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

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.

[1]  C. Schmauss,et al.  Dopamine receptor functions: lessions from knockout mice , 2001 .

[2]  H. C. Cromwell,et al.  Modulatory Actions of Dopamine on NMDA Receptor-Mediated Responses Are Reduced in D1A-Deficient Mutant Mice , 1996, The Journal of Neuroscience.

[3]  J. Nigg,et al.  Personality Mediation of Genetic Effects on Attention-Deficit/Hyperactivity Disorder , 2010, Journal of abnormal child psychology.

[4]  S. Faraone,et al.  A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population , 2009, Molecular Psychiatry.

[5]  R. Deth,et al.  How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. , 2008, Neurotoxicology.

[6]  G. Keszler,et al.  Capillary electrophoresis study on DNA-protein complex formation in the polymorphic 5' upstream region of the dopamine D4 receptor (DRD4) gene. , 2004, Current medicinal chemistry.

[7]  M. Caron,et al.  Recent advances in the molecular biology of dopamine receptors. , 1993, Annual review of neuroscience.

[8]  P. Goldman-Rakic,et al.  Interaction with Neuronal Calcium Sensor NCS-1 Mediates Desensitization of the D2 Dopamine Receptor , 2002, The Journal of Neuroscience.

[9]  Yue-Cune Chang,et al.  Prefrontal executive function and D1, D3, 5-HT2A and 5-HT6 receptor gene variations in healthy adults. , 2008, Journal of psychiatry & neuroscience : JPN.

[10]  H. Wang,et al.  Stimulated D(1) dopamine receptors couple to multiple Galpha proteins in different brain regions. , 2001, Journal of neurochemistry.

[11]  P. Asherson,et al.  No evidence for the association of DRD4 with ADHD in a Taiwanese population within-family study , 2005, BMC Medical Genetics.

[12]  E. Oord,et al.  The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder , 1999, Molecular Psychiatry.

[13]  J. Kennedy,et al.  The D4 dopamine receptor gene maps on 11p proximal to HRAS. , 1993, Genomics.

[14]  S. Iversen.  Interactions between excitatory amino acids and dopamine systems in the forebrain: implications for schizophrenia and Parkinson's disease. , 1995, Behavioural pharmacology.

[15]  D. Sibley,et al.  Molecular biology of dopamine receptors. , 1992, Trends in pharmacological sciences.

[16]  R. Gainetdinov,et al.  The Physiology, Signaling, and Pharmacology of Dopamine Receptors , 2011, Pharmacological Reviews.

[17]  J. Buitelaar,et al.  DAT1, DRD4, and DRD5 polymorphisms are not associated with ADHD in Dutch families , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[18]  M. Gill,et al.  Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder. , 2005, American journal of human genetics.

[19]  E. Borrelli,et al.  Impaired light masking in dopamine D2 receptor–null mice , 2006, Nature Neuroscience.

[20]  Susan R. George,et al.  Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1 , 1991, Nature.

[21]  Hoau Yan Wang,et al.  Stimulated D1 dopamine receptors couple to multiple Gα proteins in different brain regions , 2001 .

[22]  J. Swanson,et al.  Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. , 1996, Molecular psychiatry.

[23]  A. Graybiel,et al.  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 , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  J. Petrášek,et al.  Some ADHD polymorphisms (in genes DAT1, DRD2, DRD3, DBH, 5-HTT) in case-control study of 100 subjects 6-10 age. , 2008, Neuro endocrinology letters.

[25]  D. Sibley,et al.  New insights into dopaminergic receptor function using antisense and genetically altered animals. , 1999, Annual review of pharmacology and toxicology.

[26]  R. Loeber,et al.  Early predictors of male delinquency: a review. , 1983, Psychological bulletin.

[27]  K. Fukunaga,et al.  Novel Dopamine D2 Receptor Signaling through Proteins Interacting with the Third Cytoplasmic Loop , 2011, Molecular Neurobiology.

[28]  M. Schmidt,et al.  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 , 2004, Journal of neural transmission.

[29]  P. Muglia,et al.  A transmission disequilibrium test of the Ser9/Gly dopamine D3 receptor gene polymorphism in adult attention-deficit hyperactivity disorder , 2002, Behavioural Brain Research.

[30]  D. Grandy,et al.  Dopamine D4 receptors are heterogeneously distributed in the striosomes/matrix compartments of the striatum , 2002, Journal of neurochemistry.

[31]  D. Accili,et al.  Dopamine Receptors and Dopamine Transporter in Brain Function and Addictive Behaviors: Insights from Targeted Mouse Mutants , 1998, Developmental Neuroscience.

[32]  S. Mannuzza,et al.  Hyperactive boys almost grown up. I. Psychiatric status. , 1985, Archives of general psychiatry.

[33]  I. Craig,et al.  Functional effects of a tandem duplication polymorphism in the 5′flanking region of the DRD4 gene , 2004, Biological Psychiatry.

[34]  K. Kidd,et al.  Tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4). , 1999, American journal of medical genetics.

[35]  E. Borrelli,et al.  Absence of opiate rewarding effects in mice lacking dopamine D2 receptors , 1997, Nature.

[36]  J. Gádoros,et al.  Association between the 120‐bp duplication of the dopamine D4 receptor gene and attention deficit hyperactivity disorder: Genetic and molecular analyses , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[37]  M. Owen,et al.  A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder , 2000, Molecular Psychiatry.

[38]  E. Taylor,et al.  The parenting and family functioning of children with hyperactivity. , 1998, Journal of child psychology and psychiatry, and allied disciplines.

[39]  E. Borrelli,et al.  Structure and function of dopamine receptors , 2000, Neuroscience & Biobehavioral Reviews.

[40]  A. Addington,et al.  Association of the dopamine receptor D4 (DRD4) gene 7‐repeat allele with children with attention‐deficit/hyperactivity disorder (ADHD): An update , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[41]  D. Boomsma,et al.  Genetic and Environmental Influences on the Relation Between Attention Problems and Attention Deficit Hyperactivity Disorder , 2007, Behavior genetics.

[42]  R. Tyndale,et al.  The human dopamine D5 receptor gene: cloning and characterization of the 5'-flanking and promoter region. , 1995, Biochemistry.

[43]  Yufeng Wang,et al.  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 , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[44]  Bradford Navia,et al.  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 , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[45]  W. Roberts,et al.  Linkage study of two polymorphisms at the dopamine D3 receptor gene and attention-deficit hyperactivity disorder. , 2000, American journal of medical genetics.

[46]  B. O’Malley,et al.  In vivo regulation of central nervous system progesterone receptors: cocaine induces steroid-dependent behavior through dopamine transporter modulation of D5 receptors in rats. , 1996, Molecular Endocrinology.

[47]  I. Waldman,et al.  The relation between childhood attention-deficit hyperactivity disorder and adult antisocial behavior reexamined: The problem of heterogeneity , 1990 .

[48]  R. D. Hunt,et al.  The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. , 1996, Archives of general psychiatry.

[49]  Merja Haaparanta,et al.  The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects , 2005, Pharmacogenetics and genomics.

[50]  D. R. Smith,et al.  Behavioural assessment of mice lacking D1A dopamine receptors , 1998, Neuroscience.

[51]  D. Grandy,et al.  Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11q23. , 1992, Genomics.

[52]  S. Cichon,et al.  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. , 1996, American journal of medical genetics.

[53]  H Y Wang,et al.  Evidence for the coupling of Gq protein to D1-like dopamine sites in rat striatum: possible role in dopamine-mediated inositol phosphate formation. , 1995, Molecular pharmacology.

[54]  J. A. Chester,et al.  Mice Lacking Dopamine D4 Receptors Are Supersensitive to Ethanol, Cocaine, and Methamphetamine , 1997, Cell.

[55]  R. Klein,et al.  Hyperactive boys almost grown up. III. Methylphenidate effects on ultimate height. , 1988, Archives of general psychiatry.

[56]  C. Carpenter,et al.  Addictive Genes and the Relationship to Obesity and Inflammation , 2011, Molecular Neurobiology.

[57]  Mary L Marazita,et al.  Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis , 2002, Psychiatric genetics.

[58]  R. Todd,et al.  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. , 1996, The Journal of pharmacology and experimental therapeutics.

[59]  M. Levine,et al.  Effects of repeated amphetamine treatment on the locomotor activity of the dopamine D1A‐deficient mouse , 1997, Neuroreport.

[60]  T. Arinami,et al.  A genetic polymorphism in the promoter region of DRD4 associated with expression and schizophrenia. , 1999, Biochemical and biophysical research communications.

[61]  S. Cichon,et al.  Detection of four polymorphic sites in the human dopamine D1 receptor gene (DRD1). , 1994, Human molecular genetics.

[62]  A. Sidhu,et al.  Multiple Coupling of Human D5 Dopamine Receptors to Guanine Nucleotide Binding Proteins GS and Gz , 1998, Journal of neurochemistry.

[63]  V. Wong,et al.  Exon 3 polymorphisms of dopamine D4 receptor (DRD4) gene and attention deficit hyperactivity disorder in Chinese children , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[64]  Alessandro Usiello,et al.  Distinct functions of the two isoforms of dopamine D2 receptors , 2000, Nature.

[65]  Anna Y. Kuznetsova,et al.  A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated phospholipid methylation , 2008, Journal of Computational Neuroscience.

[66]  P. Sham,et al.  Susceptibility genes for a trait measure of attention deficit hyperactivity disorder: a pilot study in a non-clinical sample of twins , 2001, Psychiatry Research.

[67]  A J Heritch,et al.  Dopamine in schizophrenia. , 2006, The American journal of psychiatry.

[68]  L. Rohde,et al.  Attention-deficit hyperactivity disorder: a study of association with both the dopamine transporter gene and the dopamine D4 receptor gene. , 2001, American journal of medical genetics.

[69]  W. Roberts,et al.  Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor , 2000, Molecular Psychiatry.

[70]  M. Gill,et al.  Association of DRD4 in children with ADHD and comorbid conduct problems. , 2002, American journal of medical genetics.

[71]  J. Swanson,et al.  Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach , 1998, Molecular Psychiatry.

[72]  G. Paxinos,et al.  Evidence for plasticity of the dopaminergic system in Parkinsonism , 2008, Molecular Neurobiology.

[73]  R. Ebstein,et al.  Failure to replicate an excess of the long dopamine D4 exon III repeat polymorphism in ADHD in a family-based study. , 2000, American journal of medical genetics.

[74]  R. Ebstein,et al.  Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects , 1997, Molecular Psychiatry.

[75]  S. Nelson,et al.  Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD) , 2000, Molecular Psychiatry.

[76]  G. Salmon,et al.  Attention deficit hyperactivity disorder. , 2018, British journal of hospital medicine.

[77]  A. Sidhu,et al.  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 Go(*) , 1995, The Journal of Biological Chemistry.

[78]  E. Malchiodi,et al.  Distribution of D4 dopamine receptor in rat brain with sequence-specific antibodies. , 1997, Brain research. Molecular brain research.

[79]  Ellen Sidransky,et al.  American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 134B:67–72 (2005) Support for Association Between ADHD and Two Candidate Genes: NET1 and DRD1 , 2022 .

[80]  R. Braithwaite.  Attention-deficit hyperactivity disorder across the lifespan , 2013, British Journal of Psychiatry.

[81]  J. Smoller,et al.  Molecular Genetics of Attention-Deficit/Hyperactivity Disorder , 2005, Biological Psychiatry.

[82]  J. Rapoport,et al.  Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate , 2004, Molecular Psychiatry.

[83]  E K Perry,et al.  D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. , 1997, Pharmacogenetics.

[84]  Peter Dayan,et al.  A Neural Substrate of Prediction and Reward , 1997, Science.

[85]  K. Neve,et al.  Dopamine Receptors , 2008 .

[86]  S. Milgram,et al.  Association of the D2 Dopamine Receptor Third Cytoplasmic Loop with Spinophilin, a Protein Phosphatase-1-interacting Protein* , 1999, The Journal of Biological Chemistry.

[87]  P. Asherson,et al.  Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children , 2000, Molecular Psychiatry.

[88]  Z. Rónai,et al.  Association between Novelty Seeking and the −521 C/T polymorphism in the promoter region of the DRD4 gene , 2001, Molecular Psychiatry.

[89]  M. Gill,et al.  Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: Evidence of linkage and association with the SNP −616 , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[90]  K. Kidd,et al.  The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS. , 1992, Genomics.

[91]  W. Roberts,et al.  5'-untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder. , 2001, American journal of medical genetics.

[92]  Michael Gill,et al.  Absence of the 7‐repeat variant of the DRD4 VNTR is associated with drifting sustained attention in children with ADHD but not in controls , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[93]  M. Owen,et al.  Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family-based study. , 2001, American journal of medical genetics.

[94]  M. Gould,et al.  Patterns of diagnostic comorbidity in a community sample of children aged 9 through 16 years. , 1993, Journal of the American Academy of Child and Adolescent Psychiatry.

[95]  P. Goldman-Rakic,et al.  Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[96]  H. V. Van Tol,et al.  Distribution of D2 dopamine receptor mRNA in rat brain. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[97]  T. Pawson,et al.  SH3 binding domains in the dopamine D4 receptor. , 1998, Biochemistry.

[98]  J. Hoenicka,et al.  DRD2 TaqIA polymorphism is associated with urinary homovanillic acid levels in a sample of spanish male alcoholic patients , 2009, Neurotoxicity Research.

[99]  A M Graybiel,et al.  Cellular responses to psychomotor stimulant and neuroleptic drugs are abnormal in mice lacking the D1 dopamine receptor. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[100]  D. Kang,et al.  Shorter dinucleotide repeat length in the DRD5 gene is associated with attention deficit hyperactivity disorder. , 2009, Psychiatric genetics.

[101]  F. Rijsdijk,et al.  High Heritability for a Composite Index of Children’s Activity Level Measures , 2008, Behavior genetics.

[102]  I. Waldman,et al.  Candidate gene studies of ADHD: a meta-analytic review , 2009, Human Genetics.

[103]  J. Hollerman,et al.  Dopamine neurons report an error in the temporal prediction of reward during learning , 1998, Nature Neuroscience.

[104]  Thomas J. H. Chen,et al.  Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behaviour. , 1995, Pharmacogenetics.

[105]  D. Weiner,et al.  The distribution of a dopamine D2 receptor mRNA in rat brain , 1989, FEBS letters.

[106]  R. Tjian,et al.  Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. , 1991, Genes & development.

[107]  Yu-Yu Wu,et al.  A family-based association study of attention-deficit hyperactivity disorder and dopamine D2 receptor TaqI A alleles. , 2003, Chang Gung medical journal.

[108]  P. Goldman-Rakic,et al.  D1 receptors in prefrontal cells and circuits , 2000, Brain Research Reviews.

[109]  R. Todd,et al.  The Rat D4 Dopamine Receptor Couples to Cone Transducin (Gαt2) to Inhibit Forskolin-stimulated cAMP Accumulation* , 1997, The Journal of Biological Chemistry.

[110]  F. Rothhammer,et al.  Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for attention‐deficit/hyperactivity disorder in Chilean families , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[111]  Coupling of D 1 and Dopamine Receptors to Multiple G Proteins Implications for Understanding the Diversity in Receptor-G Protein Coupling , .

[112]  R. Baldessarini.  Dopamine Receptors and Clinical Medicine , 1997 .

[113]  K. Neve,et al.  Selective activation of Galphao by D2L dopamine receptors in NS20Y neuroblastoma cells. , 1998, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[114]  J. Mill,et al.  Polymorphisms in the dopamine D5 receptor (DRD5) gene and ADHD , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[115]  S. Rivkees,et al.  Functional D1 and D5 dopamine receptors are expressed in the suprachiasmatic, supraoptic, and paraventricular nuclei of primates , 1997, Synapse.

[116]  J. Gádoros,et al.  Catechol‐O‐methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[117]  M. Karin,et al.  Transcription factor AP-2 mediates induction by two different signal-transduction pathways: Protein kinase C and cAMP , 1987, Cell.

[118]  C. Yiannoutsos,et al.  Association of the dopamine beta hydroxylase gene with attention deficit hyperactivity disorder: Genetic analysis of the Milwaukee longitudinal study , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[119]  F. Amenta,et al.  Localisation of dopamine D3 receptor in the rat cerebellar cortex: a light microscope autoradiographic study , 1995, Neuroscience Letters.

[120]  J. Mill,et al.  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. , 2001, American journal of medical genetics.

[121]  R. Ebstein,et al.  Association of the dopamine D5 receptor with attention deficit hyperactivity disorder (ADHD) and scores on a continuous performance test (TOVA) , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[122]  H. V. Van Tol,et al.  Modulation of Intracellular Cyclic AMP Levels by Different Human Dopamine D4 Receptor Variants , 1995, Journal of neurochemistry.

[123]  Piu Chan,et al.  α-Synuclein and dopamine metabolism , 2007, Molecular Neurobiology.

[124]  R. Beninger,et al.  Dopaminergic mechanism of reward-related incentive learning: Focus on the dopamine d3 receptor , 2008, Neurotoxicity Research.

[125]  A. Levey,et al.  Dopamine D5 receptor immunolocalization in rat and monkey brain , 2000, Synapse.

[126]  Martin H. Schmidt,et al.  From regulatory problems in infancy to attention-deficit/hyperactivity disorder in childhood: a moderating role for the dopamine D4 receptor gene? , 2010, The Journal of pediatrics.

[127]  M. Gill,et al.  Linkage disequilibrium mapping at DAT1, DRD5 and DBH narrows the search for ADHD susceptibility alleles at these loci , 2003, Molecular Psychiatry.

[128]  C. Gerfen,et al.  Altered striatal function in a mutant mouse lacking D1A dopamine receptors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[129]  M. Gill,et al.  Dopaminergic System Genes in ADHD: Toward a Biological Hypothesis , 2002, Neuropsychopharmacology.

[130]  L S Seiden,et al.  Amphetamine: effects on catecholamine systems and behavior. , 1993, Annual review of pharmacology and toxicology.

[131]  M. Millan,et al.  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. , 1999, Molecular pharmacology.

[132]  P. Goldman-Rakic,et al.  Subcellular localization of the dopamine D2 receptor and coexistence with the calcium‐binding protein neuronal calcium sensor‐1 in the primate prefrontal cortex , 2005, The Journal of comparative neurology.

[133]  M I Posner,et al.  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. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[134]  H. Niederhofer,et al.  A preliminary report of the dopamine receptor D4 and the dopamine transporter 1 gene polymorphism and its association with attention deficit hyperactivity disorder , 2008, Neuropsychiatric disease and treatment.

[135]  E. Nestler.  Molecular mechanisms of opiate and cocaine addiction , 1997, Current Opinion in Neurobiology.

[136]  Yu Tian Wang,et al.  Direct protein–protein coupling enables cross-talk between dopamine D5 and γ-aminobutyric acid A receptors , 2000, Nature.

[137]  R. Levenson,et al.  D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N. , 2002, Molecular pharmacology.

[138]  J. Biederman,et al.  Attention-deficit/hyperactivity disorder and comorbidity. , 1999, Pediatric clinics of North America.

[139]  J. Waddington,et al.  D1-Like Dopamine Receptors: Molecular Biology and Pharmacology , 2002 .

[140]  J. Bos,et al.  Epac: defining a new mechanism for cAMP action. , 2010, Annual review of pharmacology and toxicology.

[141]  J Sergeant,et al.  The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes , 2006, Molecular Psychiatry.

[142]  Ming Xu,et al.  Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses , 1994, Cell.

[143]  G. Koob,et al.  The Neurobiology of Addiction , 1997, Alcohol health and research world.

[144]  E. Kuzhikandathil,et al.  Activation of Human D3 Dopamine Receptor Inhibits P/Q-Type Calcium Channels and Secretory Activity in AtT-20 Cells , 1999, The Journal of Neuroscience.

[145]  M. Nöthen,et al.  Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients , 1993, Biological Psychiatry.

[146]  D. Grandy,et al.  A human D1 dopamine receptor gene is located on chromosome 5 at q35.1 and identifies an EcoRI RFLP. , 1990, American journal of human genetics.

[147]  M. Owen,et al.  Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder , 2008, European Child & Adolescent Psychiatry.

[148]  J. Kennedy,et al.  A psycho-genetic study of associations between the symptoms of binge eating disorder and those of attention deficit (hyperactivity) disorder. , 2009, Journal of psychiatric research.

[149]  A. Saiardi,et al.  Dopamine D2 receptors in signal transduction and behavior. , 1997, Critical reviews in neurobiology.

[150]  E. Nestler,et al.  Opposite Modulation of Cocaine-Seeking Behavior by D1- and D2-Like Dopamine Receptor Agonists , 1996, Science.

[151]  M. Caron,et al.  Selective inhibition of adenylyl cyclase type V by the dopamine D3 receptor. , 1997, Molecular pharmacology.

[152]  Hoo-Kyun Choi,et al.  Direct and biochemical interaction between dopamine D3 receptor and elongation factor-1Bbetagamma. , 2003, Life sciences.

[153]  P. Molinoff,et al.  Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine receptors in rat brain , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[154]  H. Nakata,et al.  Oligomerization of adenosine A2A and dopamine D2 receptors in living cells. , 2003, Biochemical and biophysical research communications.

[155]  R. D. Hunt,et al.  The Contribution of α2-Noradrenergic Mechanisms to Prefrontal Cortical Cognitive Function: Potential Significance for Attention-Deficit Hyperactivity Disorder , 1996 .

[156]  Alan C. Evans,et al.  Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. , 2007, Archives of general psychiatry.

[157]  D. Safer,et al.  A survey of medication treatment for hyperactive/inattentive students. , 1988, JAMA.

[158]  I. Waldman,et al.  Dopamine DRD4 receptor polymorphism and attention deficit hyperactivity disorder , 1998, Molecular Psychiatry.

[159]  A. Sidhu,et al.  Alteration of association of agonist‐activated renal D1A dopamine receptors with G proteins in proximal tubules of the spontaneously hypertensive rat , 1998, Journal of hypertension.

[160]  David Coghill,et al.  Molecular genetics of attention-deficit/hyperactivity disorder: an overview , 2010, European Child & Adolescent Psychiatry.

[161]  A. Heath,et al.  Lack of association of dopamine D4 receptor gene polymorphisms with ADHD subtypes in a population sample of twins. , 2001, American journal of medical genetics.

[162]  Duk-Hwan Kim,et al.  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 , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[163]  J. Mill,et al.  Attention deficit hyperactivity disorder (ADHD) and the dopamine D4 receptor gene: evidence of association but no linkage in a UK sample , 2001, Molecular Psychiatry.

[164]  Kanyakumarika Sarkar,et al.  Role of gene–gene/gene–environment interaction in the etiology of eastern Indian ADHD probands , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[165]  F. Levy.  The Dopamine Theory of Attention Deficit Hyperactivity Disorder (ADHD) , 1991, The Australian and New Zealand journal of psychiatry.

[166]  E. Taylor,et al.  Attention-deficit hyperactivity disorder and hyperkinetic disorder , 1998, The Lancet.

[167]  S. Lamberts,et al.  Novel insights in dopamine receptor physiology. , 2007, European journal of endocrinology.

[168]  Z. Rónai,et al.  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 , 2002, Molecular Psychiatry.

[169]  M. Vanyukov,et al.  A dinucleotide repeat polymorphism at the gene for monoamine oxidase A and measures of aggressiveness , 1995, Psychiatry Research.

[170]  C. Hong,et al.  Twelve-Nucleotide Repeat Polymorphism of D4 Dopamine Receptor Gene in Chinese Familial Schizophrenic Patients , 1998, Biological Psychiatry.

[171]  Malcolm K Horne,et al.  Dopamine D2 receptor knockout mice develop features of Parkinson disease , 2009, Annals of neurology.

[172]  M. Wolraich,et al.  Comparison of diagnostic criteria for attention deficit disorders in a German elementary school sample. , 1995, Journal of the American Academy of Child and Adolescent Psychiatry.

[173]  Larry B. Silver,et al.  Attention Deficit Hyperactivity Disorder. A Handbook for Diagnosis and Treatment , 1991 .

[174]  V. Kustanovich,et al.  Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5 , 2004, Molecular Psychiatry.

[175]  M. Bardo,et al.  Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. , 1998, Critical reviews in neurobiology.

[176]  M. Millan,et al.  Human dopamine D(3) receptors mediate mitogen-activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism. , 1999, Molecular pharmacology.

[177]  S. Morris,et al.  Dopamine D2 Receptor Isoforms Expressed in AtT20 Cells Differentially Couple to G Proteins to Acutely Inhibit High Voltage‐Activated Calcium Channels , 1999, Journal of neurochemistry.

[178]  K. Chaudhuri,et al.  Association of dopamine D4 receptor (DRD4) polymorphisms with attention deficit hyperactivity disorder in Indian population , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[179]  D. Sibley,et al.  Comparison of dopamine D1 and D5 receptor knockout mice for cocaine locomotor sensitization , 2008, Psychopharmacology.

[180]  B. Levant,et al.  The D3 dopamine receptor in cellular and organismal function , 1998, Psychopharmacology.

[181]  G Saucier,et al.  Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. , 1999, American journal of medical genetics.

[182]  S. Faraone,et al.  Attention-deficit hyperactivity disorder , 2005, The Lancet.

[183]  Stanley J Watson,et al.  Dopamine Receptor mRNA Expression in Human Striatum and Neocortex , 1996, Neuropsychopharmacology.

[184]  H. Michel,et al.  In vivo reconstitution of dopamine D2S receptor-mediated G protein activation in baculovirus-infected insect cells: preferred coupling to Gi1 versus Gi2. , 1996, Biochemistry.

[185]  F. Limosin,et al.  Association between dopamine receptor D3 gene BalI polymorphism and cognitive impulsiveness in alcohol-dependent men , 2005, European Psychiatry.

[186]  A. Chocyk,et al.  Cortical localization of dopamine D4 receptors in the rat brain--immunocytochemical study. , 2000, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[187]  Yufeng Wang,et al.  Evaluation of potential gene–gene interactions for attention deficit hyperactivity disorder in the Han Chinese population , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[188]  W. Roberts,et al.  Further evidence from haplotype analysis for linkage of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder. , 2000, American journal of medical genetics.

[189]  M. Low,et al.  Dopamine D4 Receptor-Knock-Out Mice Exhibit Reduced Exploration of Novel Stimuli , 1999, The Journal of Neuroscience.

[190]  P. Joyce,et al.  Association of a duplicated repeat polymorphism in the 5′‐untranslated region of the DRD4 gene with novelty seeking , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[191]  R. Tannock.  Attention deficit hyperactivity disorder: advances in cognitive, neurobiological, and genetic research. , 1998, Journal of child psychology and psychiatry, and allied disciplines.

[192]  F. Castellanos,et al.  Stimulant drugs and ADHD : basic and clinical neuroscience , 2001 .

[193]  Kevin J Black,et al.  A possible substrate for dopamine-related changes in mood and behavior: Prefrontal and limbic effects of a D3-preferring dopamine agonist , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[194]  Amy S. Lee,et al.  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. , 1998, Nucleic acids research.

[195]  R. Beninger,et al.  Dopamine D1-like Receptors and Reward-related Incentive Learning , 1998, Neuroscience & Biobehavioral Reviews.

[196]  M. Martres,et al.  Chromosomal localization of the human D3 dopamine receptor gene , 1991, Human Genetics.

[197]  H. V. Van Tol,et al.  Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes. , 1994, Molecular pharmacology.

[198]  R. Klein,et al.  Adult outcome of hyperactive boys. Educational achievement, occupational rank, and psychiatric status. , 1993, Archives of general psychiatry.

[199]  D. Sibley,et al.  Striatal Excitatory Amino Acid Receptor Subunit Expression in the D1A-Dopamine Receptor-Deficient Mouse , 1998, Developmental Neuroscience.

[200]  Phil A. Silva,et al.  DSM-III disorders in preadolescent children. Prevalence in a large sample from the general population. , 1987, Archives of general psychiatry.

[201]  J. Swanson,et al.  Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention‐deficit/hyperactivity disorder (ADHD): Increased prevalence of the 2‐repeat allele , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[202]  Z. Rónai,et al.  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 , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[203]  B. Leventhal,et al.  Family-based association study of DAT1 and DRD4 polymorphism in Korean children with ADHD , 2005, Neuroscience Letters.

[204]  J. Biederman,et al.  Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. , 1991, The American journal of psychiatry.

[205]  J. Hewitt,et al.  Genetic and environmental contributions to retrospectively reported DSM-IV childhood attention deficit hyperactivity disorder , 2007, Psychological Medicine.

[206]  S. R. Nash,et al.  Dopamine receptors: from structure to function. , 1998, Physiological reviews.

[207]  Z. Vogel,et al.  Adenylyl Cyclase Interaction with the D2 Dopamine Receptor Family; Differential Coupling to Gi, Gz, and Gs , 1999, Cellular and Molecular Neurobiology.

[208]  A. Arnsten.  Dopaminergic and noradrenergic influences on cognitive functions mediated by prefrontal cortex. , 2001 .

[209]  R. Douglas Fields,et al.  Action Potential-Dependent Regulation of Gene Expression: Temporal Specificity in Ca2+, cAMP-Responsive Element Binding Proteins, and Mitogen-Activated Protein Kinase Signaling , 1997, The Journal of Neuroscience.

[210]  K. Buetow,et al.  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. , 1993, Genomics.

[211]  F. Castellanos,et al.  Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes , 2002, Nature Reviews Neuroscience.

[212]  K. Hikosaka,et al.  Increase of extracellular dopamine in primate prefrontal cortex during a working memory task. , 1997, Journal of neurophysiology.

[213]  K. Neve,et al.  Selective Activation of Gαo by D2LDopamine Receptors in NS20Y Neuroblastoma Cells , 1998, The Journal of Neuroscience.

[214]  W. Roberts,et al.  Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder , 2004, Molecular Psychiatry.

[215]  W. Roberts,et al.  Linkage of the dopamine D4 receptor gene and attention-deficit/hyperactivity disorder. , 2000, Journal of the American Academy of Child and Adolescent Psychiatry.

[216]  P. Gaszner,et al.  Combined effect of promoter polymorphisms in the dopamine D4 receptor and the serotonin transporter genes in heroin dependence. , 2005, Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology.

[217]  A. Reiersen,et al.  Association between DRD4 genotype and Autistic Symptoms in DSM-IV ADHD. , 2011, Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent.

[218]  P. Theiner,et al.  The association between TaqI A polymorphism of ANKK1 (DRD2) gene and ADHD in the Czech boys aged between 6 and 13 years. , 2010, Neuro endocrinology letters.

[219]  Vladimír Znojil,et al.  Polymorphism of DRD2 gene and ADHD. , 2006, Neuro endocrinology letters.

[220]  N M Laird,et al.  Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions. , 2000, American journal of human genetics.

[221]  Martínez-Levy Gabriela,et al.  Genetic interaction analysis for DRD4 and DAT1 genes in a group of Mexican ADHD patients , 2009, Neuroscience Letters.

[222]  D. Murphy,et al.  Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking , 1996, Nature Genetics.

[223]  C. Schmauss,et al.  Dopamine receptor functions: lessons from knockout mice [corrected]. , 2001, Pharmacology & therapeutics.

[224]  D. Cantwell,et al.  Comorbidity in ADHD: implications for research, practice, and DSM-V. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[225]  A. Sidhu,et al.  Coupling of dopamine receptor subtypes to multiple and diverse G proteins , 2000, International Journal of Developmental Neuroscience.

[226]  S. Nelson,et al.  Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder , 1999, Molecular Psychiatry.

[227]  S. Robertson,et al.  A Closer Look at Amphetamine-Induced Reverse Transport and Trafficking of the Dopamine and Norepinephrine Transporters , 2009, Molecular Neurobiology.

[228]  R. Pergolizzi,et al.  Dopamine D4 receptor gene and attention deficit hyperactivity disorder. , 2004, Pediatric neurology.