter dinucleotide repeat length in the DRD5 gene is associated with attention deficit hyperactivity disorder. Psychiatr Genet 19(1):57

    PubMed  Article  Google Scholar 

  92. 92.

    Tahir E, Yazgan Y, Cirakoglu B, Ozbay F, Waldman I, Asherson PJ (2000) Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. Mol Psychiatry 5(4):396–404

    PubMed  CAS  Article  Google Scholar 

  93. 93.

    Maher BS, Marazita ML, Ferrell RE, Vanyukov MM (2002) Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis. Psychiatr Genet 12(4):207–215

    PubMed  Article  Google Scholar 

  94. 94.

    Kustanovich V, Ishii J, Crawford L, Yang M, McGough JJ, McCracken JT, Smalley SL, Nelson SF (2004) Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5. Mol Psychiatry 9(7):711–717

    PubMed  CAS  Google Scholar 

  95. 95.

    Vanyukov MM, Moss HB, Yu LM, Deka R (1995) A dinucleotide repeat polymorphism at the gene for monoamine oxidase A and measures of aggressiveness. Psychiatry Res 59(1–2):35–41

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Eubanks JH, Djabali M, Selleri L, Grandy DK, Civelli O, McElligott DL, Evans GA (1992) Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11q23. Genomics 14(4):1010–1018

    PubMed  CAS  Article  Google Scholar 

  97. 97.

    Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63(1):182–217

    PubMed  CAS  Article  Google Scholar 

  98. 98.

    Kamiya T, Saitoh O, Yoshioka K, Nakata H (2003) Oligomerization of adenosine A2A and dopamine D2 receptors in living cells. Biochem Biophys Res Commun 306(2):544–549

    PubMed  CAS  Article  Google Scholar 

  99. 99.

    Binda AV, Kabbani N, Lin R, Levenson R (2002) D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1 N. Mol Pharmacol 62(3):507–513

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Smith FD, Oxford GS, Milgram SL (1999) Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein. J Biol Chem 274(28):19894–19900

    PubMed  CAS  Article  Google Scholar 

  101. 101.

    Kabbani N, Negyessy L, Lin R, Goldman-Rakic P, Levenson R (2002) Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor. J Neurosci 22(19):8476–8486

    PubMed  CAS  Google Scholar 

  102. 102.

    Boyson SJ, McGonigle P, Molinoff PB (1986) Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine receptors in rat brain. J Neurosci 6(11):3177–3188

    PubMed  CAS  Google Scholar 

  103. 103.

    Meador-Woodruff JH, Mansour A, Bunzow JR, Van Tol HH, Watson SJ, Civelli O (1989) Distribution of D2 dopamine receptor mRNA in rat brain. Proc Natl Acad Sci USA 86(19):7625–7628

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Weiner DM, Brann MR (1989) The distribution of a dopamine D2 receptor mRNA in rat brain. FEBS Lett 253(1–2):207–213

    PubMed  CAS  Article  Google Scholar 

  105. 105.

    Negyessy L, Goldman-Rakic PS (2005) Subcellular localization of the dopamine D2 receptor and coexistence with the calcium-binding protein neuronal calcium sensor-1 in the primate prefrontal cortex. J Comp Neurol 488(4):464–475

    PubMed  CAS  Article  Google Scholar 

  106. 106.

    Doi M, Yujnovsky I, Hirayama J, Malerba M, Tirotta E, Sassone-Corsi P, Borrelli E (2006) Impaired light masking in dopamine D2 receptor-null mice. Nat Neurosci 9(6):732–734

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Usiello A, Baik JH, Rouge-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E (2000) Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408(6809):199–203

    PubMed  CAS  Article  Google Scholar 

  108. 108.

    Heber D, Carpenter CL (2011) Addictive genes and the relationship to obesity and inflammation. Mol Neurobiol 44(2):160–165

    PubMed  CAS  Article  Google Scholar 

  109. 109.

    Tinsley RB, Bye CR, Parish CL, Tziotis-Vais A, George S, Culvenor JG, Li QX, Masters CL, Finkelstein DI, Horne MK (2009) Dopamine D2 receptor knockout mice develop features of Parkinson disease. Ann Neurol 66(4):472–484

    PubMed  CAS  Article  Google Scholar 

  110. 110.

    Glickstein SB, Schmauss C (2001) Dopamine receptor functions: lessons from knockout mice [corrected]. Pharmacol Ther 91(1):63–83

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Maldonado R, Saiardi A, Valverde O, Samad TA, Roques BP, Borrelli E (1997) Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 388(6642):586–589

    PubMed  CAS  Article  Google Scholar 

  112. 112.

    Comings DE (1997) IBC's international conference on dopaminergic disorders novel approaches for drug discovery and development. The Ritz-Carlton, Boston

    Google Scholar 

  113. 113.

    Blum K, Sheridan PJ, Wood RC, Braverman ER, Chen TJ, Comings DE (1995) Dopamine D2 receptor gene variants: association and linkage studies in impulsive–addictive–compulsive behaviour. Pharmacogenetics 5(3):121–141

    PubMed  CAS  Article  Google Scholar 

  114. 114.

    Ponce G, Hoenicka J, Rodriguez-Jimenez R, Gozalo A, Jimenez M, Monasor R, Aragues M, Rubio G, Jimenez-Arriero MA, Ramos JA, Palomo T (2004) IDRD2 TaqIA polymorphism is associated with urinary homovanillic acid levels in a sample of Spanish male alcoholic patients. Neurotox Res 6(5):373–377

    PubMed  CAS  Article  Google Scholar 

  115. 115.

    Laakso A, Pohjalainen T, Bergman J, Kajander J, Haaparanta M, Solin O, Syvalahti E, Hietala J (2005) The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects. Pharmacogenet Genomics 15(6):387–391

    PubMed  CAS  Article  Google Scholar 

  116. 116.

    Thompson J, Thomas N, Singleton A, Piggott M, Lloyd S, Perry EK, Morris CM, Perry RH, Ferrier IN, Court JA (1997) D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 7(6):479–484

    PubMed  CAS  Article  Google Scholar 

  117. 117.

    Park PS, Kim DK, Jung CH (2008) Dopamine transporter gene and dopamine D2, D3, D4 receptor gene polymorphisms in attention deficit hyperactivity disorder. J Kor Acad Child Adolesc Psychiatry 19(1):19–27

    Google Scholar 

  118. 118.

    Paclt I, Drtilkova I, Kopeckova M, Theiner P, Sery O, Cermakova N (2010) The association between TaqI A polymorphism of ANKK1 (DRD2) gene and ADHD in the Czech boys aged between 6 and 13 years. Neuro Endocrinol Lett 31(1):131–136

    PubMed  CAS  Google Scholar 

  119. 119.

    Kopeckova M, Paclt I, Petrasek J, Pacltova D, Malikova M, Zagatova V (2008) Some ADHD polymorphisms (in genes DAT1, DRD2, DRD3, DBH, 5-HTT) in case–control study of 100 subjects 6–10 age. Neuro Endocrinol Lett 29(2):246–251

    PubMed  CAS  Google Scholar 

  120. 120.

    Qian Q, Wang Y, Li J, Yang L, Wang B, Zhou R, Glatt SJ, Faraone SV (2007) Evaluation of potential gene–gene interactions for attention deficit hyperactivity disorder in the Han Chinese population. Am J Med Genet B Neuropsychiatr Genet 144B(2):200–206

    PubMed  CAS  Article  Google Scholar 

  121. 121.

    Sery O, Drt I, Lkov AI, Theiner P, Pitelov AR, Staif R, Znojil V, Lochman J, Didden W (2006) Polymorphism of DRD2 gene and ADHD. Neuro Endocrinol Lett 27(1–2):236–240

    PubMed  CAS  Google Scholar 

  122. 122.

    Huang YS, Lin SK, Wu YY, Chao CC, Chen CK (2003) A family-based association study of attention-deficit hyperactivity disorder and dopamine D2 receptor TaqI A alleles. Chang Gung Med J 26(12):897–903

    PubMed  Google Scholar 

  123. 123.

    Rowe DC, Van den Oord EJ, Stever C, Giedinghagen LN, Gard JM, Cleveland HH, Gilson M, Terris ST, Mohr JH, Sherman S, Abramowitz A, Waldman ID (1999) The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder. Mol Psychiatry 4(6):580–586

    PubMed  CAS  Article  Google Scholar 

  124. 124.

    Le Coniat M, Sokoloff P, Hillion J, Martres MP, Giros B, Pilon C, Schwartz JC, Berger R (1991) Chromosomal localization of the human D3 dopamine receptor gene. Hum Genet 87(5):618–620

    PubMed  Article  Google Scholar 

  125. 125.

    Ricci A, Vega JA, Mammola CL, Amenta F (1995) Localisation of dopamine D3 receptor in the rat cerebellar cortex: a light microscope autoradiographic study. Neurosci Lett 190(3):163–166

    PubMed  CAS  Article  Google Scholar 

  126. 126.

    Meador-Woodruff JH, Damask SP, Wang J, Haroutunian V, Davis KL, Watson SJ (1996) Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology 15(1):17–29

    PubMed  CAS  Article  Google Scholar 

  127. 127.

    Shafer RA, Levant B (1998) The D3 dopamine receptor in cellular and organismal function. Psychopharmacology (Berl) 135(1):1–16

    CAS  Article  Google Scholar 

  128. 128.

    Kuzhikandathil EV, Oxford GS (1999) Activation of human D3 dopamine receptor inhibits P/Q-type calcium channels and secretory activity in AtT-20 cells. J Neurosci 19(5):1698–1707

    PubMed  CAS  Google Scholar 

  129. 129.

    Cussac D, Newman-Tancredi A, Pasteau V, Millan MJ (1999) Human dopamine D(3) receptors mediate mitogen-activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism. Mol Pharmacol 56(5):1025–1030

    PubMed  CAS  Google Scholar 

  130. 130.

    Fields RD, Eshete F, Stevens B, Itoh K (1997) Action potential-dependent regulation of gene expression: temporal specificity in ca2+, cAMP-responsive element binding proteins, and mitogen-activated protein kinase signaling. J Neurosci 17(19):7252–7266

    PubMed  CAS  Google Scholar 

  131. 131.

    Cho DI, Oak MH, Yang HJ, Choi HK, Janssen GM, Kim KM (2003) Direct and biochemical interaction between dopamine D3 receptor and elongation factor-1Bbetagamma. Life Sci 73(23):2991–3004

    PubMed  CAS  Article  Google Scholar 

  132. 132.

    Black KJ, Hershey T, Koller JM, Videen TO, Mintun MA, Price JL, Perlmutter JS (2002) A possible substrate for dopamine-related changes in mood and behavior: prefrontal and limbic effects of a D3-preferring dopamine agonist. Proc Natl Acad Sci USA 99(26):17113–17118

    PubMed  CAS  Article  Google Scholar 

  133. 133.

    Beninger RJ, Banasikowski TJ (2008) Dopaminergic mechanism of reward-related incentive learning: focus on the dopamine D(3) receptor. Neurotox Res 14(1):57–70

    PubMed  CAS  Article  Google Scholar 

  134. 134.

    Lane HY, Liu YC, Huang CL, Hsieh CL, Chang YL, Chang L, Chang YC, Chang WH (2008) Prefrontal executive function and D1, D3, 5-HT2A and 5-HT6 receptor gene variations in healthy adults. J Psychiatry Neurosci 33(1):47–53

    PubMed  Google Scholar 

  135. 135.

    Limosin F, Romo L, Batel P, Ades J, Boni C, Gorwood P (2005) Association between dopamine receptor D3 gene BalI polymorphism and cognitive impulsiveness in alcohol-dependent men. Eur Psychiatry 20(3):304–306

    PubMed  CAS  Article  Google Scholar 

  136. 136.

    Muglia P, Jain U, Kennedy JL (2002) A transmission disequilibrium test of the Ser9/Gly dopamine D3 receptor gene polymorphism in adult attention-deficit hyperactivity disorder. Behav Brain Res 130(1–2):91–95

    PubMed  CAS  Article  Google Scholar 

  137. 137.

    Barr CL, Wigg KG, Wu J, Zai C, Bloom S, Tannock R, Roberts W, Malone M, Schachar R, Kennedy JL (2000) Linkage study of two polymorphisms at the dopamine D3 receptor gene and attention-deficit hyperactivity disorder. Am J Med Genet 96(1):114–117

    PubMed  CAS  Article  Google Scholar 

  138. 138.

    Guan L, Wang B, Chen Y, Yang L, Li J, Qian Q, Wang Z, Faraone SV, Wang Y (2009) A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population. Mol Psychiatry 14(5):546–554

    PubMed  CAS  Article  Google Scholar 

  139. 139.

    Davis C, Patte K, Levitan RD, Carter J, Kaplan AS, Zai C, Reid C, Curtis C, Kennedy JL (2009) A psycho-genetic study of associations between the symptoms of binge eating disorder and those of attention deficit (hyperactivity) disorder. J Psychiatr Res 43(7):687–696

    PubMed  Article  Google Scholar 

  140. 140.

    Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N, Anney R, Franke B, Gill M, Ebstein R, Buitelaar J, Sham P, Campbell D, Knight J, Andreou P, Altink M, Arnold R, Boer F, Buschgens C, Butler L, Christiansen H, Feldman L, Fleischman K, Fliers E, Howe-Forbes R, Goldfarb A, Heise A, Gabriels I, Korn-Lubetzki I, Johansson L, Marco R, Medad S, Minderaa R, Mulas F, Muller U, Mulligan A, Rabin K, Rommelse N, Sethna V, Sorohan J, Uebel H, Psychogiou L, Weeks A, Barrett R, Craig I, Banaschewski T, Sonuga-Barke E, Eisenberg J, Kuntsi J, Manor I, McGuffin P, Miranda A, Oades RD, Plomin R, Roeyers H, Rothenberger A, Sergeant J, Steinhausen HC, Taylor E, Thompson M, Faraone SV, Asherson P (2006) The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry 11(10):934–953

    PubMed  CAS  Article  Google Scholar 

  141. 141.

    Petronis A, Van Tol HH, Lichter JB, Livak KJ, Kennedy JL (1993) The D4 dopamine receptor gene maps on 11p proximal to HRAS. Genomics 18(1):161–163

    PubMed  CAS  Article  Google Scholar 

  142. 142.

    Gelernter J, Kennedy JL, van Tol HH, Civelli O, Kidd KK (1992) The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS. Genomics 13(1):208–210

    PubMed  CAS  Article  Google Scholar 

  143. 143.

    Defagot MC, Malchiodi EL, Villar MJ, Antonelli MC (1997) Distribution of D4 dopamine receptor in rat brain with sequence-specific antibodies. Brain Res Mol Brain Res 45(1):1–12

    PubMed  CAS  Article  Google Scholar 

  144. 144.

    Wedzony K, Chocyk A, Mackowiak M, Fijal K, Czyrak A (2000) Cortical localization of dopamine D4 receptors in the rat brain—immunocytochemical study. J Physiol Pharmacol 51(2):205–221

    PubMed  CAS  Google Scholar 

  145. 145.

    Rivera A, Cuellar B, Giron FJ, Grandy DK, de la Calle A, Moratalla R (2002) Dopamine D4 receptors are heterogeneously distributed in the striosomes/matrix compartments of the striatum. J Neurochem 80(2):219–229

    PubMed  CAS  Article  Google Scholar 

  146. 146.

    Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M (2008) How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 29(1):190–201

    PubMed  CAS  Article  Google Scholar 

  147. 147.

    Kuznetsova AY, Deth RC (2008) A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated phospholipid methylation. J Comput Neurosci 24(3):314–329

    PubMed  Article  Google Scholar 

  148. 148.

    Dulawa SC, Grandy DK, Low MJ, Paulus MP, Geyer MA (1999) Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J Neurosci 19(21):9550–9556

    PubMed  CAS  Google Scholar 

  149. 149.

    Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G, Fang Y, Larson JL, McDougall JA, Chester JA, Saez C, Pugsley TA, Gershanik O, Low MJ, Grandy DK (1997) Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90(6):991–1001

    PubMed  CAS  Article  Google Scholar 

  150. 150.

    Das M, Das BA, Bhaduri N, Sarkar K, Ghosh P, Sinha S, Ray A, Chatterjee A, Mukhopadhyay K (2011) Role of gene–gene/gene–environment interaction in the etiology of eastern Indian ADHD probands. Prog Neuropsychopharmacol Biol Psychiatry 35(2):577–587

    PubMed  CAS  Article  Google Scholar 

  151. 151.

    Gabriela ML, John DG, Magdalena BV, Ariadna GS, Francisco DL, Liz SM, Lino PC, Josefina RG, Ernesto RZ, Carlos CF (2009) Genetic interaction analysis for DRD4 and DAT1 genes in a group of Mexican ADHD patients. Neurosci Lett 451(3):257–260

    PubMed  Article  CAS  Google Scholar 

  152. 152.

    Niederhofer H, Menzel F, Gobel K, Hackenberg B, Richter R, Walter MH, Gross C, Huber M, Pycha R, Menzel HJ (2008) A preliminary report of the dopamine receptor D(4) and the dopamine transporter 1 gene polymorphism and its association with attention deficit hyperactivity disorder. Neuropsychiatr Dis Treat 4(4):701–705

    PubMed  CAS  Article  Google Scholar 

  153. 153.

    Johnson KA, Kelly SP, Robertson IH, Barry E, Mulligan A, Daly M, Lambert D, McDonnell C, Connor TJ, Hawi Z, Gill M, Bellgrove MA (2008) Absence of the 7-repeat variant of the DRD4 VNTR is associated with drifting sustained attention in children with ADHD but not in controls. Am J Med Genet B Neuropsychiatr Genet 147B(6):927–937

    PubMed  Article  Google Scholar 

  154. 154.

    Gornick MC, Addington A, Shaw P, Bobb AJ, Sharp W, Greenstein D, Arepalli S, Castellanos FX, Rapoport JL (2007) Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD): an update. Am J Med Genet B Neuropsychiatr Genet 144(3):379–382

    Google Scholar 

  155. 155.

    Cheuk DK, Li SY, Wong V (2006) Exon 3 polymorphisms of dopamine D4 receptor (DRD4) gene and attention deficit hyperactivity disorder in Chinese children. Am J Med Genet B Neuropsychiatr Genet 141B(8):907–911

    PubMed  Article  Google Scholar 

  156. 156.

    Leung PW, Lee CC, Hung SF, Ho TP, Tang CP, Kwong SL, Leung SY, Yuen ST, Lieh-Mak F, Oosterlaan J, Grady D, Harxhi A, Ding YC, Chi HC, Flodman P, Schuck S, Spence MA, Moyzis R, Swanson J (2005) Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention-deficit/hyperactivity disorder (ADHD): increased prevalence of the 2-repeat allele. Am J Med Genet B Neuropsychiatr Genet 133B(1):54–56

    PubMed  Article  Google Scholar 

  157. 157.

    Kim YS, Leventhal BL, Kim SJ, Kim BN, Cheon KA, Yoo HJ, Kim SJ, Badner J, Cook EH (2005) Family-based association study of DAT1 and DRD4 polymorphism in Korean children with ADHD. Neurosci Lett 390(3):176–181

    PubMed  CAS  Article  Google Scholar 

  158. 158.

    Brookes KJ, Xu X, Chen CK, Huang YS, Wu YY, Asherson P (2005) No evidence for the association of DRD4 with ADHD in a Taiwanese population within-family study. BMC Med Genet 6:31

    PubMed  Article  CAS  Google Scholar 

  159. 159.

    Qian Q, Wang Y, Zhou R, Yang L, Faraone SV (2004) Family-based and case–control association studies of DRD4 and DAT1 polymorphisms in Chinese attention deficit hyperactivity disorder patients suggest long repeats contribute to genetic risk for the disorder. Am J Med Genet B Neuropsychiatr Genet 128B(1):84–89

    PubMed  Article  Google Scholar 

  160. 160.

    Arcos-Burgos M, Castellanos FX, Konecki D, Lopera F, Pineda D, Palacio JD, Rapoport JL, Berg K, Bailey-Wilson J, Muenke M (2004) Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate. Mol Psychiatry 9(3):252–259

    PubMed  CAS  Article  Google Scholar 

  161. 161.

    Smith KM, Daly M, Fischer M, Yiannoutsos CT, Bauer L, Barkley R, Navia BA (2003) Association of the dopamine beta hydroxylase gene with attention deficit hyperactivity disorder: genetic analysis of the Milwaukee longitudinal study. Am J Med Genet B Neuropsychiatr Genet 119B(1):77–85

    PubMed  Article  Google Scholar 

  162. 162.

    Holmes J, Payton A, Barrett J, Harrington R, McGuffin P, Owen M, Ollier W, Worthington J, Gill M, Kirley A, Hawi Z, Fitzgerald M, Asherson P, Curran S, Mill J, Gould A, Taylor E, Kent L, Craddock N, Thapar A (2002) Association of DRD4 in children with ADHD and comorbid conduct problems. Am J Med Genet 114(2):150–153

    PubMed  Article  Google Scholar 

  163. 163.

    Mill J, Curran S, Kent L, Richards S, Gould A, Virdee V, Huckett L, Sharp J, Batten C, Fernando S, Simanoff E, Thompson M, Zhao J, Sham P, Taylor E, Asherson P (2001) Attention deficit hyperactivity disorder (ADHD) and the dopamine D4 receptor gene: evidence of association but no linkage in a UK sample. Mol Psychiatry 6(4):440–444

    PubMed  CAS  Article  Google Scholar 

  164. 164.

    Todd RD, Neuman RJ, Lobos EA, Jong YJ, Reich W, Heath AC (2001) Lack of association of dopamine D4 receptor gene polymorphisms with ADHD subtypes in a population sample of twins. Am J Med Genet 105(5):432–438

    PubMed  CAS  Article  Google Scholar 

  165. 165.

    Curran S, Mill J, Sham P, Rijsdijk F, Marusic K, Taylor E, Asherson P (2001) QTL association analysis of the DRD4 exon 3 VNTR polymorphism in a population sample of children screened with a parent rating scale for ADHD symptoms. Am J Med Genet 105(4):387–393

    PubMed  CAS  Article  Google Scholar 

  166. 166.

    Roman T, Schmitz M, Polanczyk G, Eizirik M, Rohde LA, Hutz MH (2001) Attention-deficit hyperactivity disorder: a study of association with both the dopamine transporter gene and the dopamine D4 receptor gene. Am J Med Genet 105(5):471–478

    Google Scholar 

  167. 167.

    Kotler M, Manor I, Sever Y, Eisenberg J, Cohen H, Ebstein RP, Tyano S (2000) Failure to replicate an excess of the long dopamine D4 exon III repeat polymorphism in ADHD in a family-based study. Am J Med Genet 96(3):278–281

    PubMed  CAS  Article  Google Scholar 

  168. 168.

    Hawi Z, McCarron M, Kirley A, Daly G, Fitzgerald M, Gill M (2000) No association of the dopamine DRD4 receptor (DRD4) gene polymorphism with attention deficit hyperactivity disorder (ADHD) in the Irish population. Am J Med Genet 96(3):268–272

    PubMed  CAS  Article  Google Scholar 

  169. 169.

    Holmes J, Payton A, Barrett JH, Hever T, Fitzpatrick H, Trumper AL, Harrington R, McGuffin P, Owen M, Ollier W et al (2000) A family-based and case–control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder. Mol Psychiatry 5(5):523

    PubMed  CAS  Article  Google Scholar 

  170. 170.

    Comings DE, Gonzalez N, Wu S, Gade R, Muhleman D, Saucier G, Johnson P, Verde R, Rosenthal RJ, Lesieur HR, Rugle LJ, Miller WB, MacMurray JP (1999) Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. Am J Med Genet 88(4):358–368

    PubMed  CAS  Article  Google Scholar 

  171. 171.

    Swanson JM, Sunohara GA, Kennedy JL, Regino R, Fineberg E, Wigal T, Lerner M, Williams L, LaHoste GJ, Wigal S (1998) Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach. Mol Psychiatry 3(1):38–41

    PubMed  CAS  Article  Google Scholar 

  172. 172.

    Rowe DC, Stever C, Giedinghagen LN, Gard J, Cleveland HH, Terris ST, Mohr JH, Sherman S, Abramowitz A, Waldman ID (1998) Dopamine DRD4 receptor polymorphism and attention deficit hyperactivity disorder. Mol Psychiatry 3(5):419–426

    PubMed  CAS  Article  Google Scholar 

  173. 173.

    Sunohara GA, Roberts W, Malone M, Schachar RJ, Tannock R, Basile VS, Wigal T, Wigal SB, Schuck S, Moriarty J, Swanson JM, Kennedy JL, Barr CL (2000) Linkage of the dopamine D4 receptor gene and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 39(12):1537–1542

    PubMed  CAS  Article  Google Scholar 

  174. 174.

    Reiersen AM, Todorov AA (2011) Association between DRD4 genotype and autistic symptoms in DSM-IV ADHD. J Can Acad Child Adolesc Psychiatry 20(1):15

    PubMed  Google Scholar 

  175. 175.

    Becker K, Blomeyer D, El-Faddagh M, Esser G, Schmidt MH, Banaschewski T, Laucht M (2010) From regulatory problems in infancy to attention-deficit/hyperactivity disorder in childhood: a moderating role for the dopamine D4 receptor gene? J Pediatr 156(5):798–803

    PubMed  CAS  Article  Google Scholar 

  176. 176.

    Kereszturi E, Tarnok Z, Bognar E, Lakatos K, Farkas L, Gadoros J, Sasvari-Szekely M, Nemoda Z (2008) Catechol-O-methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children. Am J Med Genet B Neuropsychiatr Genet 147B(8):1431–1435

    PubMed  CAS  Article  Google Scholar 

  177. 177.

    Carrasco X, Rothhammer P, Moraga M, Henriquez H, Chakraborty R, Aboitiz F, Rothhammer F (2006) Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for attention-deficit/hyperactivity disorder in Chilean families. Am J Med Genet B Neuropsychiatr Genet 141B(1):51–54

    PubMed  Article  Google Scholar 

  178. 178.

    El-Faddagh M, Laucht M, Maras A, Vohringer L, Schmidt MH (2004) Association of dopamine D4 receptor (DRD4) gene with attention-deficit/hyperactivity disorder (ADHD) in a high-risk community sample: a longitudinal study from birth to 11 years of age. J Neural Transm 111(7):883–889

    PubMed  CAS  Article  Google Scholar 

  179. 179.

    Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z (2004) Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: evidence of linkage and association with the SNP -616. Am J Med Genet B Neuropsychiatr Genet 131B(1):33–37

    PubMed  Article  Google Scholar 

  180. 180.

    Frank Y, Pergolizzi RG, Perilla MJ (2004) Dopamine D4 receptor gene and attention deficit hyperactivity disorder. Pediatr Neurol 31(5):345–348

    PubMed  Article  Google Scholar 

  181. 181.

    Lunetta KL, Faraone SV, Biederman J, Laird NM (2000) Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions. Am J Hum Genet 66(2):605–614

    PubMed  CAS  Article  Google Scholar 

  182. 182.

    McCracken JT, Smalley SL, McGough JJ, Crawford L, Del Homme M, Cantor RM, Liu A, Nelson SF et al (2000) Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD). Mol Psychiatry 5(5):531–536

    PubMed  CAS  Article  Google Scholar 

  183. 183.

    Smalley SL, Bailey JN, Palmer CG, Cantwell DP, McGough JJ, Del'Homme MA, Asarnow JR, Woodward JA, Ramsey C, Nelson SF et al (1998) Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder. Mol Psychiatry 3(5):427

    PubMed  CAS  Article  Google Scholar 

  184. 184.

    LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL (1996) Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry 1(2):121–124

    PubMed  CAS  Google Scholar 

  185. 185.

    Payton A, Holmes J, Barrett JH, Sham P, Harrington R, McGuffin P, Owen M, Ollier W, Worthington J, Thapar A (2001) Susceptibility genes for a trait measure of attention deficit hyperactivity disorder: a pilot study in a non-clinical sample of twins. Psychiatry Res 105(3):273–278

    PubMed  CAS  Article  Google Scholar 

  186. 186.

    Asghari V, Schoots O, van Kats S, Ohara K, Jovanovic V, Guan HC, Bunzow JR, Petronis A, Van Tol HH (1994) Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes. Mol Pharmacol 46(2):364–373

    PubMed  CAS  Google Scholar 

  187. 187.

    Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH (1995) Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem 65(3):1157–1165

    PubMed  CAS  Article  Google Scholar 

  188. 188.

    Kotler M, Cohen H, Segman R, Gritsenko I, Nemanov L, Lerer B, Kramer I, Zer-Zion M, Kletz I, Ebstein RP (1997) Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects. Mol Psychiatry 2(3):251–254

    PubMed  CAS  Article  Google Scholar 

  189. 189.

    Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH (1996) Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nat Genet 12(1):81–84

    PubMed  CAS  Article  Google Scholar 

  190. 190.

    Bhaduri N, Das M, Sinha S, Chattopadhyay A, Gangopadhyay PK, Chaudhuri K, Singh M, Mukhopadhyay K (2006) Association of dopamine D4 receptor (DRD4) polymorphisms with attention deficit hyperactivity disorder in Indian population. Am J Med Genet B Neuropsychiatr Genet 141B(1):61–66

    PubMed  CAS  Article  Google Scholar 

  191. 191.

    Shaw P, Gornick M, Lerch J, Addington A, Seal J, Greenstein D, Sharp W, Evans A, Giedd JN, Castellanos FX, Rapoport JL (2007) Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 64(8):921–931

    PubMed  Article  Google Scholar 

  192. 192.

    Swanson J, Oosterlaan J, Murias M, Schuck S, Flodman P, Spence MA, Wasdell M, Ding Y, Chi HC, Smith M et al (2000) Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention. Proc Natl Acad Sci 97(9):4754

    PubMed  CAS  Article  Google Scholar 

  193. 193.

    Yang JW, Jang WS, Hong SD, Ji YI, Kim DH, Park J, Kim SW, Joung YS (2008) A case–control association study of the polymorphism at the promoter region of the DRD4 gene in Korean boys with attention deficit-hyperactivity disorder: evidence of association with the -521 C/T SNP. Prog Neuropsychopharmacol Biol Psychiatry 32(1):243–248

    PubMed  CAS  Article  Google Scholar 

  194. 194.

    Kereszturi E, Kiraly O, Csapo Z, Tarnok Z, Gadoros J, Sasvari-Szekely M, Nemoda Z (2007) Association between the 120-bp duplication of the dopamine D4 receptor gene and attention deficit hyperactivity disorder: genetic and molecular analyses. Am J Med Genet B Neuropsychiatr Genet 144B(2):231–236

    PubMed  CAS  Article  Google Scholar 

  195. 195.

    Seaman MI, Fisher JB, Chang F, Kidd KK (1999) Tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4). Am J Med Genet 88(6):705–709

    PubMed  CAS  Article  Google Scholar 

  196. 196.

    Ronai Z, Guttman A, Keszler G, Sasvari-Szekely M (2004) Capillary electrophoresis study on DNA–protein complex formation in the polymorphic 5′ upstream region of the dopamine D4 receptor (DRD4) gene. Curr Med Chem 11(8):1023–1029

    PubMed  CAS  Article  Google Scholar 

  197. 197.

    D'Souza UM, Russ C, Tahir E, Mill J, McGuffin P, Asherson PJ, Craig IW (2004) Functional effects of a tandem duplication polymorphism in the 5′ flanking region of the DRD4 gene. Biol Psychiatry 56(9):691–697

    PubMed  Article  CAS  Google Scholar 

  198. 198.

    Rogers G, Joyce P, Mulder R, Sellman D, Miller A, Allington M, Olds R, Wells E, Kennedy M (2004) Association of a duplicated repeat polymorphism in the 5′-untranslated region of the DRD4 gene with novelty seeking. Am J Med Genet B Neuropsychiatr Genet 126B(1):95–98

    PubMed  Article  Google Scholar 

  199. 199.

    Barr CL, Feng Y, Wigg KG, Schachar R, Tannock R, Roberts W, Malone M, Kennedy JL (2001) 5′-untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder. Am J Med Genet 105(1):84–90

    PubMed  CAS  Article  Google Scholar 

  200. 200.

    Martel MM, Nikolas M, Jernigan K, Friderici K, Nigg JT (2010) Personality mediation of genetic effects on attention-deficit/hyperactivity disorder. J Abnorm Child Psychol 38(5):633–643

    PubMed  Article  Google Scholar 

  201. 201.

    Szilagyi A, Boor K, Szekely A, Gaszner P, Kalasz H, Sasvari-Szekely M, Barta C (2005) Combined effect of promoter polymorphisms in the dopamine D4 receptor and the serotonin transporter genes in heroin dependence. Neuropsychopharmacol Hung 7(1):28–33

    PubMed  Google Scholar 

  202. 202.

    Okuyama Y, Ishiguro H, Toru M, Arinami T (1999) A genetic polymorphism in the promoter region of DRD4 associated with expression and schizophrenia. Biochem Biophys Res Commun 258(2):292–295

    PubMed  CAS  Article  Google Scholar 

  203. 203.

    Lakatos K, Nemoda Z, Toth I, Ronai Z, Ney K, Sasvari-Szekely M, Gervai J (2002) Further evidence for the role of the dopamine D4 receptor (DRD4) gene in attachment disorganization: interaction of the exon III 48-bp repeat and the −521 C/T promoter polymorphisms. Mol Psychiatry 7(1):27–31

    PubMed  CAS  Article  Google Scholar 

  204. 204.

    Ronai Z, Szekely A, Nemoda Z, Lakatos K, Gervai J, Staub M, Sasvari-Szekely M (2001) Association between novelty seeking and the −521 C/T polymorphism in the promoter region of the DRD4 gene. Mol Psychiatry 6(1):35–38

    PubMed  CAS  Article  Google Scholar 

  205. 205.

    Guan LL, Wang YF, Li J, Wang B, Yang L, Qian QJ (2007) Association analysis of dopamine D4 receptor gene polymorphism and attention deficit hyperactivity disorder with/without disruptive behavior disorder]. Beijing da xue xue bao. Yi xue ban=. J Peking Univ Health Sci 39(3):233

    CAS  Google Scholar 

  206. 206.

    Williams T, Tjian R (1991) Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. Genes Dev 5(4):670–682

    PubMed  CAS  Article  Google Scholar 

  207. 207.

    Imagawa M, Chiu R, Karin M (1987) Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP. Cell 51(2):251–260

    PubMed  CAS  Article  Google Scholar 

  208. 208.

    Wu F, Lee AS (1998) Identification of AP-2 as an interactive target of Rb and a regulator of the G1/S control element of the hamster histone H3.2 promoter. Nucleic Acids Res 26(21):4837–4845

    PubMed  CAS  Article  Google Scholar 

  209. 209.

    Ronai Z, Szantai E, Szmola R, Nemoda Z, Szekely A, Gervai J, Guttman A, Sasvari-Szekely M (2004) A novel A/G SNP in the −615th position of the dopamine D4 receptor promoter region as a source of misgenotyping of the −616 C/G SNP. Am J Med Genet B Neuropsychiatr Genet 126B(1):74–78

    PubMed  CAS  Article  Google Scholar 

  210. 210.

    Catalano M, Nobile M, Novelli E, Nothen MM, Smeraldi E (1993) Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients. Biol Psychiatry 34(7):459–464

    PubMed  CAS  Article  Google Scholar 

  211. 211.

    Barr CL, Wigg KG, Bloom S, Schachar R, Tannock R, Roberts W, Malone M, Kennedy JL (2000) Further evidence from haplotype analysis for linkage of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder. Am J Med Genet 96(3):262–267

    PubMed  CAS  Article  Google Scholar 

  212. 212.

    Hong CJ, Chiu HJ, Chang YS, Sim CB (1998) Twelve-nucleotide repeat polymorphism of D4 dopamine receptor gene in Chinese familial schizophrenic patients. Biol Psychiatry 43(6):432–435

    PubMed  CAS  Article  Google Scholar 

  213. 213.

    Uh M, White BH, Sidhu A (1998) Alteration of association of agonist-activated renal D1(A) dopamine receptors with G proteins in proximal tubules of the spontaneously hypertensive rat. J Hypertens 16(9):1307–1313

    PubMed  CAS  Article  Google Scholar 

  214. 214.

    Kimura K, White BH, Sidhu A (1995) Coupling of human D-1 dopamine receptors to different guanine nucleotide binding proteins. Evidence that D-1 dopamine receptors can couple to both Gs and G(o). J Biol Chem 270(24):14672–14678

    PubMed  CAS  Article  Google Scholar 

  215. 215.

    Sidhu A (1998) Coupling of D1 and D5 dopamine receptors to multiple G proteins: implications for understanding the diversity in receptor-G protein coupling. Mol Neurobiol 16(2):125–134

    PubMed  CAS  Article  Google Scholar 

  216. 216.

    Sidhu A, Kimura K, Uh M, White BH, Patel S (1998) Multiple coupling of human D5 dopamine receptors to guanine nucleotide binding proteins Gs and Gz. J Neurochem 70(6):2459–2467

    PubMed  CAS  Article  Google Scholar 

  217. 217.

    Obadiah J, Avidor-Reiss T, Fishburn CS, Carmon S, Bayewitch M, Vogel Z, Fuchs S, Levavi-Sivan B (1999) Adenylyl cyclase interaction with the D2 dopamine receptor family; differential coupling to Gi, Gz, and Gs. Cell Mol Neurobiol 19(5):653–664

    PubMed  CAS  Article  Google Scholar 

  218. 218.

    Wolfe SE, Morris SJ (1999) Dopamine D2 receptor isoforms expressed in AtT20 cells differentially couple to G proteins to acutely inhibit high voltage-activated calcium channels. J Neurochem 73(6):2375–2382

    PubMed  CAS  Article  Google Scholar 

  219. 219.

    Watts VJ, Wiens BL, Cumbay MG, Vu MN, Neve RL, Neve KA (1998) Selective activation of Galphao by D2L dopamine receptors in NS20Y neuroblastoma cells. J Neurosci 18(21):8692–8699

    PubMed  CAS  Google Scholar 

  220. 220.

    Grunewald S, Reilander H, Michel H (1996) In vivo reconstitution of dopamine D2S receptor-mediated G protein activation in baculovirus-infected insect cells: preferred coupling to Gi1 versus Gi2. Biochemistry 35(48):15162–15173

    PubMed  CAS  Article  Google Scholar 

  221. 221.

    O'Hara CM, Tang L, Taussig R, Todd RD, O'Malley KL (1996) Dopamine D2L receptor couples to G alpha i2 and G alpha i3 but not G alpha i1, leading to the inhibition of adenylate cyclase in transfected cell lines. J Pharmacol Exp Ther 278(1):354–360

    PubMed  Google Scholar 

  222. 222.

    Newman-Tancredi A, Cussac D, Audinot V, Pasteau V, Gavaudan S, Millan MJ (1999) G protein activation by human dopamine D3 receptors in high-expressing Chinese hamster ovary cells: A guanosine-5′-O-(3-[35S]thio)-triphosphate binding and antibody study. Mol Pharmacol 55(3):564–574

    PubMed  CAS  Google Scholar 

  223. 223.

    Robinson SW, Caron MG (1997) Selective inhibition of adenylyl cyclase type V by the dopamine D3 receptor. Mol Pharmacol 52(3):508–514

    PubMed  CAS  Google Scholar 

  224. 224.

    Levy F (1991) The dopamine theory of attention deficit hyperactivity disorder (ADHD). Aust N Z J Psychiatry 25(2):277–283

    PubMed  CAS  Article  Google Scholar 

  225. 225.

    Yamaguchi I, Harmon SK, Todd RD, O'Malley KL (1997) The rat D4 dopamine receptor couples to cone transducin (Galphat2) to inhibit forskolin-stimulated cAMP accumulation. J Biol Chem 272(26):16599–16602

    PubMed  CAS  Article  Google Scholar 

  226. 226.

    Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH (1998) SH3 binding domains in the dopamine D4 receptor. Biochemistry 37(45):15726–15736

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgments

The manuscript is supported by the National Nature Science Foundation of China (NSFC) (81101016), New Century Excellent Talents in University (NCET-10-0421), and the Ministry of Science and Technology of China (2011DFG33250).

Conflicts of interest

The authors declared no conflicts of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ling-Qiang Zhu.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 471 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wu, J., Xiao, H., Sun, H. et al. Role of Dopamine Receptors in ADHD: A Systematic Meta-analysis. Mol Neurobiol 45, 605–620 (2012). https://doi.org/10.1007/s12035-012-8278-5

Download citation

Keywords

  • ADHD
  • Dopamine receptor
  • Meta-analysis