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ADHD and the Dopamine Transporter: Are There Reasons to Pay Attention?

  • Chapter
Neurotransmitter Transporters

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 175))

Abstract

The catecholamine dopamine (DA) plays an important role as a neurotransmitter in the brain in circuits linked to motor function, reward, and cognition. The presynaptic DA transporter (DAT) inactivates DA following release and provides a route for non-exocytotic DA release (efflux) triggered by amphetamines. The synaptic role of DATs first established through antagonist studies and more recently validated through mouse gene-knockout experiments, raises questions as to whether altered DAT structure or regulation support clinical disorders linked to compromised DA signaling, including drug abuse, schizophrenia, and attention deficit hyperactivity disorder (ADHD). As ADHD appears to have highly heritable components and the most commonly prescribed therapeutics for ADHD target DAT, studies ranging from brain imaging to genomic and genetic analyses have begun to probe the DAT gene and its protein for possible contributions to the disorder and/or its treatment. In this review, after a brief overview of ADHD prevalence and diagnostic criteria, we examine the rationale and experimental findings surrounding a role for human DAT in ADHD. Based on the available evidence from our lab and labs of workers in the field, we suggest that although a common variant within the human DAT (hDAT) gene (SLC6A3) is unlikely to play a major role in the ADHD, contributions of hDAT to risk may be most evident in phenotypic subgroups. The in vitro and in vivo validation of functional variants, pursued for contributions to endophenotypes in a within family approach, may help elucidate DAT and DA contributions to ADHD and its treatment.

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References

  • Adell A, Artigas F (2004) The somatodendritic release of dopamine in the ventral tegmental area and its regulation by afferent transmitter systems. Neurosci Biobehav Rev 28:415–431

    Article  PubMed  CAS  Google Scholar 

  • Almasy L, Blangero J (2001) Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am J Med Genet 105:42–44

    Article  PubMed  CAS  Google Scholar 

  • American Psychiatric Association (1994) Attention-deficit and disruptive behavior disorders. Diagnostic and statistical manual of mental disorders: DSM-IV, 4th edn. American Psychiatric Association, Washington

    Google Scholar 

  • Applegate B, Lahey BB, Hart EL, Biederman J, Hynd GW, Barkley RA, Ollendick T, Frick PJ, Greenhill L, McBurnett K, Newcorn JH, Kerdyk L, Garfinkel B, Waldman I, Shaffer D (1997) Validity of the age-of-onset criterion for ADHD: a report from the DSM-IV field trials. J Am Acad Child Adolesc Psychiatry 36:1211–1221

    Article  PubMed  CAS  Google Scholar 

  • Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG, Rapoport JL, Berg K, Bailey-Wilson JE, Muenke M (2004) Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am J Hum Genet 75:998–1014

    Article  PubMed  CAS  Google Scholar 

  • Arnold LE, Abikoff HB, Cantwell DP, Conners CK, Elliott G, Greenhill LL, Hechtman L, Hinshaw SP, Hoza B, Jensen PS, Kraemer HC, March JS, Newcorn JH, Pelham WE, Richters JE, Schiller E, Severe JB, Swanson JM, Vereen D, Wells KC (1997) National Institute of Mental Health Collaborative Multimodal Treatment Study of Children with ADHD (the MTA). Design challenges and choices. Arch Gen Psychiatry 54:865–870

    PubMed  CAS  Google Scholar 

  • Bakker SC, van der Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls DL, Monsuur AJ, van’t Slot R, Minderaa RB, Gunning WB, Pearson PL, Sinke RJ (2003) A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet 72:1251–1260

    Article  PubMed  CAS  Google Scholar 

  • Barkley RA, Biederman J (1997) Toward a broader definition of the age-of-onset criterion for attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 36:1204–1210

    Article  PubMed  CAS  Google Scholar 

  • Barkley RA, Edwards G, Laneri M, Fletcher K, Metevia L (2001) Executive functioning, temporal discounting, and sense of time in adolescents with attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). J Abnorm Child Psychol 29:541–556

    Article  PubMed  CAS  Google Scholar 

  • Barnett R, Maruff P, Vance A, Luk ES, Costin J, Wood C, Pantelis C (2001) Abnormal executive function in attention deficit hyperactivity disorder: the effect of stimulant medication and age on spatial working memory. Psychol Med 31:1107–1115

    Article  PubMed  CAS  Google Scholar 

  • Baughman FA Jr (2000) Dopamine-transporter density in patients with ADHD. Lancet 355:1460–1461; author reply 1461–1462

    Article  PubMed  Google Scholar 

  • Bauman AL, Apparsundaram S, Ramamoorthy S, Wadzinski BE, Vaughan RA, Blakely RD (2000) Cocaine and antidepressant-sensitive biogenic amine transporters exist in regulated complexes with protein phosphatase 2A. J Neurosci 20:7571–7578

    PubMed  CAS  Google Scholar 

  • Berquin PC, Giedd JN, Jacobsen LK, Hamburger SD, Krain AL, Rapoport JL, Castellanos FX (1998) Cerebellum in attention-deficit hyperactivity disorder: a morphometric MRI study. Neurology 50:1087–1093

    PubMed  CAS  Google Scholar 

  • Berridge KC, Aldridge JW, Houchard KR, Zhuang X (2005) Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette’s. BMC Biol 3:4

    Article  PubMed  CAS  Google Scholar 

  • Biederman J, Wilens T, Mick E, Spencer T, Faraone SV (1999) Pharmacotherapy of attentiondeficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics 104:e20

    Article  PubMed  CAS  Google Scholar 

  • Birnbaum HG, Kessler RC, Lowe SW, Secnik K, Greenberg PE, Leong SA, Swensen AR (2005) Costs of attention deficit-hyperactivity disorder (ADHD) in the US: excess costs of persons with ADHD and their family members in 2000. Curr Med Res Opin 21:195–206

    Article  PubMed  Google Scholar 

  • Bosse R, Fumagalli F, Jaber M, Giros B, Gainetdinov RR, Wetsel WC, Missale C, Caron MG (1997) Anterior pituitary hypoplasia and dwarfism in mice lacking the dopamine transporter. Neuron 19:127–138

    Article  PubMed  CAS  Google Scholar 

  • Buck KJ, Amara SG (1994) Chimeric dopamine-norepinephrine transporters delineate structural domains influencing selectivity for catecholamines and 1-methyl-4-phenyl-pyridinium. Proc Natl Acad Sci U S A 91:12584–12588

    Article  PubMed  CAS  Google Scholar 

  • Bunney WE Jr, Garland BL (1982) A second generation catecholamine hypothesis. Pharmacopsychiatria 15:111–115

    PubMed  CAS  Google Scholar 

  • Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27:699–711

    Article  PubMed  CAS  Google Scholar 

  • Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Lane CR, Lim EP, Kalayanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 22:231–238

    Article  PubMed  CAS  Google Scholar 

  • Carneiro A, Ingram SL, Beaulieu J-M, Sweeney A, Amara SG, Thomas SM, Caron MG, Torres GE (2002) The multiple LIM domain-containing adaptor protein Hic-5 synaptically colocalizes and interacts with the dopamine transporter. J Neurosci 22:7045–7054

    PubMed  CAS  Google Scholar 

  • Carvelli L, Moron JA, Kahlig KM, Ferrer JV, Sen N, Lechleiter JD, Leeb-Lundberg LM, Merrill G, Lafer EM, Ballou LM, Shippenberg TS, Javitch JA, Lin RZ, Galli A (2002) PI3-kinase regulation of dopamine uptake. J Neurochem 81:859–869

    Article  PubMed  CAS  Google Scholar 

  • Carvelli L, McDonald PW, Blakely RD, Defelice LJ (2004) Dopamine transporters depolarize neurons by a channel mechanism. Proc Natl Acad Sci U S A 101:16046–16051

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Castellanos FX, Giedd JN, Berquin PC, Walter JM, Sharp W, Tran T, Vaituzis AC, Blumenthal JD, Nelson J, Bastain TM, Zijdenbos A, Evans AC, Rapoport JL (2001) Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 58:289–295

    Article  PubMed  CAS  Google Scholar 

  • Chang KD, Steiner H, Ketter TA (2000) Psychiatric phenomenology of child and adolescent bipolar offspring. J Am Acad Child Adolesc Psychiatry 39:453–460

    Article  PubMed  CAS  Google Scholar 

  • Chang M, Lee S-H, Kim J-H, Lee K-H, Kim Y-S, Son H, Lee Y-S (2001) Protein kinase C-mediated functional regulation of dopamine transporter is not achieved by direct phosphorylation of the dopamine transporter protein. J Neurochem 77:754–761

    Article  PubMed  CAS  Google Scholar 

  • Chen JJ, Li Z, Pan H, Murphy DL, Tamir H, Koepsell H, Gershon MD (2001) Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter: abnormal intestinal mobility and the expression of cation transporters. J Neurosci 21:6348–6361

    PubMed  CAS  Google Scholar 

  • Cheon KA, Ryu YH, Kim YK, Namkoong K, Kim CH, Lee JD (2003) Dopamine transporter density in the basal ganglia assessed with [123I]IPT SPET in children with attention deficit hyperactivity disorder. Eur J Nucl Med Mol Imaging 30:306–311

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Chhabildas N, Pennington BF, Willcutt EG (2001) A comparison of the neuropsychological profiles of the DSM-IV subtypes of ADHD. J Abnorm Child Psychol 29:529–540

    Article  PubMed  CAS  Google Scholar 

  • Choong K, Shen R (2004) Prenatal ethanol exposure alters the postnatal development of the spontaneous electrical activity of dopamine neurons in the ventral tegmental area. Neuroscience 126:1083–1091

    Article  PubMed  CAS  Google Scholar 

  • Contin M, Martinelli P, Mochi M, Albani F, Riva R, Scaglione C, Dondi M, Fanti S, Pettinato C, Baruzzi A (2004) Dopamine transporter gene polymorphism, SPECT imaging, and levodopa response in patients with Parkinson disease. Clin Neuropharmacol 27:111–115

    Article  PubMed  CAS  Google Scholar 

  • Corman SL, Fedutes BA, Culley CM (2004) Atomoxetine: the first nonstimulant for the management of attention-deficit/hyperactivity disorder. Am J Health Syst Pharm 61:2391–2399

    PubMed  CAS  Google Scholar 

  • Cornblatt BA, Malhotra AK (2001) Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. Am J Med Genet 105:11–15

    Article  PubMed  CAS  Google Scholar 

  • Cornish KM, Manly T, Savage R, Swanson J, Morisano D, Butler N, Grant C, Cross G, Bentley L, Hollis CP (2005) Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample. Mol Psychiatry (in press)

    Google Scholar 

  • Cowell RM, Kantor L, Hewlett GH, Frey KA, Gnegy ME (2000) Dopamine transporter antagonists block phorbol ester-induced dopamine release and dopamine transporter phosphorylation in striatal synaptosomes. Eur J Pharmacol 389:59–65

    Article  PubMed  CAS  Google Scholar 

  • Daws LC, Callaghan PD, Moron JA, Kahlig KM, Shippenberg TS, Javitch JA, Galli A (2002) Cocaine increases dopamine uptake and cell surface expression of dopamine transporters. Biochem Biophys Res Commun 290:1545–1550

    Article  PubMed  CAS  Google Scholar 

  • Diehl DJ, Gershon S (1992) The role of dopamine in mood disorders. Compr Psychiatry 33:115–120

    Article  PubMed  CAS  Google Scholar 

  • Dienes KA, Chang KD, Blasey CM, Adleman NE, Steiner H (2002) Characterization of children of bipolar parents by parent report CBCL. J Psychiatr Res 36:337–345

    Article  PubMed  Google Scholar 

  • DiMaio S, Grizenko N, Joober R (2003) Dopamine genes and attention-deficit hyperactivity disorder: a review. J Psychiatry Neurosci 28:27–38

    PubMed  Google Scholar 

  • Doucette-Stamm LA, Blakely DJ, Tian J, Mockus S, Mao JI (1995) Population genetic study of the human dopamine transporter gene (DAT1). Genet Epidemiol 12:303–308

    Article  PubMed  CAS  Google Scholar 

  • Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ (1999) Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 354:2132–2133

    Article  PubMed  CAS  Google Scholar 

  • Dresel S, Krause J, Krause KH, LaFougere C, Brinkbaumer K, Kung HF, Hahn K, Tatsch K (2000) Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med 27:1518–1524

    Article  PubMed  CAS  Google Scholar 

  • Dresel SH, Kung MP, Plossl K, Meegalla SK, Kung HF (1998) Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT-1 to the central dopamine transporters in rats. Eur J Nucl Med 25:31–39

    Article  PubMed  CAS  Google Scholar 

  • Dumartin B, Jaber M, Gonon F, Caron MG, Giros B, Bloch B (2000) Dopamine tone regulates D1 receptor trafficking and delivery in striatal neurons in dopamine transporter-deficient mice. Proc Natl Acad Sci U S A 97:1879–1884

    Article  PubMed  CAS  Google Scholar 

  • Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 98:6917–6922

    Article  PubMed  CAS  Google Scholar 

  • Faraone SV, Biederman J (1998) Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 44:951–958

    Article  PubMed  CAS  Google Scholar 

  • Faraone SV, Biederman J, Wozniak J, Mundy E, Mennin D, O’Donnell D (1997) Is comorbidity with ADHD a marker for juvenile-onset mania? J Am Acad Child Adolesc Psychiatry 36:1046–1055

    Article  PubMed  CAS  Google Scholar 

  • Faraone SV, Biederman J, Monuteaux MC (2000) Toward guidelines for pedigree selection in genetic studies of attention deficit hyperactivity disorder. Genet Epidemiol 18:1–16

    Article  PubMed  CAS  Google Scholar 

  • Fauchey V, Jaber M, Caron MG, Bloch B, Le Moine C (2000) Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter. Eur J Neurosci 12:19–26

    Article  PubMed  CAS  Google Scholar 

  • Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL, Newbury DF, Crawford LR, Palmer CG, Woodward JA, Del’Homme M, Cantwell DP, Nelson SF, Monaco AP, Smalley SL (2002) A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet 70:1183–1196

    Article  PubMed  CAS  Google Scholar 

  • Fleckenstein AE, Haughey HM, Metzger RR, Kokoshka JM, Riddle EL, Hanson JE, Gibb JW, Hanson GR (1999) Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function. Eur J Pharmacol 382:45–49

    Article  PubMed  CAS  Google Scholar 

  • Ford T, Goodman R, Meltzer H (2003) The British Child and Adolescent Mental Health Survey 1999: the prevalence of DSM-IV disorders. J Am Acad Child Adolesc Psychiatry 42:1203–1211

    Article  PubMed  Google Scholar 

  • Foster JD, Pananusorn B, Vaughan RA (2002) Dopamine transporters are phosphorylated on N-terminal serines in rat striatum. J Biol Chem 277:25178–25186

    Article  PubMed  CAS  Google Scholar 

  • Frengen E, Zhao B, Howe S, Weichenhan D, Osoegawa K, Gjernes E, Jessee J, Prydz H, Huxley C, de Jong PJ (2000) Modular bacterial artificial chromosome vectors for transfer of large inserts into mammalian cells. Genomics 68:118–126

    Article  PubMed  CAS  Google Scholar 

  • Fuke S, Suo S, Takahashi N, Koike H, Sasagawa N, Ishiura S (2001) The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression. Pharmacogenomics J 1:152–156

    PubMed  CAS  Google Scholar 

  • Fuke S, Sasagawa N, Ishiura S (2005) Identification and characterization of the Hesr1/Hey1 as a candidate trans-acting factor on gene expression through the 3′ non-coding polymorphic region of the human dopamine transporter (DAT1) gene. J Biochem (Tokyo) 137:205–216

    CAS  Google Scholar 

  • Gaffaney JD, Vaughan RA (2004) Uptake inhibitors but not substrates induce protease resistance in extracellular loop two of the dopamine transporter. Mol Pharmacol 65:692–701

    Article  PubMed  CAS  Google Scholar 

  • Gainetdinov RR, Caron MG (2001) Genetics of childhood disorders: XXIV. ADHD, part 8: hyperdopaminergic mice as an animal model of ADHD. J Am Acad Child Adolesc Psychiatry 40:380–382

    Article  PubMed  CAS  Google Scholar 

  • Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG (1999) Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283:397–401

    Article  PubMed  CAS  Google Scholar 

  • Garcia B, Wei Y, Moron JA, Lin RZ, Javitch JA, Galli A (2005) Akt is essential for insulin modulation of amphetamine-induced human dopamine transporter cell surface redistribution. Mol Pharmacol 68:102–109

    PubMed  CAS  Google Scholar 

  • Gelernter J, Kranzler H, Lacobelle J (1998) Population studies of polymorphisms at loci of neuropsychiatric interest (tryptophanhydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), mu opioid receptor (OPRM1), and ciliary neurotrophic factor (CNTF)). Genomics 52:289–297

    Article  PubMed  CAS  Google Scholar 

  • Gerner RH, Post RM, Bunney WE Jr (1976) A dopaminergic mechanism in mania. Am J Psychiatry 133:1177–1180

    PubMed  CAS  Google Scholar 

  • Giros B, el Mestikawy S, Godinot N, Zheng K, Han H, Yang-Feng T, Caron MG (1992) Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter. Mol Pharmacol 42:383–390

    PubMed  CAS  Google Scholar 

  • Giros B, Wang YM, Suter S, McLeskey SB, Pifl C, Caron MG (1994) Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transporters. J Biol Chem 269:15985–15988

    PubMed  CAS  Google Scholar 

  • Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612

    Article  PubMed  CAS  Google Scholar 

  • Goldberg NR, Beuming T, Soyer OS, Goldstein RA, Weinstein H, Javitch JA (2003) Probing confirmational changes in neurotransmitter transporters: a structural context. Eur J Pharmacol 479:3–12

    Article  PubMed  CAS  Google Scholar 

  • Granas C, Ferrer J, Loland CJ, Javitch JA, Gether U (2003) N-terminal truncation of the dopamine transporter abolishes phorbol ester-and substance P receptor-stimulated phosphorylation without impairing transporter internalization. J Biol Chem 278:4990–5000

    Article  PubMed  CAS  Google Scholar 

  • Greenwood TA, Kelsoe JR (2003) Promoter and intronic variants affect the transcriptional regulation of the human dopamine transporter gene. Genomics 82:511–520

    Article  PubMed  CAS  Google Scholar 

  • Gresch PJ, Sved AF, Zigmond MJ, Finlay JM (1995) Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex. J Neurochem 65:111–116

    PubMed  CAS  Google Scholar 

  • Group MC (2004) National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-month outcomes of treatment strategies for attention-deficit/hyperactivity disorder. Pediatrics 113:754–761

    Article  Google Scholar 

  • Grunhage F, Schulze TG, Muller DJ, Lanczik M, Franzek E, Albus M, Borrmann-Hassenbach M, Knapp M, Cichon S, Maier W, Rietschel M, Propping P, Nothen MM (2000) Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1). Mol Psychiatry 5:275–282

    Article  PubMed  CAS  Google Scholar 

  • Harpin VA (2005) The effect of ADHD on the life of an individual, their family, and community from preschool to adult life. Arch Dis Child 90Suppl 1:i2–7

    Article  PubMed  Google Scholar 

  • Hastrup H, Karlin A, Javitch JA (2001) Symmetrical dimer of the human dopamine transporter revealed by cross-linking Cys-306 at the extracellular end of the sixth transmembrane segment. Proc Natl Acad Sci U S A 98:10055–10060

    Article  PubMed  CAS  Google Scholar 

  • Hastrup H, Sen N, Javitch JA (2003) The human dopamine transporter forms a tetramer in the plasma membrane: cross-linking of a cysteine in the fourth transmembrane segment is sensitive to cocaine analogs. J Biol Chem 278:45045–45048

    Article  PubMed  CAS  Google Scholar 

  • Heinz A, Goldman D, Jones DW, Palmour R, Hommer D, Gorey JG, Lee KS, Linnoila M, Weinberger DR (2000) Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 22:133–139

    Article  PubMed  CAS  Google Scholar 

  • Herskovits EH, Megalooikonomou V, Davatzikos C, Chen A, Bryan RN, Gerring JP (1999) Is the spatial distribution of brain lesions associated with closed-head injury predictive of subsequent development of attention-deficit/hyperactivity disorder? Analysis with brain-image database. Radiology 213:389–394

    PubMed  CAS  Google Scholar 

  • Huff RA, Vaughan RA, Kuhar MJ, Uhl GR (1997) Phorbol esters increase dopamine transporter phosphorylation and decrease transport Vmax. Mol Chem Neuropathol 68:225–232

    CAS  Google Scholar 

  • Inoue-Murayama M, Adachi S, Mishima N, Mitani H, Takenaka O, Terao K, Hayasaka I, Ito S, Murayama Y (2002) Variation of variable number of tandem repeat sequences in the 3′-untranslated region of primate dopamine transporter genes that affects reporter gene expression. Neurosci Lett 334:206–210

    Article  PubMed  CAS  Google Scholar 

  • Itokawa M, Lin Z, Cai NS, Wu C, Kitayama S, Wang JB, Uhl GR (2000) Dopamine transporter transmembrane domain polar mutants: ΔG and ΔΔG values implicate regions important for transporter functions. Mol Pharmacol 57:1093–1103

    PubMed  CAS  Google Scholar 

  • Jacobsen LK, Staley JK, Zoghbi SS, Seibyl JP, Kosten TR, Innis RB, Gelernter J (2000) Prediction of dopamine transporter binding availability by genotype: a preliminary report. Am J Psychiatry 157:1700–1703

    Article  PubMed  CAS  Google Scholar 

  • Jiang YH, Sahoo T, Michaelis RC, Bercovich D, Bressler J, Kashork CD, Liu Q, Shaffer LG, Schroer RJ, Stockton DW, Spielman RS, Stevenson RE, Beaudet AL (2004) A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. Am J Med Genet 131:1–10

    Article  Google Scholar 

  • Johansen EB, Aase H, Meyer A, Sagvolden T (2002) Attention-deficit/hyperactivity disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes. Behav Brain Res 130:37–45

    Article  PubMed  Google Scholar 

  • Jones SR, Gainetdinov RR, Jaber M, Giros B, Wightman RM, Caron MG (1998) Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci U S A 95:4029–4034

    Article  PubMed  CAS  Google Scholar 

  • Jones SR, Gainetdinov RR, Hu XT, Cooper DC, Wightman RM, White FJ, Caron MG (1999a) Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat Neurosci 2:649–655

    Article  PubMed  CAS  Google Scholar 

  • Jones SR, Joseph JD, Barak LS, Caron MG, Wightman RM (1999b) Dopamine neuronal transport kinetics and effects of amphetamine. J Neurochem 73:2406–2414

    Article  PubMed  CAS  Google Scholar 

  • Kahlig KM, Javitch JA, Galli A (2004) Amphetamine regulation of dopamine transport. Combined measurements of transporter currents and transporter imaging support the endocytosis of an active carrier. J Biol Chem 279:8966–8975

    Article  PubMed  CAS  Google Scholar 

  • Kang AM, Palmatier MA, Kidd KK (1999) Global variation of a 40-bp VNTR in the 3′-untranslated region of the dopamine transporter gene (SLC6A3). Biol Psychiatry 46:151–160

    Article  PubMed  CAS  Google Scholar 

  • Kavelaars A, Cobelens PM, Teunis MA, Heijnen CJ (2005) Changes in innate and acquired immune responses in mice with targeted deletion of the dopamine transporter gene. J Neuroimmunol 161:162–168

    Article  PubMed  CAS  Google Scholar 

  • Kawarai T, Kawakami H, Yamamura Y, Nakamura S (1997) Structure and organization of the gene encoding human dopamine transporter. Gene 195:11–18

    Article  PubMed  CAS  Google Scholar 

  • Kempton S, Vance A, Maruff P, Luk E, Costin J, Pantelis C (1999) Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children. Psychol Med 29:527–538

    Article  PubMed  CAS  Google Scholar 

  • Khoshbouei H, Sen N, Guptaroy B, Johnson L, Lund D, Gnegy ME, Galli A, Javitch JA (2004) N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux. PLoS Biol 2:387–393

    Article  Google Scholar 

  • Kirley A, Lowe N, Hawi Z, Mullins C, Daly G, Waldman I, McCarron M, O’Donnell D, Fitzgerald M, Gill M (2003) Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD. Am J Med Genet B Neuropsychiatr Genet 121:50–54

    Article  PubMed  Google Scholar 

  • Kitayama S, Shimada S, Xu H, Markham L, Donovan DM, Uhl GR (1992) Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding. Proc Natl Acad Sci U S A 89:7782–7785

    Article  PubMed  CAS  Google Scholar 

  • Kitayama S, Dohi T, Uhl G (1994) Phorbol esters alter functions of the expressed dopamine transporter. Eur J Pharmacol 268:115–119

    Article  PubMed  CAS  Google Scholar 

  • Kouzmenko AP, Pereira AM, Singh BS (1997) Intronic sequences are involved in neural targeting of human dopamine transporter gene expression. Biochem Biophys Res Commun 240:807–811

    Article  PubMed  CAS  Google Scholar 

  • Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K (2000) Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography. Neurosci Lett 285:107–110

    Article  PubMed  CAS  Google Scholar 

  • Krause KH, Dresel S, Krause J, Kung HF, Tatsch K, Lochmuller H (2002) Elevated striatal dopamine transporter in a drug naive patient with Tourette syndrome and attention deficit/hyperactivity disorder: positive effect of methylphenidate. J Neurol 249:1116–1118

    Article  PubMed  Google Scholar 

  • Krishnan KR (2005) Psychiatric and medical comorbidities of bipolar disorder. Psychosom Med 67:1–8

    Article  PubMed  Google Scholar 

  • 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 9:711–717

    PubMed  CAS  Google Scholar 

  • Lee KH, Kim MY, Kim DH, Lee YS (2004) Syntaxin 1A and receptor for activated C kinase interact with the N-terminal region of human dopamine transporter. Neurochem Res 29:1405–1409

    Article  PubMed  CAS  Google Scholar 

  • Li LB, Chen N, Ramamoorthy S, Chi L, Cui XN, Wang LC, Reith ME (2004a) The role of N-glycosylation in function and surface trafficking of the human dopamine transporter. J Biol Chem 279:21012–21020

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Liu Z, Monroe H, Culiat CT (2002) Integrated plat form for detection of DNA sequence variants using capillary array electrophoresis. Electrophoresis 23:1499–1511

    Article  PubMed  CAS  Google Scholar 

  • Li ZS, Pham TD, Tamir H, Chen JJ, Gershon MD (2004b) Enteric dopaminergic neurons: definition, developmental lineage, and effects of extrinsic denervation. J Neurosci 24:1330–1339

    Article  PubMed  CAS  Google Scholar 

  • Lin Z, Uhl GR (2003) Human dopamine transporter gene variation: effects of protein coding variants V55A and V382A on expression and uptake activities. Pharmacogenomics J 3:159–168

    Article  PubMed  CAS  Google Scholar 

  • Lin Z, Wang W, Kopajtic T, Revay RS, Uhl GR (1999) Dopamine transporter: transmembrane phenylalanine mutations can selectively influence dopamine uptake and cocaine analog recognition. Mol Pharmacol 56:434–447

    PubMed  CAS  Google Scholar 

  • Lin Z, Itokawa M, Uhl GR (2000a) Dopamine transporter proline mutations influence dopamine uptake, cocaine analog recognition, and expression. Faseb J 14:715–728

    PubMed  CAS  Google Scholar 

  • Lin Z, Wang W, Uhl GR (2000b) Dopamine transporter tryptophan mutants highlight candidate dopamine-and cocaine-selective domains. Mol Pharmacol 58:1581–1592

    PubMed  CAS  Google Scholar 

  • Lin Z, Zhang PW, Zhu X, Melgari JM, Huff R, Spieldoch RL, Uhl GR (2003) Phosphatidylinositol 3-kinase, protein kinase C, and MEK1/2 kinase regulation of dopamine transporters (DAT) require N-terminal DAT phosphoacceptor sites. J Biol Chem 278:20162–20170

    Article  PubMed  CAS  Google Scholar 

  • Little KY, Elmer LW, Zhong H, Scheys JO, Zhang L (2002) Cocaine induction of dopamine transporter trafficking to the plasma membrane. Mol Pharmacol 61:436–445

    Article  PubMed  CAS  Google Scholar 

  • Loder MK, Melikian HE (2003) The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines. J Biol Chem 278:22168–22174

    Article  PubMed  CAS  Google Scholar 

  • Loo SK, Specter E, Smolen A, Hopfer C, Teale PD, Reite ML (2003) Functional effects of the DAT1 polymorphism on EEG measures in ADHD. J Am Acad Child Adolesc Psychiatry 42:986–993

    Article  PubMed  Google Scholar 

  • Lynch DR, Mozley PD, Sokol S, Maas NM, Balcer LJ, Siderowf AD (2003) Lack of effect of polymorphisms in dopamine metabolism related genes on imaging of TRODAT-1 in striatum of asymptomatic volunteers and patients with Parkinson’s disease. Mov Disord 18:804–812

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Martinez D, Gelernter J, Abi-Dargham A, van Dyck CH, Kegeles L, Innis RB, Laruelle M (2001) The variable number of tandem repeats polymorphism of the dopamine transporter gene is not associated with significant change in dopamine transporter phenotype in humans. Neuropsychopharmacology 24:553–560

    Article  PubMed  CAS  Google Scholar 

  • Marx J (1999) How stimulant drugs may calm hyperactivity. Science 283:306

    Article  PubMed  CAS  Google Scholar 

  • Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasser S (2002) Dopamine transport function is elevated in cocaine users. J Neurochem 81:292–300

    Article  PubMed  CAS  Google Scholar 

  • Max JE, Fox PT, Lancaster JL, Kochunov P, Mathews K, Manes FF, Robertson BA, Arndt S, Robin DA, Lansing AE (2002) Putamen lesions and the development of attentiondeficit/hyperactivity symptomatology. J Am Acad Child Adolesc Psychiatry 41:563–571

    Article  PubMed  Google Scholar 

  • Mazei MS, Pluto CP, Kirkbride B, Pehek EA (2002) Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat. Brain Res 936:58–67

    Article  PubMed  CAS  Google Scholar 

  • Mazei-Robison MS, Blakely RD (2005) Expression studies of naturally occurring human dopamine transporter variants identifies a novel state of transporter inactivation associated with val382ala. Neuropharmacology 49:737–749

    Article  PubMed  CAS  Google Scholar 

  • Mazei-Robison MS, Couch RS, Shelton RC, Stein MA, Blakely RD (2005) Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder. Neuropharmacology 49:724–736

    Article  PubMed  CAS  Google Scholar 

  • Meinild AK, Sitte HH, Gether U (2004) Zinc potentiates an uncoupled anion conductance associated with the dopamine transporter. J Biol Chem 279:49671–49679

    Article  PubMed  CAS  Google Scholar 

  • Melikian H, Buckley K (1999) Membrane trafficking regulates the activity of the human dopamine transporter. J Neurosci 19:7699–7710

    PubMed  CAS  Google Scholar 

  • Mill J, Asherson P, Craig I, D’Souza UM (2005) Transient expression analysis of allelic variants of a VNTR in the dopamine transporter gene (DAT1). BMC Genet 6:3

    Article  PubMed  CAS  Google Scholar 

  • Miller GM, Madras BK (2002) Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression. Mol Psychiatry 7:44–55

    Article  PubMed  CAS  Google Scholar 

  • Mitchell RJ, Howlett S, Earl L, White NG, McComb J, Schanfield MS, Briceno I, Papiha SS, Osipova L, Livshits G, Leonard WR, Crawford MH (2000) Distribution of the 3′ VNTR polymorphism in the human dopamine transporter gene in world populations. Hum Biol 72:295–304

    PubMed  CAS  Google Scholar 

  • Moron JA, Zakharova I, Ferrer JV, Merrill GA, Hope B, Lafer EM, Lin ZC, Wang JB, Javitch JA, Galli A, Shippenberg TS (2003) Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity. J Neurosci 23:8480–8488

    PubMed  CAS  Google Scholar 

  • Mostofsky SH, Reiss AL, Lockhart P, Denckla MB (1998) Evaluation of cerebellar size in attention-deficit hyperactivity disorder. J Child Neurol 13:434–439

    PubMed  CAS  Google Scholar 

  • Norregaard L, Frederiksen D, Nielsen EO, Gether U (1998) Delineation of an endogenous zinc-binding site in the human dopamine transporter. EMBO J 17:4266–4273

    Article  PubMed  CAS  Google Scholar 

  • Ogdie MN, Macphie IL, Minassian SL, Yang M, Fisher SE, Francks C, Cantor RM, McCracken JT, McGough JJ, Nelson SF, Monaco AP, Smalley SL (2003) A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet 72:1268–1279

    Article  PubMed  CAS  Google Scholar 

  • Ogdie MN, Fisher SE, Yang M, Ishii J, Francks C, Loo SK, Cantor RM, McCracken JT, McGough JJ, Smalley SL, Nelson SF (2004) Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11. Am J Hum Genet 75:661–668

    Article  PubMed  CAS  Google Scholar 

  • Page G, Barc-Pain S, Pontcharraud R, Cante A, Piriou A, Barrier L (2004) Theup-regulationof the striataldopamine transporter’s activity by cAMP is PKA-, CaMKII-and phosphatase dependent. Neurochem Int 45:627–632

    Article  PubMed  CAS  Google Scholar 

  • Paule MG, Rowland AS, Ferguson SA, Chelonis JJ, Tannock R, Swanson JM, Castellanos FX (2000) Attention deficit/hyperactivity disorder: characteristics, interventions and models. Neurotoxicol Teratol 22:631–651

    Article  PubMed  CAS  Google Scholar 

  • Pelham WE Jr, Wheeler T, Chronis A (1998) Empirically supported psychosocial treatments for attention deficit hyperactivity disorder. J Clin Child Psychol 27:190–205

    Article  PubMed  Google Scholar 

  • Pogorelov VM, Rodriguiz RM, Insco ML, Caron MG, Wetsel WC (2005) Novelty seeking and stereotypic activation of behavior in mice with disruption of the dat1 gene. Neuropsychopharmacology 30:1818–1831

    Article  PubMed  CAS  Google Scholar 

  • Pristupa ZB, McConkey F, Liu F, Man HY, Lee FJ, Wang YT, Niznik HB (1998) Protein kinasemediated bidirectional trafficking and functional regulation of the human dopamine transporter. Synapse 30:79–87

    Article  PubMed  CAS  Google Scholar 

  • Purper-Ouakil D, Wohl M, Mouren MC, Verpillat P, Ades J, Gorwood P (2005) Meta-analysis of family-based association studies between the dopamine transporter gene and attention deficit hyperactivity disorder. Psychiatr Genet 15:53–59

    Article  PubMed  CAS  Google Scholar 

  • Ralph RJ, Paulus MP, Fumagalli F, Caron MG, Geyer MA (2001) Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists. J Neurosci 21:305–313

    PubMed  CAS  Google Scholar 

  • Ralph-Williams RJ, Paulus MP, Zhuang X, Hen R, Geyer MA (2003) Valproate attenuates hyperactive and perseverative behaviors in mutant mice with a dysregulated dopamine system. Biol Psychiatry 53:352–359

    Article  PubMed  CAS  Google Scholar 

  • Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237:1219–1223

    PubMed  CAS  Google Scholar 

  • Rodriguiz RM, Chu R, Caron MG, Wetsel WC(2004) Aberrant responses in social interaction of dopamine transporter knockout mice. Behav Brain Res 148:185–198

    Article  PubMed  CAS  Google Scholar 

  • Roman T, Szobot C, Martins S, Biederman J, Rohde LA, Hutz MH (2002) Dopamine transporter gene and response tomethylphenidate in attention-deficit/hyperactivity disorder. Pharmacogenetics 12:497–499

    Article  PubMed  CAS  Google Scholar 

  • Rowland AS, Umbach DM, Catoe KE, Stallone L, Long S, Rabiner D, Naftel AJ, Panke D, Faulk R, Sandler DP (2001) Studying the epidemiology of attention-deficit hyperactivity disorder: screening method and pilot results. Can J Psychiatry 46:931–940

    PubMed  CAS  Google Scholar 

  • Sacchetti P, Brownschidle LA, Granneman JG, Bannon MJ (1999) Characterization of the 5′-flanking region of the human dopamine transporter gene. Brain Res Mol Brain Res 74:167–174

    Article  PubMed  CAS  Google Scholar 

  • Sarkis EH (2000) “Model” behavior. Science 287:2160–2162

    PubMed  CAS  Google Scholar 

  • Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, Lamb ME, Leeb-Lundberg LM, Carvelli L, Javitch JA, Galli A (2000) Amphetamine-induced loss of human dopamine transporter activity: Aninternalization-dependent and cocaine-sensitivemechanism. Proc Natl Acad Sci U S A 97:6850–6855

    Article  PubMed  CAS  Google Scholar 

  • Sawaguchi T (2001) The effects of dopamine and its antagonists on directional delay-period activity of prefrontal neurons in monkeys during an oculomotor delayed-response task. Neurosci Res 41:115–128

    Article  PubMed  CAS  Google Scholar 

  • Slaats-Willemse D, Swaab-Barneveld H, de Sonneville L, van der Meulen E, Buitelaar J (2003) Deficient response inhibition as a cognitive endophenotype of ADHD. J Am Acad Child Adolesc Psychiatry 42:1242–1248

    Article  PubMed  Google Scholar 

  • Slaats-Willemse D, Swaab-Barneveld H, De Sonneville L, Buitelaar J (2005) Familial clustering of executive functioning in affected sibling pair families with ADHD. J Am Acad Child Adolesc Psychiatry 44:385–391

    Article  PubMed  Google Scholar 

  • Smalley SL, Kustanovich V, Minassian SL, Stone JL, Ogdie MN, McGough JJ, McCracken JT, MacPhie IL, Francks C, Fisher SE, Cantor RM, Monaco AP, Nelson SF (2002) Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism. Am J Hum Genet 71:959–963

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Solanto MV, Abikoff H, Sonuga-Barke E, Schachar R, Logan GD, Wigal T, Hechtman L, Hinshaw S, Turkel E (2001) The ecological validity of delay aversion and response inhibition as measures of impulsivity in AD/HD: a supplement to the NIMH multimodal treatment study of AD/HD. J Abnorm Child Psychol 29:215–228

    Article  PubMed  CAS  Google Scholar 

  • Sonuga-Barke EJ (2002) Psychological heterogeneity in AD/HD-a dual pathway model of behaviour and cognition. Behav Brain Res 130:29–36

    Article  PubMed  Google Scholar 

  • Sorkina T, Doolen S, Galperin E, Zahniser NR, Sorkin A (2003) Oligomerization of dopamine transporters visualized in living cells by fluorescence resonance energy transfer microscopy. J Biol Chem 278:28274–28283

    Article  PubMed  CAS  Google Scholar 

  • Sorkina T, Hoover BR, Zahniser NR, Sorkin A (2005) Constitutive and protein kinase Cinduced internalization of the dopamine transporter ismediated by a clathrin-dependent mechanism. Traffic 6:157–170

    Article  PubMed  CAS  Google Scholar 

  • Spielewoy C, Roubert C, Hamon M, Nosten-Bertrand M, Betancur C, Giros B (2000) Behavioural disturbances associated with hyperdopaminergia in dopamine-transporter knockout mice. Behav Pharmacol 11:279–290

    PubMed  CAS  Google Scholar 

  • Stein MA, Sarampote CS, Waldman ID, Robb AS, Conlon C, Pearl PL, Black DO, Seymour KE, Newcorn JH (2003) A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics 112:e404

    Article  PubMed  Google Scholar 

  • Stein MA, Waldman ID, Sarampote CS, Seymour KE, Robb AS, Conlon C, Kim SJ, Cook EH (2005) Dopamine transporter genotype and methylphenidate dose response in children with ADHD. Neuropsychopharmacology 30:1374–1382

    Article  PubMed  CAS  Google Scholar 

  • Stins JF, van Baal GC, Polderman TJ, Verhulst FC, Boomsma DI (2004) Heritability of Stroop and flanker performance in 12-year old children. BMC Neurosci 5:49

    Article  PubMed  Google Scholar 

  • Strandburg RJ, Marsh JT, Brown WS, Asarnow RF, Higa J, Harper R, Guthrie D (1996) Continuous-processing—related event-related potentials in children with attention deficit hyperactivity disorder. Biol Psychiatry 40:964–980

    Article  PubMed  CAS  Google Scholar 

  • Sulzer D, Maidment NT, Rayport S (1993) Amphetamine and other weak bases act topromote reverse transport of dopamine in ventral midbrain neurons. Mol Chem Neuropathol 60:527–535

    CAS  Google Scholar 

  • Swanson JM (2000) Dopamine-transporter density in patient swith ADHD. Lancet 355:1461; author reply 1461–1462

    Article  PubMed  CAS  Google Scholar 

  • Swanson JM, McBurnett K, Wigal T, Pfiffner LJ, Lerner MA, Williams L, Christian D, Tamm L, WillCutt E, Crowley K, Clevenger W, Khouzam N, Woo C, Crinella FM, Fisher TD (1993) The effect of stimulant medication on ADD children: a ‘review of reviews’. Except Child 60:154–162

    Google Scholar 

  • Syringas M, Janin F, Mezghanni S, Giros B, Costentin J, Bonnet JJ (2000) Structural domains of chimeric dopamine-noradrenaline human transporters involved in the Na(+)-and Cl(−)-dependence of dopamine transport. Mol Pharmacol 58:1404–1411

    PubMed  CAS  Google Scholar 

  • Thapar A, Holmes J, Poulton K, Harrington R (1999) Genetic basis of attention deficit and hyperactivity. Br J Psychiatry 174:105–111

    Article  PubMed  CAS  Google Scholar 

  • Torres GE, Yao WD, Mohn RR, Quan H, Kim K, Levey AI, Staudinger J, Caron MG (2001) Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1. Neuron 30:121–134

    Article  PubMed  CAS  Google Scholar 

  • Torres GE, Carneiro A, Seamans K, Fiorentini C, Sweeney A, Yao WD, Caron MG (2003) Oligomerization and trafficking of the hum and opamine transporter. Mutational analysis identifies critical domains important for the functional expression of the transporter. J Biol Chem 278:2731–2739

    Article  PubMed  CAS  Google Scholar 

  • Uhl GR, Lin Z (2003) The top 20 dopamine transporter mutants: structure-function relationships and cocaine actions. Eur J Pharmacol 479:71–82

    Article  PubMed  CAS  Google Scholar 

  • van Dyck CH, Quinlan DM, Cretella LM, Staley JK, Malison RT, Baldwin RM, Seibyl JP, Innis RB (2002) Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder. Am J Psychiatry 159:309–312

    Article  PubMed  Google Scholar 

  • Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR (1992a) Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 14:1104–1106

    Article  PubMed  CAS  Google Scholar 

  • Vandenbergh DJ, Persico AM, Uhl GR (1992b) A human dopamine transporter Cdna predicts reduced glycosylation, displays a novel repetitive element and provides raciallydimorphic TaqI RFLPs. Brain Res Mol Brain Res 15:161–166

    Article  PubMed  CAS  Google Scholar 

  • Vandenbergh DJ, Thompson MD, Cook EH, Bendahhou E, Nguyen T, Krasowski MD, Zarrabian D, Comings D, Sellers EM, Tyndale RF, George SR, O’Dowd BF, Uhl GR (2000) Human dopamine transporter gene: coding region conservation among normal, Tourette’s disorder, alcohol dependence and attention-deficit hyperactivity disorder populations. Mol Psychiatry 5:283–292

    Article  PubMed  CAS  Google Scholar 

  • Vaughan RA, Huff RA, Uhl GR, Kuhar MJ (1997) Protein kinase C-mediated phosphorylation and functional regulation of dopamine transporters in striatal synaptosomes. J Biol Chem 272:15541–15546

    Article  PubMed  CAS  Google Scholar 

  • Veenstra-Vanderweele J, Christian SL, Cook EH Jr (2004) Autism as a paradigmatic complex genetic disorder. Annu Rev Genomics Hum Genet 5:379–405

    Article  PubMed  CAS  Google Scholar 

  • Vles JS, Feron FJ, Hendriksen JG, Jolles J, van Kroonenburgh MJ, Weber WE (2003) Methylphenidate down-regulates the dopamine receptor and transporter system in children with attention deficit hyperkinetic disorder (ADHD). Neuropediatrics 34:77–80

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, Gatley SJ, Fowler JS, Wang GJ, Swanson J (2000) Serotonin and the therapeutic effects of ritalin. Science 288:11

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, Wang G, Fowler JS, Logan J, Gerasimov M, Maynard L, Ding Y, Gatley SJ, Gifford A, Franceschi D (2001) Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 21:RC121

    PubMed  CAS  Google Scholar 

  • Waldman ID, Rowe DC, Abramowitz A, Kozel ST, Mohr JH, Sherman SL, Cleveland HH, Sanders ML, Gard JM, Stever C (1998) Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet 63:1767–1776

    Article  PubMed  CAS  Google Scholar 

  • Walker JK, Gainetdinov RR, Mangel AW, Caron MG, Shetzline MA (2000) Mice lacking the dopamine transporter display altered regulation of distal colonic motility. Am J Physiol Gastrointest Liver Physiol 279:G311–318

    PubMed  CAS  Google Scholar 

  • Wang W, Sonders MS, Ukairo OT, Scott H, Kloetzel MK, Surratt CK (2003) Dissociation of high-affinity cocaine analog binding and dopamine uptake inhibition at the dopamine transporter. Mol Pharmacol 64:430–439

    Article  PubMed  CAS  Google Scholar 

  • West SA, Strakowski SM, Sax KW, Minnery KL, McElroy SL, Keck PE Jr (1995) The comorbidity of attention-deficit hyperactivity disorder in adolescent mania: potential diagnostic and treatment implications. Psychopharmacol Bull 31:347–351

    PubMed  CAS  Google Scholar 

  • Winsberg BG, Comings DE (1999) Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J Am Acad Child Adolesc Psychiatry 38:1474–1477

    Article  PubMed  CAS  Google Scholar 

  • Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (2001) Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21:1787–1794

    PubMed  CAS  Google Scholar 

  • Wozniak J, Biederman J, Kiely K, Ablon JS, Faraone SV, Mundy E, Mennin D (1995a) Manialike symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry 34:867–876

    Article  PubMed  CAS  Google Scholar 

  • Wozniak J, Biederman J, Mundy E, Mennin D, Faraone SV (1995b) A pilot family study of childhood-onset mania. J Am Acad Child Adolesc Psychiatry 34:1577–1583

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Gu HH (2003) Cocaine affinity decreased by mutations of aromatic residue phenylalanine 105 in the transmembrane domain 2 of dopamine transporter. Mol Pharmacol 63:653–658

    Article  PubMed  CAS  Google Scholar 

  • Zahniser NR, Doolen S (2001) Chronic and acute regulation of Na+/Cl−-dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther 92:21–55

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Coffey LL, Reith MEA (1997) Regulation of the functional activity of the human dopamine transporter by protein kinase C. Biochem Pharmacol 53:677–688

    Article  PubMed  CAS  Google Scholar 

  • Zhuang X, Oosting RS, Jones SR, Gainetdinov RR, Miller GW, Caron MG, Hen R (2001) Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci U S A 98:1982–1987

    Article  PubMed  CAS  Google Scholar 

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Mazei-Robison, M.S., Blakely, R.D. (2006). ADHD and the Dopamine Transporter: Are There Reasons to Pay Attention?. In: Sitte, H.H., Freissmuth, M. (eds) Neurotransmitter Transporters. Handbook of Experimental Pharmacology, vol 175. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-29784-7_17

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