Skip to main content
SpringerLink
Log in

Gene Organization and Polymorphisms of Monoamine Transporters

Relationship to Psychiatric and Other Complex Diseases

  • Chapter
Neurotransmitter Transporters

Part of the book series: Contemporary Neuroscience ((CNEURO))

  • 255 Accesses

Abstract

The monoamine neurotransmitters norepinephrine (NE), dopamine (DA), and serotonin (5-HT), play important roles in mood, cognition, learning, motor activity, reward, sleep, appetite, and cardiovascular functions. The availability of extracellular NE, DA, and 5-HT is limited by presynaptically localized transporters—NET, DAT, and SERT, respectively. The MA transporters retrieve released neurotransmitter, thus limiting the spread and duration of synaptic excitability and allowing neurotransmitter to be repackaged into synaptic vesicles. NET and SERT are the targets for many antidepressants, such as the tricyclic agents and the selective serotonin reuptake inhibitors (SSRIs) and with DAT, are the targets for the psychostimulants amphetamine and cocaine (1).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Barker, E. L. and Blakely, R. D. (1995) Norepinephrine and serotonin transporters: molecular targets of antidepressant drugs, in Psychopharmacology: The Fourth Generation of Progress. ( Bloom, F. E. and Kupfer, D. J., eds.), Raven Press, New York, NY.

    Google Scholar 

  2. Amara, S. G. and Kuhar, M. J. (1993) Neurotransmitter transporters: recent progress. Annu. Rev. Neurosci. 16, 73–93.

    PubMed  CAS  Google Scholar 

  3. Melikian, H. E., McDonald, J. K, Gu, H., Rudnick, G., Moore, K. R., and Blakely, R. D. (1994) Human norepinephrine transporter. Biosynthetic studies using a site-directed polyclonal antibody. J. Biol. Chem. 269, 12, 29012, 297.

    Google Scholar 

  4. Melikian, H. E., Ramamoorthy, S., Tate, C. G., and Blakely, R. D. (1996) Inability to N-glycosylate the human norepinephrine transporter reduces protein stability, surface trafficking, and transport activity but not ligand recognition. Mol. Pharmacol. 50, 266–276.

    PubMed  CAS  Google Scholar 

  5. Apparsundaram, S., Galli, A., DeFelice, L. J., Hartzell, H. C., and Blakely, R. D. (1998) Acute regulation of norepinephrine transport: I. protein kinase C- linked muscarinic receptors influence transport capacity and transporter density in SK-N-SH cells. J. Pharmacol. Exp. Ther. 287, 733–743.

    PubMed  CAS  Google Scholar 

  6. Apparsundaram, S., Schroeter, S., Giovanetti, E., and Blakely, R. D. (1998) Acute regulation of norepinephrine transport: II. PKC-modulated surface expression of human norepinephrine transporter proteins. J. Pharmacol. Exp. Ther. 287, 744–751.

    PubMed  CAS  Google Scholar 

  7. Bauman, A. L., Apparsundaram, S., Ramamoorthy, S., Wadzinski, B. E., Vaughan, R. A., and Blakely, R. D. (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 

  8. Ramamoorthy, S. and Blakely, R. D. (1999) Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science 285, 763–766.

    PubMed  CAS  Google Scholar 

  9. Bengel, D., Murphy, D. L., Andrews, A. M., Wichems, C. H., Feltner, D., Heils, A., et al. (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol. Pharmacol. 53, 649–655.

    PubMed  CAS  Google Scholar 

  10. Giros, B., Jaber, M., Jones, S. R., Wightman, R. M., and Caron, M. G. (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379, 606–612.

    PubMed  CAS  Google Scholar 

  11. Xu, F., Gainetdinov, R. R., Wetsel, W. C., Jones, S. R., Bohn, L. M., Miller, G. W., et al. (2000) Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nature Neurosci. 3, 465–471.

    PubMed  CAS  Google Scholar 

  12. Pacholczyk, T., Blakely, R. D., and Amara, S. G. (1991) Expression cloning of a cocaine-and antidepressant-sensitive human noradrenaline transporter. Nature 350, 350–354.

    PubMed  CAS  Google Scholar 

  13. Ramamoorthy, S., Prasad, P. D., Kulanthaivel, P., Leibach, F. H., Blakely, R. D., and Ganapathy, V. (1993) Expression of a cocaine-sensitive norepinephrine transporter in the human placental syncytiotrophoblast. Biochemistry 32, 1346–1353.

    PubMed  CAS  Google Scholar 

  14. Pörzgen, P., Bönisch, H., Hammermann, R., and Brüss, M. (1998) The human noradrenaline transporter gene contains multiple polyadenylation sites and two alternatively spliced C-terminal exons. Biochim. Biophys. Acta 1398, 365–370.

    PubMed  Google Scholar 

  15. Gelernter, J., Kruger, S., Pakstis, A. J., Pacholczyk, T., Sparkes, R. S., Kidd, K. K., et al. (1993) Assignment of the norepinephrine transporter protein (NET1) locus to chromosome 16. Genomics 18, 690–692.

    PubMed  CAS  Google Scholar 

  16. Brüss, M., Kunz, J., Lingen, B., and Bönisch, H. (1993) Chromosomal mapping of the human gene for the tricyclic antidepressant-sensitive noradrenaline transporter. Human Genet. 91, 278–280.

    Google Scholar 

  17. Pörzgen, P., Bönisch, H., and Brüss, M. (1995) Molecular cloning and organization of the coding region of the human norepinephrine transporter gene [published erratum appears in Biochem. Biophys. Res. Commun. (1996) 227(2), 642,643]. Biochem. Biophys. Res. Commun. 215, 1145–1150.

    PubMed  Google Scholar 

  18. Kim, C. H., Kim, H. S., Cubells, J. F., and Kim, K. S. (1999) A previously undescribed intron and extensive 5’ upstream sequence, but not Phox2amediated transactivation, are necessary for high level cell type-specific expression of the human norepinephrine transporter gene. J. Biol. Chem. 274, 6507–6518.transporter. Hum. Genet. 91, 278–280.

    Google Scholar 

  19. Meyer, J., Wiedemann, P., Okladnova, O., Bruss, M., Staab, T., Stober, G., et al. (1998) Cloning and functional characterization of the human norepinephrine transporter gene promoter. J. Neural Transm. 105, 1341–1350.

    PubMed  CAS  Google Scholar 

  20. Burton, L. D., Kippenberger, A. G., Lingen, B., Bruss, M., Bonisch, H. and Christie, D. L. (1998) A variant of the bovine noradrenaline transporter reveals the importance of the C-terminal region for correct targeting to the membrane and functional expression. Biochem. J. 330, 909–914.

    PubMed  CAS  Google Scholar 

  21. Kitayama, S., Ikeda, T., Mitsuhata, C., Sato, T., Morita, K., and Dohi, T. (1999) Dominant negative isoform of rat norepinephrine transporter produced by alternative RNA splicing. J. Biol. Chem. 274, 10,731–10, 736.

    Google Scholar 

  22. Torres, G. E., Tao, W. D., Mohn, A. R., Quan, H., Kim, K. M., Levey, A. L., et. al. (2001) Functional interaction between monoamine plasma membrane transporters and the synaptic PD2 domain-containing protein PICK1. Neuron. 30, 121–134.

    PubMed  CAS  Google Scholar 

  23. Leonard, B. E. (1997) The role of noradrenaline in depression: a review. J. Psychopharmacol. 11, S39 - S47.

    PubMed  CAS  Google Scholar 

  24. Ressler, K. J. and Nemeroff, C. B. (1999) Role of norepinephrine in the pathophysiology and treatment of mood disorders. Biol. Psychiatry 46, 1219–1233.

    PubMed  CAS  Google Scholar 

  25. Schildkraut, J. J. (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am. J. Psychiatry 122, 509–522.

    PubMed  CAS  Google Scholar 

  26. Brady, L. S. (1994) Stress, antidepressant drugs, and the locus coeruleus. Brain Res. Bull. 35, 545–556.

    PubMed  CAS  Google Scholar 

  27. Linner, L., Arborelius, L., Nomikos, G. G., Bertilsson, L., and Svensson, T. H. (1999) Locus coeruleus neuronal activity and noradrenaline availability in the frontal cortex of rats chronically treated with imipramine: effect of alpha 2-adrenoceptor blockade. Biol. Psychiatry 46, 766–774.

    PubMed  CAS  Google Scholar 

  28. Klimek, V., Stockmeier, C., Overholser, J., Meltzer, H. Y., Kalka, S., Dilley, G., and Ordway, G. A. (1997) Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J. Neurosci. 17, 8451–8458.

    PubMed  CAS  Google Scholar 

  29. Eisenhofer, G., Cox, H. S., and Esler, M. D. (1990) Parallel increases in noradrenaline reuptake and release into plasma during activation of the sympathetic nervous system in rabbits. Naunyn Schmiedebergs Arch. Pharmacol. 342, 328–335.

    PubMed  CAS  Google Scholar 

  30. Eisenhofer, G., Esler, M. D., Meredith, I. T., Dart, A., Cannon, R. O., Quyyumi, A. A., et al. (1992) Sympathetic nervous function in human heart as assessed by cardiac spillovers of dihydroxyphenylglycol and norepinephrine. Circulation 85, 1775–1785.

    PubMed  CAS  Google Scholar 

  31. Imamura, M., Lander, H. H., and Levi, R. (1996) Activation of histamine H-3 receptor inhibits carrier-mediated norepinephrine release during protracted myocardialeschemia. Comparison with adenosine Al-receptors and alpha-2 adrenoceptors, Circ. Res. 78, 475–481.

    PubMed  CAS  Google Scholar 

  32. Bohm, M., La Rosee, K., Schwinger, R. H., and Erdmann, E. (1995) Evidence for reduction of norepinephrine uptake sites in the failing human heart. J. Am. Coll. Cardiol. 25, 146–153.

    PubMed  CAS  Google Scholar 

  33. Liang, C. S., Fan, T. H., Sullebarger, J. T., and Sakamoto, S. (1989) Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation. J. Clin. Invest. 84, 1267–1275.

    PubMed  CAS  Google Scholar 

  34. Merlet, P., Dubois-Rande, J. L., Adnot, S., Bourguignon, M. H., Benvenuti, C., Loisance, D., et al. (1992) Myocardial beta-adrenergic desensitization and neuronal norepinephrine uptake function in idiopathic dilated cardiomyopathy. J. Cardiovasc. Pharmacol. 19, 10–16.

    PubMed  CAS  Google Scholar 

  35. Schafers, M., Dutka, D., Rhodes, C. G., Lammertsma, A. A., Hermansen, F., Schober, O., et al. (1998) Myocardial presynaptic and postsynaptic autonomic dysfunction in hypertrophic cardiomyopathy. Circ. Res. 82, 57–62.

    PubMed  CAS  Google Scholar 

  36. Esler, M., Jackman, G., Bobik, A., Leonard, P., Kelleher, D., Skews, H., et al. (1981) Norepinephrine kinetics in essential hypertension. Defective neuronal uptake of norepinephrine in some patients. Hypertension 3, 149–156.

    PubMed  CAS  Google Scholar 

  37. Gelernter, J., Kruger, S., Kidd, K. K., and Amara, S. (1993) TaqI RFLP at norepinephrine transporter protein (NET) locus. Human Mol. Genet. 2, 820.

    CAS  Google Scholar 

  38. Hadley, D., Hoff, M., Holik, J., Reimherr, F., Wender, P., Coon, H., et al. (1995) Manic-depression and the norepinephrine transporter gene. Human Hered. 45, 165–168.

    CAS  Google Scholar 

  39. Roses, A. D. (2000) Pharmacogenetics and the practice of medicine. Nature 405, 857–865.

    PubMed  CAS  Google Scholar 

  40. Cargill, M., Altshuler, D., Ireland, J., Sklar, P., Ardlie, K., Patil, N., et al. (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22, 231–238.

    PubMed  CAS  Google Scholar 

  41. Weiss, K. M. and Terwilliger, J. D. (2000) How many diseases does it take to map a gene with SNPs? Nature Genet. 26, 151–157.

    PubMed  CAS  Google Scholar 

  42. Robertson, D. (1999) The epidemic of orthostatic tachycardia and orthostatic intolerance. Am. J. Med. Sci. 317, 75–77.

    PubMed  CAS  Google Scholar 

  43. Jacob, G., Shannon, J. R., Costa, F., Furlan, R., Biaggioni, I., Mosqueda-Garcia, R., et al. (1999) Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance. Circulation 99, 1706–1712.

    PubMed  CAS  Google Scholar 

  44. Shannon, J. R., Flattern, N. L., Jordan, J., Jacob, G., Black, B. K., Biaggioni, I., et al. (2000) Clues to the origin of orthostatic intolerance: a genetic defect in the cocaine-and antidepressant sensitive norepinephrine transporter. N. Engl. J. Med. 342, 541–549.

    PubMed  CAS  Google Scholar 

  45. Goldstein, D. S., Brush, Jr., J. E., Eisenhofer, G., Stull, R., and Esler, M. (1988) In vivo measurement of neuronal uptake of norepinephrine in the human heart. Circulation 78, 41–48.

    PubMed  CAS  Google Scholar 

  46. Novi, A. M. (1968) An electron microscopic study of the innervation of papillary muscles in the rat. Anat. Rec. 160, 123–141.

    PubMed  CAS  Google Scholar 

  47. Stöber, G., Nothen, M. M., Porzgen, P., Bruss, M., Bonisch, H., Knapp, M., et al. (1996) Systematic search for variation in the human norepinephrine transporter gene: identification of five naturally occurring missense mutations and study of association with major psychiatric disorders. Am. J. Med. Genet. 67, 523–532.

    PubMed  Google Scholar 

  48. Stöber, G., Hebebrand, J., Cichon, S., Bruss, M., Bonisch, H., Lehmkuhl, G., et al. (1999) Tourette syndrome and the norepinephrine transporter gene: results of a systematic mutation screening. Am. J. Med. Genet. 88, 158–163.

    PubMed  Google Scholar 

  49. Owen, D., Du, L., Bakish, D., Lapierre, Y. D., and Hrdina, P. D. (1999) Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression. Psychiatry Res. 87, 1–5.

    PubMed  CAS  Google Scholar 

  50. Runkel, F., Bruss, M., Nothen, M. M., Stober, G., Propping, P., and Bonisch, H. (2000) Pharmacological properties of naturally occurring variants of the human norepinephrine transporter. Pharmacogenetics 10, 397–405.

    PubMed  CAS  Google Scholar 

  51. Halushka, M. K., Fan, J. B., Bentley, K., Hsie, L., Shen, N., Weder, A., et al. (1999) Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nature Genet. 22, 239–247.

    PubMed  CAS  Google Scholar 

  52. Hahn, M. K., Mazei, M. S., Robertson, D., and Blakely, R. D. (2000) Role of human norepinephrine transporter gene single nucleotide polymorphisms in cardiovascular disease. Am. J. Med. Genet. 67, 369.

    Google Scholar 

  53. Giros, B., el Mestikawy, S., Bertrand, L., and Caron, M. G. (1991) Cloning and functional characterization of a cocaine-sensitive dopamine transporter. FEBS Lett. 295, 149–154.

    PubMed  CAS  Google Scholar 

  54. Kilty, J. E., Lorang, D., and Amara, S. G. (1991) Cloning and expression of a cocaine-sensitive rat dopamine transporter. Science 254, 578, 579.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  56. Vandenbergh, D. J., Persico, A. M., and Uhl, G. R. (1992) A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs. Brain Res. Mol. Brain Res. 15, 161–166.

    PubMed  CAS  Google Scholar 

  57. Donovan, D. M., Vandenbergh, D. J., Perry, M. P., Bird, G. S., Ingersoll, R., Nanthakumar, E., et al. (1995) Human and mouse dopamine transporter genes: conservation of 5’-flanking sequence elements and gene structures. Brain Res. Mol. Brain Res. 30, 327–335.

    PubMed  CAS  Google Scholar 

  58. Vandenbergh, D. J., Persico, A. M., Hawkins, A. L., Griffin, C. A., Li, X., Jabs, E. W., et al. (1992) Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 14, 1104–1106.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  60. Vandenbergh, D. J., Thompson, M. D., Cook, E. H., Bendahhou, E., Nguyen, T., Krasowski, M. D., et al. (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.

    PubMed  CAS  Google Scholar 

  61. Carlsson, A. (1987) Perspectives on the discovery of central monoaminergic neurotransmission. Annu. Rev. Neurosci. 10, 19–40.

    PubMed  CAS  Google Scholar 

  62. Bannon, M. J., Granneman, J. G., and Kapatos, G. (1995) The dopamine transporter. Potential involvement in neuropsychiatric disorders, in Psychopharmacology: The Fourth Generation of Progress. ( Bloom, F. E. and Kupfer, D. J., eds.), Raven Press, New York, NY, pp. 179–187.

    Google Scholar 

  63. Gainetdinov, R. R., Jones, S. R., and Caron, M. G. (1999) Functional hyperdopaminergia in dopamine transporter knock-out mice. Biol. Psychiatry 46, 303–311.

    PubMed  CAS  Google Scholar 

  64. Byerley, W., Hoff, M., Holik, J., Caron, M. G., and Giros, B. (1993) VNTR polymorphism for the human dopamine transporter gene (DAT1). Hum. Mol. Genet. 2, 335.

    PubMed  CAS  Google Scholar 

  65. Sano, A., Kondoh, K., Kakimoto, Y., and Kondo, I. (1993) A 40-nucleotide repeat polymorphism in the human dopamine transporter gene. Human Genet. 91, 405, 406.

    Google Scholar 

  66. Gelernter, J., Kranzler, H., and Lacobelle, J. (1998) Population studies of polymorphisms at loci of neuropsychiatric interest (tryptophan hydroxylase [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.

    CAS  Google Scholar 

  67. Kang, A. M., Palmatier, M. A., and Kidd, M. A. (1999) Global variation of a 40-bp VNTR in the 3’-untranslated region of the dopamine transporter gene (SLC6A3). Biol. Psychiatry 46, 151–160.

    PubMed  CAS  Google Scholar 

  68. Mitchell, R. J., Howlett, S., Earl, L., White, N. G., McComb, J., Schanfield, M. S., et al. (2000) Distribution of the 3’ VNTR polymorphism in the human dopamine transporter gene in world populations. Human Biol. 72, 295–304.

    PubMed  CAS  Google Scholar 

  69. Grunhage, F., Schulze, T. G., Muller, D. J., Lanczik, M., Franzek, E., Albus, M., et al. (2000) Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1). Mol. Psychiatry 5, 275–282.

    PubMed  CAS  Google Scholar 

  70. Ueno, S., Nakamura, M., Mikami, M., Kondoh, K., Ishiguro, H., Arinami, T., et al. (1999) Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism. Mol. Psychiatry 4, 552–557.

    PubMed  CAS  Google Scholar 

  71. Morino, H., Kawarai, T., Izumi, Y., Kazuta, T., Oda, M., Komure, O., et al. (2000) A single nucleotide polymorphism of dopamine transporter gene is associated with Parkinson’s disease. Ann. Neurol. 47, 528–531.

    PubMed  CAS  Google Scholar 

  72. Greenwood, T. A., Alexander, M., Keck, P. E., McElroy, S., Sadovnick, A. D., Remick, R. A., et al. (2001) Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder. Am. J. Med. Genet. 105, 145–151.

    PubMed  CAS  Google Scholar 

  73. Manki, H., Kanba, S., Muramatsu, T., Higuchi, S., Suzuki, E., Matsushita, S., et al. (1996) Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders. J. Affect. Disord. 40, 7–13.

    PubMed  CAS  Google Scholar 

  74. Rubic, C., Schmidt, F., Knapp, M., Spandel, J., Wiegand, C., Meyer, J., et al. (2001) The human dopamine transporter gene: the 5’-flanking region reveals five diallelic polymorphic sites in a caucasian population sample. Neurosci. Lett. 297, 125–128.

    Google Scholar 

  75. Waldman, I. D., Robinson, B. F., and Feigon, S. A. (1997) Linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder: extending the transmission disequilibrium test (TDT) to examine genetic heterogeneity. Genet. Epidemiol. 14, 699–704.

    PubMed  CAS  Google Scholar 

  76. Kelsoe, J. R., Sadovnick, A. D., Kristbjarnarson, H., Bergesch, P., Mroczkowski-Parker, Z., Drennan, M., et al. (1996) Possible locus for bipolar disorder near the dopamine transporter on chromosome 5. Am. J. Med. Genet. 67, 533–540.

    PubMed  CAS  Google Scholar 

  77. Kirov, G., Jones, I., McCandless, F., Craddock, N., and Owen, M. J. (1999) Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5. Mol. Psychiatry 4, 558–565.

    PubMed  CAS  Google Scholar 

  78. Koob, G. F., Sanna, P. P., and Bloom, F. E. (1998) Neuroscience of addiction. Neuron 21, 467–476.

    PubMed  CAS  Google Scholar 

  79. Rocha, B. A., Fumagalli, F., Gainetdinov, R. R., Jones, S. R., Ator, R., Giros, B., et al. (1998) Cocaine self-administration in dopamine-transporter knockout mice [see comments] [published erratum appears in Nature Neurosci. (1998) 1(4), 330]. Nature Neurosci. 1, 132–137.

    PubMed  CAS  Google Scholar 

  80. Gelernter, J., Kranzler, H. R., Satel, S. L., and Rao, P. A. (1994) Genetic association between dopamine transporter protein alleles and cocaine-induced paranoia. Neuropsychopharmacology 11, 195–200.

    PubMed  CAS  Google Scholar 

  81. Persico, A. M., Vandenbergh, D. J., Smith, S. S., and Uhl, G. R. (1993) Dopamine transporter gene polymorphisms are not associated with polysubstance abuse. Biol. Psychiatry 34, 265–267.

    PubMed  CAS  Google Scholar 

  82. Lerman, C., Caporaso, N. E., Audrain, J., Main, D., Bowman, E. D., Lockshin, B., et al. (1999) Evidence suggesting the role of specific genetic factors in cigarette smoking. Health Psychol. 18, 14–20.

    PubMed  CAS  Google Scholar 

  83. Sabol, S. Z., Nelson, M. L., Fisher, C., Gunzerath, L., Brody, C. L., Hu, S., et al. (1999) A genetic association for cigarette smoking behavior [comment]. Health Psychol. 18, 7–13.

    PubMed  CAS  Google Scholar 

  84. Jorm, A. F., Henderson, A. S., Jacomb, P. A., Christensen, H., Korten, A. E., Rodgers, B., et al. (2000) Association of smoking and personality with a polymorphism of the dopamine transporter gene: results from a community survey. Am. J. Med. Genet. 96, 331–334.

    PubMed  CAS  Google Scholar 

  85. Sander, T., Harms, H., Podschus, J., Finckh, U., Nickel, B., Rolfs, A., et al. (1997) Allelic association of a dopamine transporter gene polymorphism in alcohol dependence with withdrawal seizures or delirium. Biol. Psychiatry 41, 299–304.

    PubMed  CAS  Google Scholar 

  86. Schmidt, L. G., Harms, H., Kuhn, S., Rommelspacher, H., and Sander, T. (1998) Modification of alcohol withdrawal by the A9 allele of the dopamine transporter gene. Am. J. Psychiatry 155, 474–478.

    PubMed  CAS  Google Scholar 

  87. Sander, T., Berlin, W., Ostapowicz, A., Samochowiec, J., Gscheidel, N., and Hoehe, M. R. (2000) Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and Susceptibility to idiopathic generalized epilepsy. Epilepsy Res. 41, (2000) 75–81.

    PubMed  CAS  Google Scholar 

  88. Franke, P., Schwab, S. G., Knapp, M., Gansicke, M., Delmo, C., Zill, P., Trixler, M., et al. (1999) DAT1 gene polymorphism in alcoholism: a family-based association study. Biol. Psychiatry 45, 652–654.

    PubMed  CAS  Google Scholar 

  89. Heinz, A., Goldman, D., Jones, D. W., Palmour, R., Hommer, D., Gorey, J. G., et al. (2000) Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 22, 133–139.

    PubMed  CAS  Google Scholar 

  90. Muramatsu, T. and Higuchi, S. (1995) Dopamine transporter gene polymorphism and alcoholism. Biochem. Biophys. Res. Commun. 211, 28–32.

    PubMed  CAS  Google Scholar 

  91. Swanson, J. M., Flodman, P., Kennedy, J., Spence, M. A., Moyzis, R., Schuck, S., et al. (2000) Dopamine genes and ADHD. Neurosci. Biobehay. Rev. 24, 21–25.

    CAS  Google Scholar 

  92. Cook, Jr., E. H., Stein, M. A., Krasowski, M. D., Cox, N. J., Olkon, D. M., Kieffer, J. E., et al. (1995) Association of attention-deficit disorder and the dopamine transporter gene. Am. J. Hum. Genet. 56, 993–998.

    PubMed  CAS  Google Scholar 

  93. Gill, M., Daly, G., Heron, S., Hawi, Z., and Fitzgerald, M. (1997) Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. Mol. Psychiatry 2, 311–313.

    PubMed  CAS  Google Scholar 

  94. Waldman, I. D., Rowe, D. C., Abramowitz, A., Kozel, S. T., Mohr, J. H., Sherman, S. L., et al. (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. Human Genet. 63, 1767–1776.

    CAS  Google Scholar 

  95. Daly, G., Hawi, Z., Fitzgerald, M., and Gill, M. (1999) Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. Mol. Psychiatry 4, 192–196.

    PubMed  CAS  Google Scholar 

  96. Curran, S., Mill, J., Tahir, E., Kent, L., Richards, S., Gould, A., et al. (2001) Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples. Mol. Psychiatry 6, 425–428.

    PubMed  CAS  Google Scholar 

  97. Holmes, J., Payton, A., Barrett, J. H., Hever, T., Fitzpatrick, H., Trumper, A. L., et al. (2000) A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder. Mol. Psychiatry 5, 523–530.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  99. Jorm, A. F., Prior, M., Sanson, A., Smart, D., Zhang, Y., and Easteal, S. (2001) Association of a polymorphism of the dopamine transporter gene with externalizing behavior problems and associated temperament traits: a longitudinal study from infancy to the mid-teens. Am. J. Med. Genet. 105, 346–350.

    PubMed  CAS  Google Scholar 

  100. Barr, C. L., Xu, C., Kroft, J., Feng, Y., Wigg, K., Zai, G., et al. (2001) Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder. Biol. Psychiatry 49, 333–339.

    PubMed  CAS  Google Scholar 

  101. Dougherty, D. D., Bonab, A. A., Spencer, T. J., Rauch, S. L., Madras, B. K., and Fischman, A. J. (1999) Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 354, 2132, 2133.

    Google Scholar 

  102. Dresel, S., Krause, J., Krause, K. H., LaFougere, C., Brinkbaumer, K., Kung, H. F., et al. (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.

    PubMed  CAS  Google Scholar 

  103. Krause, K. H., Dresel, S. H., Krause, J., Kung, H. F., and 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.

    PubMed  CAS  Google Scholar 

  104. Persico, A. M., Wang, Z. W., Black, D. W., Andreasen, N. C., Uhl, G. R., and Crowe, R. R. (1995) Exclusion of close linkage of the dopamine transporter gene with schizophrenia spectrum disorders. Am. J. Psychiatry 152, 134–136.

    PubMed  CAS  Google Scholar 

  105. Persico, A. M. and Catalano, M. (1998) Lack of association between dopamine transporter gene polymorphisms and delusional disorder. Am. J. Med. Genet. 81, 163–165.

    PubMed  CAS  Google Scholar 

  106. Inada, T., Sugita, T., Dobashi, I., Inagaki, A., Kitao, Y., Matsuda, G., et al. (1996) Dopamine transporter gene polymorphism and psychiatric symptoms seen in schizophrenic patients at their first episode. Am. J. Med. Genet. 67, 406–408.

    PubMed  CAS  Google Scholar 

  107. Persico, A. M. and Macciardi, F. (1997) Genotypic association between dopamine transporter gene polymorphisms and schizophrenia. Am. J. Med. Genet. 74, 53–57.

    PubMed  CAS  Google Scholar 

  108. Daniels, J., Williams, J., Asherson, P., McGuffin, P., and Owen, M. (1995) No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT). Am. J. Med. Genet. 60, 85–87.

    PubMed  CAS  Google Scholar 

  109. Maier, W., Minges, J., Eckstein, N., Brodski, C., Albus, M., Lerer, B., et al. (1996) Genetic relationship between dopamine transporter gene and schizophrenia: linkage and association. Schizophr. Res. 20, 175–180.

    PubMed  CAS  Google Scholar 

  110. Gelernter, J., Vandenbergh, D., Kruger, S. D., Pauls, D. L., Kurlan, R., Pakstis, A. J., et al. (1995) The dopamine transporter protein gene (SLC6A3): primary linkage mapping and linkage studies in Tourette syndrome. Genomics 30, 459–463.

    PubMed  CAS  Google Scholar 

  111. Comings, D. E., Wu, S., Chiu, C., Ring, R. H., Gade, R., Ahn, C., et al. (1996) Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: the additive and subtractive effect of the three dopaminergic genes—DRD2, D beta H, and DATI. Am. J. Med. Genet. 67, 264–288.

    PubMed  CAS  Google Scholar 

  112. Hagan, J. J., Middlemiss, D. N., Sharpe, P. C., and Poste, G. H. (1997) Parkinson’s disease: prospects for improved drug therapy. Trends Pharmacol. Sci. 18, 156–163.

    PubMed  CAS  Google Scholar 

  113. Mercier, G., Turpin, J. C., and Lucotte, G. (1999) Variable number tandem repeat dopamine transporter gene polymorphism and Parkinson’s disease: no association found. J. Neurol. 246, 45–47.

    PubMed  CAS  Google Scholar 

  114. Le Couteur, D. G., Leighton, P. W., McCann, S. J., and Pond, S. (1997) Association of a polymorphism in the dopamine-transporter gene with Parkinson’s disease. Mov. Disord. 12, 760–763.

    PubMed  Google Scholar 

  115. Dix, D. J., Lin, P. N., McKenzie, A. R., Walden, W. E., and Theil, E. C. (1993) The influence of the base-paired flanking region on structure and function of the ferritin mRNA iron regulatory element. J. Mol. Biol. 231, 230–240.

    PubMed  CAS  Google Scholar 

  116. Kislauskis, E. H., Li, Z., Singer, R. H., and Taneja, K. L. (1993) Isoformspecific 3’-untranslated sequences sort alpha-cardiac and beta-cytoplasmic actin messenger RNAs to different cytoplasmic compartments [published erratum appears in J. Cell Biol. (1993) 123(6 Pt 2), following 1907]. J. Cell Biol. 123, 165–172.

    CAS  Google Scholar 

  117. Schiavi, S. C., Wellington, C. L., Shyu, A. B., Chen, C. Y., Greenberg, M. E., and Belasco, J. G. (1994) Multiple elements in the c-fos protein-coding region facilitate mRNA deadenylation and decay by a mechanism coupled to translation. J. Biol. Chem. 269, 3441–3448.

    PubMed  CAS  Google Scholar 

  118. Jacobsen, L. K., Staley, J. K., Zoghbi, S. S., Seibyl, J. P., Kosten, T. R., Innis, R. B., et al. (2000) Prediction of dopamine transporter binding availability by genotype: a preliminary report. Am. J. Psychiatry 157, 1700–1703.

    PubMed  CAS  Google Scholar 

  119. Laine, T. P., Ahonen, A., Torniainen, P., Heikkila, J., Pyhtinen, J., Rasanen, P., et al. (1999) Dopamine transporters increase in human brain after alcohol withdrawal. Mol. Psychiatry 4, 189–191.

    PubMed  CAS  Google Scholar 

  120. Martinez, D., Gelernter, J., Abi-Dargham, A., van Dyck, C. H., Kegeles, L., Innis, R. B., et al. (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.

    PubMed  CAS  Google Scholar 

  121. Ramamoorthy, S., Bauman, A. L., Moore, K. R., Han, H., Yang-Feng, T., Chang, A. S., et al. (1993) Antidepressant-and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc. Natl. Acad. Sci. USA 90, 2542–2546.

    PubMed  CAS  Google Scholar 

  122. Gelernter, J., Pakstis, A. J., and Kidd, K. K. (1995) Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17. Human Genet. 95, 677–680.

    CAS  Google Scholar 

  123. Lesch, K. P., Wolozin, B. L., Estler, H. C., Murphy, D. L., and Riederer, P. (1993) Isolation of a cDNA encoding the human brain serotonin transporter. J. Neural Transm. Gen. Sect. 91, 67–72.

    PubMed  CAS  Google Scholar 

  124. Austin, M. C., Bradley, C. C., Mann, J. J., and Blakely, R. D. (1994) Expression of serotonin transporter messenger RNA in the human brain. J. Neurochem. 62, 2362–2367.

    PubMed  CAS  Google Scholar 

  125. Lesch, K. P., Balling, U., Gross, J., Strauss, K., Wolozin, B. L., Murphy, D. L., et al. (1994) Organization of the human serotonin transporter gene. J. Neural Transm. Gen. Sect. 95, 157–162.

    PubMed  CAS  Google Scholar 

  126. Heils, A., Teufel, A., Petri, S., Seemann, M., Bengel, D., Balling, U., Riederer, P., et al. (1995) Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J. Neural Transm. Gen. Sect. 102, 247–254.

    PubMed  CAS  Google Scholar 

  127. Battersby, S., Ogilvie, A. D., Blackwood, D. H., Shen, S., Mugit, M. M., Muir, W. J., et al. (1999) Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3’ untranslated region of the human serotonin transporter gene. J. Neurochem. 72, 1384–1388.

    PubMed  CAS  Google Scholar 

  128. Bradley, C. C. and Blakely, R. D. (1997) Alternative splicing of the human serotonin transporter gene. J. Neurochem. 69, 1356–1367.

    PubMed  CAS  Google Scholar 

  129. Flattern, N. L. and Blakely, R. D. (2000) Modified structure of the human serotonin transporter promoter. Mol. Psychiatry 5, 110–115.

    Google Scholar 

  130. Lesch, K. P., Jatzke, S., Meyer, J., Stober, G., Okladnova, O., Mossner, R., et al. Mosaicism for a serotonin transporter gene promoter-associated deletion: decreased recombination in depression. J. Neural Transm. 106, 1223–1230.

    Google Scholar 

  131. Mortensen, O. V., Thomassen, M., Larsen, M. B., Whittemore, S. R., and Wiborg, O. (1999) Functional analysis of a novel human serotonin transporter gene promoter in immortalized raphe cells. Brain Res. Mol. Brain Res. 68, 141–148.

    PubMed  CAS  Google Scholar 

  132. Owens, M. J. and Nemeroff, C. B. (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin. Chem. 40, 288–295.

    PubMed  CAS  Google Scholar 

  133. Ernouf, D., Compagnon, P., Lothion, P., Narcisse, G., Benard, J. Y., and Daoust, M. (1993) Platelets 3H 5-HT uptake in descendants from alcoholic patients: a potential risk factor for alcohol dependence? Life Sci. 52, 989–995.

    PubMed  CAS  Google Scholar 

  134. Sellers, E. M., Higgins, G. A., and Sobell, M. B. (1992) 5-HT and alcohol abuse. Trends Pharmacol. Sci. 13, 69–75.

    Google Scholar 

  135. Coccaro, E. F., (1989) Central serotoni and impulsive aggression. Br. J. Psychiatry Suppl. 52–62.

    Google Scholar 

  136. Collier, D. A., Arranz, M. J., Sham, P., Battersby, S., Vallada, H., Gill, P., et al. (1996) The serotonin transporter is a potential susceptibility factor for bipolar affective disorder. Neuroreport 7, 1675–1679.

    PubMed  CAS  Google Scholar 

  137. Heils, A., Teufel, A., Petri, S., Stober, G., Riederer, P., Bengel, D., et al. (1996) Allelic variation of human serotonin transporter gene expression. J. Neurochem. 66, 2621–2624.

    PubMed  CAS  Google Scholar 

  138. Heils, A., Mossner, R., and Lesch, K. P. (1997) The human serotonin transporter gene polymorphism—basic research and clinical implications. J. Neural Transm. 104, 1005–1014.

    PubMed  CAS  Google Scholar 

  139. Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., et al. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531.

    PubMed  CAS  Google Scholar 

  140. Lesch, K. P., Wolozin, B. L., Murphy, D. L., and Reiderer, P. (1993) Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J. Neurochem. 60, 2319–2322.

    PubMed  CAS  Google Scholar 

  141. Meltzer, H. Y. and Arora, R. C. (1988) Genetic control of serotonin uptake in blood platelets: a twin study. Psychiatry Res. 24, 263–269.

    PubMed  CAS  Google Scholar 

  142. Greenberg, B. D., Tolliver, T. J., Huang, S. J., Li, Q., Bengel, D., and Murphy, D. L. (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am. J. Med. Genet. 88, 83–87.

    PubMed  CAS  Google Scholar 

  143. Willeit, M., Stastny, J., Pivker, W., Prascha-Kieder, N., Nevmeister, A., Asenbaum, S., et al. (2001) No evidence for in vivo regulation of mid-brain serotonin transporter availablility by serotonin transporter promoter gene polymorphism. Biol. Psychiatry 50, 8–12.

    PubMed  CAS  Google Scholar 

  144. Delbruck, S. J., Wendel, B., Grunewald, I., Sander, T., Morris-Rosendahl, D., Crocq, M. A., et al. (1997) A novel allelic variant of the human serotonin transporter gene regulatory polymorphism. Cytogenet. Cell Genet. 79, 214–220.

    PubMed  CAS  Google Scholar 

  145. Gelernter, J., Kranzler, H., and Cubells, J. F. (1997) Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African-and European-American and Japanese populations and in alcohol-dependent subjects. Human Genet. 101, 243–246.

    CAS  Google Scholar 

  146. Gelernter, J., Cubells, J. F., Kidd, J. R., Pakstis, A. J., and Kidd, K. K. (1999) Population studies of polymorphisms of the serotonin transporter protein gene. Am. J. Med. Genet. 88, 61–66.

    PubMed  CAS  Google Scholar 

  147. Kunugi, H., Hattori, M., Kato, T., Tatsumi, M., Sakai, T., Sasaki, T., et al. (1997) Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol. Psychiatry 2, 457–462.

    PubMed  CAS  Google Scholar 

  148. Michaelovsky, E., Frisch, A., Rockah, R., Peleg, L., Magal, N., Shohat, M., et al. (1999) A novel allele in the promoter region of the human serotonin transporter gene. Mol. Psychiatry 4, 97–99.

    PubMed  CAS  Google Scholar 

  149. Nakamura, M., Ueno, S., Sano, A., and Tanabe, H. (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol. Psychiatry 5, 32–38.

    PubMed  CAS  Google Scholar 

  150. MacKenzie A. and Quinn, J. (1999) A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc. Natl. Acad. Sci. USA 96, 15,251–15, 255.

    Google Scholar 

  151. Fiskerstrand, C. E., Lovejoy, E. A., and Quinn, J. P. (1999) An intronic polymorphic domain often associated with susceptibility to affective disorders has allele dependent differential enhancer activity in embryonic stem cells. FEBS Lett. 458, 171–174.

    PubMed  CAS  Google Scholar 

  152. Gelernter, J. and Freimer, M. (1994) PstI RFLP at the SERT locus. Human Mol. Genet. 3, 383.

    CAS  Google Scholar 

  153. Lesch, K. P., Gross, J., Franzek, E., Wolozin, B. L., Riederer, P., and Murphy, D. L. (1995) Primary structure of the serotonin transporter in unipolar depression and bipolar disorder. Biol. Psychiatry 37, 215–223.

    PubMed  CAS  Google Scholar 

  154. Glatt, C. E., DeYoung, J. A., Delgado, S., Service, S. K., Giacomini, K. M., Edwards, R. H., et al. (2001) Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes. Nature Genet. 27, 435–438.

    PubMed  CAS  Google Scholar 

  155. Nakamura, T., Muramatsu, T., Ono, Y., Matsushita, S., Higuchi, S., Mizushima, H., et al. (1997) Serotonin transporter gene regulatory region polymorphism and anxiety-related traits in the Japanese. Am. J. Med. Genet. 74, 544–545.

    PubMed  CAS  Google Scholar 

  156. Ball, D., Hill, L., Freeman, B., Eley, T. C., Strelau, J., Riemann, R., et al. (1997) The serotonin transporter gene and peer-rated neuroticism. Neuroreport 8, 1301–1304.

    PubMed  CAS  Google Scholar 

  157. Deary, I. J., Battersby, S., Whiteman, M. C., Connor, J. M., Fowkes, F. G., and Harmar, A. (1999) Neuroticism and polymorphisms in the serotonin transporter gene. Psychol. Med. 29, 735–739.

    PubMed  CAS  Google Scholar 

  158. Ebstein, R. P., Gritsenko, I., Nemanov, L., Frisch, A., Osher, Y., and Belmaker, R. H. (1997) No association between the serotonin transporter gene regulatory region polymorphism and the Tridimensional Personality Questionnaire (TPQ) temperament of harm avoidance. Mol. Psychiatry 2, 224–226.

    PubMed  CAS  Google Scholar 

  159. Jorm, A. F., Henderson, A. S., Jacomb, P. A., Christensen, H., Korten, A. E., Rodgers, B., Tan, X., (1998) An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms. Mol. Psychiatry 3, 449–451.

    PubMed  CAS  Google Scholar 

  160. Flory, J. D., Manuck, S. B., Ferrell, R. E., Dent, K. M., Peters, D. G., and Muldoon, M. F. (1999) Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism. Mol. Psychiatry 4, 93–96.

    PubMed  CAS  Google Scholar 

  161. Osher, Y., Hamer, D., and Benjamin, J. (2000) Association and linkage of anxiety-related traits with a functional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling pairs. Mol. Psychiatry 5, 216–219.

    PubMed  CAS  Google Scholar 

  162. Benjamin, J., Osher, Y., Lichtenberg, P., Bachner-Melman, R., Gritsenko, I., Kotler, M., et al. (2000) An interaction between the catechol Omethyltransferase and serotonin transporter promoter region polymorphisms contributes to tridimensional personality questionnaire persistence scores in normal subjects. Neuropsychobiology 41, 48–53.

    PubMed  CAS  Google Scholar 

  163. Hu, S., Brody, C. L., Fisher, C., Gunzerath, L., Nelson, M. L., Sabol, S. Z., Sirota, L. A., et al. (2000) Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior. Mol. Psychiatry 5, 181–188.

    PubMed  CAS  Google Scholar 

  164. Lerman, C., Caporaso, N. E., Audrain, J., Main, D., Boyd, N. R., and Shields, P. G. (2000) Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence. Mol. Psychiatry 5, 189–192.

    PubMed  CAS  Google Scholar 

  165. Greenberg, B. D., Li, Q., Lucas, F. R., Hu, S., Sirota, L. A., Benjamin, J., et al. (2000) Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am. J. Med. Genet. 96, 202–216.

    PubMed  CAS  Google Scholar 

  166. Harmar, A. J., Ogilvie, A. D., Battersby, S., Smith, C. A., Blackwood, D. H., Muir, W. J., et al. (1996) The serotonin transporter gene and affective disorder. Cold Spring Harb. Symp. Quant. Biol. 61, 791–795.

    PubMed  CAS  Google Scholar 

  167. Ogilvie, A. D., Battersby, S., Bubb, V. J., Fink, G., Harmar, A. J., Goodwim, G. M., et al. (1996) Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 347, 731–733.

    PubMed  CAS  Google Scholar 

  168. Stöber, G., Heils, A., and Lesch, K. P. (1996) Serotonin transporter gene polymorphism and affective disorder. Lancet 347, 1340–1341.

    PubMed  Google Scholar 

  169. Furlong, R. A., Ho, L., Walsh, C., Rubinsztein, J. S., Jain, S., Paykel, E. S., et al. (1998) Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders. Am. J. Med. Genet. 81, 58–63.

    PubMed  CAS  Google Scholar 

  170. Hoehe, M. R., Wendel, B., Grunewald, I., Chiaroni, P., Levy, N., MorrisRosendahl, D., et al. (1998) Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders. Am. J. Med. Genet. 81, 1–3.

    PubMed  CAS  Google Scholar 

  171. Saleem, Q., Ganesh, S., Vijaykumar, M., Reddy, Y. C., Brahmachari, S. K., et al. (2000) Association analysis of 5HT transporter gene in bipolar disorder in the Indian population. Am. J. Med. Genet. 96, 170–172.

    PubMed  CAS  Google Scholar 

  172. Esterling, L. E., Yoshikawa, T., Turner, G., Badner, J. A., Bengel, D., Gershon, E. S., et al. (1998) Serotonin transporter (5-HTT) gene and bipolar affective disorder. Am. J. Med. Genet. 81, 37–40.

    PubMed  CAS  Google Scholar 

  173. Mundo, E., Walker, M., Tims, H., Macciardi, F., and Kennedy, J. L. (2000) Lack of linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and bipolar disorder. Am. J. Med. Genet. 96, 379–383.

    PubMed  CAS  Google Scholar 

  174. Mynett-Johnson, L., Kealey, C., Claffey, E., Curtis, D., Bouchier-Hayes, L., Powell, C., et al. (2000) Multimarkerhaplotypes within the serotonin transporter gene suggest evidence of an association with bipolar disorder. Am. J. Med. Genet. 96, 845–849.

    PubMed  CAS  Google Scholar 

  175. Collier, D. A., Stober, G., Li, T., Heils, A., Catalano, M., Di Bella, D., et al. (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol. Psychiatry 1, 453–460.

    PubMed  CAS  Google Scholar 

  176. Gutierrez, B., Pintor, L., Gasto, C., Rosa, A., Bertranpetit, J., Vieta, E., and Fananas, L. (1998) Variability in the serotonin transporter gene and increased risk for major depression with melancholia. Human Genet. 103, 319–322.

    CAS  Google Scholar 

  177. Rosenthal, N. E., Mazzanti, C. M., Barnett, R. L., Hardin, T. A., Turner, E. H., Lam, G. K., et al. (1998) Role of serotonin transporter promoter repeat length polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder. Mol. Psychiatry 3, 175–177.

    PubMed  CAS  Google Scholar 

  178. Frisch, A., Postilnick, D., Rockah, R., Michaelovsky, E., Postilnick, S., Birman, E., et al. (1999) Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways. Mol. Psychiatry 4, 389–392.

    PubMed  CAS  Google Scholar 

  179. Minov, C., Baghai, T. C., Schule, C., Zwanzger, P., Schwarz, M. J., Zill, P., et al. (2001) Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression. Neurosci. Lett. 303, 119–122.

    PubMed  CAS  Google Scholar 

  180. Seretti, A., Cusin, C., Lattuada, E., Di Bella, D., Catalano, M., and Smeraldi, E. (1999) Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. Mol. Psychiatry 4, 280–283.

    PubMed  CAS  Google Scholar 

  181. Smeraldi, E., Zanardi, R., Benedetti, F., Di Bella, D., Perez, J., and Catalano, M. (1998) Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry 3, 508–511.

    PubMed  CAS  Google Scholar 

  182. Zanardi, R., Benedetti, F., Di Bella, D., Catalano, M., and Smeraldi, E. (2000) Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J. Clin. Psychopharmacol. 20, 105–107.

    PubMed  CAS  Google Scholar 

  183. Zanardi, R., Serretti, A., Rossini, D., Franchini, L., Cusin, C., Lattuada, E., et al. (2001) Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-httlpr in delusional and nondelusional depression. Biol. Psychiatry 50, 323–330.

    PubMed  CAS  Google Scholar 

  184. Pollock, B. G., Ferrell, R. E., Mulsant, B. H., Mazumdar, S., Miller, M., Sweet, R. A., et al. (2000) Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23, 587–590.

    PubMed  CAS  Google Scholar 

  185. Gorwood, P., Batel, P., Ades, J., Hamon, M., and Boni, C. (2000) Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior. Biol. Psychiatry 48, 259–264.

    PubMed  CAS  Google Scholar 

  186. Mann, J. J., Huang, Y. Y., Underwood, M. D., Kassir, S. A., Oppenheim, S., et al. (2000) A serotonin transporter gene promoter polymorphism (5HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch. Gen. Psychiatry 57, 729–738.

    PubMed  CAS  Google Scholar 

  187. Russ, M. J., Lachman, H. M., Kashdan, T., Saito, T., and BajmakovicKacila, S. (2000) Analysis of catechol-O-methyltransferase and 5-hydroxytryptamine transporter polymorphisms in patients at risk for suicide. Psychiatry Res. 93, 73–78.

    PubMed  CAS  Google Scholar 

  188. Fitch, D., Lesage, A., Seguin, M., Trousignant, M., Bankelfat, C., Rouleau, G. A., et al. (2001) Suicide and the serotonin transporter gene. Mol. Psychiatry 6, 127–128.

    PubMed  CAS  Google Scholar 

  189. Evans, J., Battersby, S., Ogilvie, A. D., Smith, C. A., Harmar, A. J., Nutt, D. J., and Goodwin, G. M. (1997) Association of short alleles of a VNTR of the serotonin transporter gene with anxiety symptoms in patients presenting after deliberate self harm. Neuropharmacology 36, 439–443.

    PubMed  CAS  Google Scholar 

  190. Hammoumi, S., Payen, A., Favre, J. D., Balmes, J. L., Benard, J. Y., Husson, M., et al. (1999) Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence? Alcohol 17, 107–112.

    PubMed  CAS  Google Scholar 

  191. Matsushita, S., Yoshino, A., Murayama, M., Kimura, M., Muramatsu, T., and Higuchi, S. (2001) Association study of serotonin transporter gene regulatory region polymorphism and alcoholism. Am. J. Med. Genet. 105, 446–450.

    PubMed  CAS  Google Scholar 

  192. Sander, T., Harms, H., Lesch, K. P., Dufeu, P., Kuhn, S., Hoehe, M., et al. (1997) Association analysis of a regulatory variation of the serotonin transporter gene with severe alcohol dependence. Alcohol Clin. Exp. Res. 21, 1356–1359.

    PubMed  CAS  Google Scholar 

  193. Thompson, M. D., Gonzalez, N., Nguyen, T., Comings, D. E., George, S. R., and BF, O. D. (2000) Serotonin transporter gene polymorphisms in alcohol dependence. Alcohol 22, 61–67.

    PubMed  CAS  Google Scholar 

  194. Turker, T., Sodmann, R., Goebel, U., Jatzke, S., Knapp, M., Lesch, K. P., et al. (1998) High ethanol tolerance in young adults is associated with the low-activity variant of the promoter of the human serotonin transporter gene. Neurosci. Lett. 248, 147–150.

    PubMed  CAS  Google Scholar 

  195. Schuckit, M. A., Mazzanti, C., Smith, T. L., Ahmed, U., Radel, M., Iwata, N., et al. (1999) Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study. Biol. Psychiatry 45, 647–651.

    PubMed  CAS  Google Scholar 

  196. Little, K. Y., McLaughlin, D. P., Zhang, L., Livermore, C. S., Dalack, G. W., McFinton, P. R., et al. (1998) Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. Am. J. Psychiatry 155, 207–213.

    PubMed  CAS  Google Scholar 

  197. Heinz, A., Jones, D. W., Mazzanti, C., Goldman, D., Ragan, P., Hommer, D., et al. (2000) A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol. Psychiatry 47, 643–649.

    PubMed  CAS  Google Scholar 

  198. Cloninger, C. R. (1987) Neurogenetic adaptive mechanisms in alcoholism. Science 236, 410–416.

    PubMed  CAS  Google Scholar 

  199. Sander, T., Harms, H, Dufeu, P., Kuhn, S., Hoehe, M., Lesch, K. P., et al. (1998) Serotonin transporter gene variants in alcohol-dependent subjects with dissocial personality disorder. Biol. Psychiatry 43, 908–912.

    PubMed  CAS  Google Scholar 

  200. Hallikainen, T., Saito, T., Lachman, H. M., Volavka, J., Pohjalainen, T., Ryynanen, O. P., et al. (1999) Association between low activity serotonin transporter promoter genotype and early onset alcoholism with habitual impulsive violent behavior. Mol. Psychiatry 4, 385–388.

    PubMed  CAS  Google Scholar 

  201. Preuss, U. W., Soyka, M., Bahlmann, M., Wenzel, K., Behrens, S., de Jonge, S., et al. (2000) Serotonin transporter gene regulatory region polymorphism (5-HTTLPR), l3H]paroxetine binding in healthy control subjects and alcohol-dependent patients and their relationships to impulsivity. Psychiatry Res. 96, 51–61.

    PubMed  CAS  Google Scholar 

  202. Bondy, B., Erfurth, A., de Jonge, S., Kruger, M., and Meyer, H. (2000) Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide. Mol. Psychiatry 5, 193–195.

    PubMed  CAS  Google Scholar 

  203. Courtet, P., Baud, P., Abbar, M., Boulenger, J. P., Castelnau, D., Mouthon, D., et al. (2001) Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene. Mol. Psychiatry 6, 338–341.

    PubMed  CAS  Google Scholar 

  204. Mendes de Oliveira, J. R., Otto, P. A., Vallada, H., Lauriano, V., Elkis, H., Lafer, B., et al. (1998) Analysis of a novel functional polymorphism within the promoter region of the serotonin transporter gene (5-HTT) in Brazilian patients affected by bipolar disorder and schizophrenia. Am. J. Med. Genet. 81, 225–227.

    Google Scholar 

  205. Serretti, A., Catalano, M., and Smeraldi, E. (1999) Serotonin transporter gene is not associated with symptomatology of schizophrenia. Schizophr. Res. 35, 33–39.

    PubMed  CAS  Google Scholar 

  206. Tsai, S. J., Hong, C. J., Yu, Y. W., Lin, C. H., Song, H. L., Lai, H. C., et al. (2000) Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Schizophr. Res. 44, 177–181.

    PubMed  CAS  Google Scholar 

  207. Malhotra, A. K., Goldman, D., Mazzanti, C., Clifton, A., Breier, A., and Pickar, D. (1998) A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics. Mol. Psychiatry 3, 328–332.

    PubMed  CAS  Google Scholar 

  208. Hranilovic, D., Schwab, S. G., Jernej, B., Knapp, M., Lerer, B., Albus, M., et al. (2000) Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings. Mol. Psychiatry 5, 91–95.

    PubMed  CAS  Google Scholar 

  209. Bonnet-Brilhault, F., Laurent, C., Thibaut, F., Campion, D., Chavand, O., Samolyk, D., et al. (1997) Serotonin transporter gene polymorphism and schizophrenia: an association study. Biol. Psychiatry 42, 634–636.

    PubMed  CAS  Google Scholar 

  210. Bengel, D., Greenberg, B. D., Cora-Locatelli, G., Altemus, M., Heils, A., Li, Q., and Murphy, D. L. (1999) Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder. Mol. Psychiatry 4, 463–466.

    PubMed  CAS  Google Scholar 

  211. McDougle, C. J., Epperson, C. N., Price, L. H., and Gelernter, J. (1998) Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Mol. Psychiatry 3, 270–273.

    PubMed  CAS  Google Scholar 

  212. Billett, E. A., Richter, M. A., King, N., Heils, A., Lesch, K. P., and Kennedy, J. L. (1997) Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene. Mol. Psychiatry 2, 403–406.

    PubMed  CAS  Google Scholar 

  213. Hanna, G. L., Himle, J. A., Curtis, G. C., Koram, D. Q., VeenstraVanderWeele, J., Leventhal, B. L., et al. (1998) Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder. Neuropsychopharmacology 18, 102–111.

    PubMed  CAS  Google Scholar 

  214. Altemus, M., Murphy, D. L., Greenberg, B., and Lesch, K. P. (1996) Intact coding region of the serotonin transporter gene in obsessive-compulsive disorder. Am. J. Med. Genet. 67, 409–411.

    PubMed  CAS  Google Scholar 

  215. Hanna, G. L., Veenstra-Vander Weele, J., Cox, N. J., Boehnke, M., Himle, J. A., Curtis, G. C., et al. (1999) Genome scan of early-onset obsessive-compulsive disorder. Annual Meeting of the American Academy of Child and Adolescent Psychiatry.

    Google Scholar 

  216. Anderson, G. M., Freedman, D. X., Cohen, D. J., Volkmar, F. R., Hoder, E. L., McPhedran, P., Minderaa, R. B., et al. (1987) Whole blood serotonin in autistic and normal subjects. J. Child Psychol. Psychiatry 28, 885–900.

    PubMed  CAS  Google Scholar 

  217. Cook, Jr., E. H., Courchesne, R., Lord, C., Cox, N. J., Yan, S., Lincoln, A., et al. (1997) Evidence of linkage between the serotonin transporter and autistic disorder. Mol. Psychiatry 2, 247–250.

    PubMed  Google Scholar 

  218. Klauck, S. M., Poustka, F., Benner, A., Lesch, K. P., and Poustka, A. (1997) Serotonin transporter (5-HTT) gene variants associated with autism? Human Mol. Genet. 6, 2233–2238.

    CAS  Google Scholar 

  219. Yirmiya, N., Pilowsky, T., Nemanov, L., Arbelle, S., Feinsilver, T., Fried, I., et al. (2001) Evidence for an association with the serotonin transporter promoter region polymorphism and autism. Am. J. Med. Genet. 105, 381–386.

    PubMed  CAS  Google Scholar 

  220. Tordjman, S., Gutknecht, L., Carlier, M., Spitz, E., Antoine, C., Slama, F., et al. (2001) Role of the serotonin transporter gene in the behavioral expression of autism. Mol. Psychiatry 6, 434–439.

    PubMed  CAS  Google Scholar 

  221. M. G. S. o. A. C. (IMGSAC) (2001) A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am. J. Hum. Genet. 69, 570–581.

    Google Scholar 

  222. Zhong, N., Ye, L., Ju, W., Brown, W. T., Tsiouris, J., and Cohen, I. (1999) 5-HTTLPR variants not associated with autistic spectrum disorders. Neurogenetics 2, 129–131.

    Google Scholar 

  223. Hu, M., Retz, W., Baader, M., Pesold, B., Adler, G., Henn, F. A., et al. (2000) Promoter polymorphism of the 5-HT transporter and Alzheimer’s disease. Neurosci. Lett. 294, 63–65.

    PubMed  CAS  Google Scholar 

  224. Oliveira, J. R., Gallindo, R. M., Maia, L. G., Brito-Marques, P. R., Otto, P. A., Passos-Bueno, M. R., Morais, Jr., M. A., et al. (1998) The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer’s disease. Mol. Psychiatry 3, 438–441.

    PubMed  CAS  Google Scholar 

  225. Zill, P., Padberg, F., de Jonge, S., Hampel, H., Burger, K., Stubner, S., et al. (2000) Serotonin transporter (5-HTT) gene polymorphism in psychogeriatric patients. Neurosci. Lett. 284, 113–115.

    PubMed  CAS  Google Scholar 

  226. Matsushita, S., Muramatsu, T., Kimura, M., Shirakawa, O., Mita, T., Nakai, T., et al. (1997) Serotonin transporter gene regulatory region polymorphism and panic disorder. Mol. Psychiatry 2, 390–392.

    PubMed  CAS  Google Scholar 

  227. Hinney, A., Barth, N., Ziegler, A., von Prittwitz, S., Hamann, A., Hennighausen, K., et al. (1997) Serotonin transporter gene-linked polymorphic region: allele distributions in relationship to body weight and in anorexia nervosa. Life Sci. 61, PL 295–303.

    Google Scholar 

  228. Sundaramurthy, D., Pieri, L. F., Gape, H., Markham, A. F., and Campbell, D. A. (2000) Analysis of the serotonin transporter gene linked polymorphism (5-HTTLPR) in anorexia nervosa. Am. J. Med. Genet. 96, 53–55.

    PubMed  CAS  Google Scholar 

  229. Di Bella, D. D., Catalano, M., Cavallini, M. C., Riboldi, C., and Bellodi, L. (2000) Serotonin transporter linked polymorphic region in anorexia nervosa and bulimia nervosa [letter]. Mol. Psychiatry 5, 233–234.

    PubMed  Google Scholar 

  230. Biederman, J. and Spencer, T. (1999) Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol. Psychiatry 46, 1234–1242.

    PubMed  CAS  Google Scholar 

  231. Wade, P. R., Chen, J., Jaffe, B., Kassem, I. S., Blakely, R. D., and Gershon, M. D. (1996) Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J. Neurosci. 16, 2352–2364.

    PubMed  CAS  Google Scholar 

  232. Wade, P. R., Tamir, H., Kirchgessner, A. L., and Gershon, M. D. (1994) Analysis of the role of 5-HT in the enteric nervous system using antiidiotopic antibodies to 5-HT receptors. Am. J. Physiol. 266, G403 - G416.

    PubMed  CAS  Google Scholar 

  233. O’Malley, P. G., Wong, P. W., Kroenke, K., Roy, M. J., and Wong, R. K. (1998) The value of screening for psychiatric disorders prior to upper endoscopy. J. Psychosom. Res. 44, 279–287.

    PubMed  Google Scholar 

Download references

Authors
  1. Maureen K. Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Randy D. Blakely
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, Peoria, IL, USA

    Maarten E. A. Reith

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Springer Science+Business Media New York

About this chapter

Cite this chapter

Hahn, M.K., Blakely, R.D. (2002). Gene Organization and Polymorphisms of Monoamine Transporters. In: Reith, M.E.A. (eds) Neurotransmitter Transporters. Contemporary Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-158-9_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-158-9_4

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-267-4

  • Online ISBN: 978-1-59259-158-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation