Cellular and Molecular Life Sciences

, Volume 67, Issue 12, pp 1971–1986 | Cite as

The dopamine D4 receptor: biochemical and signalling properties

  • Pieter Rondou
  • Guy Haegeman
  • Kathleen Van CraenenbroeckEmail author


Dopamine is an important neurotransmitter that regulates several key functions in the brain, such as motor output, motivation and reward, learning and memory, and endocrine regulation. Dopamine does not mediate fast synaptic transmission, but rather modulates it by triggering slow-acting effects through the activation of dopamine receptors, which belong to the G-protein-coupled receptor superfamily. Besides activating different effectors through G-protein coupling, dopamine receptors also signal through interaction with a variety of proteins, collectively termed dopamine receptor-interacting proteins. We focus on the dopamine D4 receptor, which contains an important polymorphism in its third intracellular loop. This polymorphism has been the subject of numerous studies investigating links with several brain disorders, such as attention-deficit hyperactivity disorder and schizophrenia. We provide an overview of the structure, signalling properties and regulation of dopamine D4 receptors, and briefly discuss their physiological and pathophysiological role in the brain.


GPCR Dopamine D4 receptor Variable number of tandem repeats (VNTR) Dimerization Internalization Dopamine receptor-interacting protein (DRIP) Attention-deficit hyperactivity disorder (ADHD) 



The dopamine D4 receptor work was financially supported by FWO (Fonds voor Wetenschappelijk Onderzoek) Vlaanderen (project no. G010909N). Kathleen Van Craenenbroeck has a post-doctoral FWO fellowship.


  1. 1.
    Iversen SD, Iversen LL (2007) Dopamine: 50 years in perspective. Trends Neurosci 30:188–193PubMedCrossRefGoogle Scholar
  2. 2.
    Olanow CW, Lees A, Obeso J (2008) Levodopa therapy for Parkinson’s disease: challenges and future prospects. Mov Disord 23(Suppl 3):S495–S496PubMedCrossRefGoogle Scholar
  3. 3.
    Girault JA, Greengard P (2004) The neurobiology of dopamine signaling. Arch Neurol 61:641–644PubMedCrossRefGoogle Scholar
  4. 4.
    Barnes TD, Kubota Y, Hu D, Jin DZ, Graybiel AM (2005) Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories. Nature 437:1158–1161PubMedCrossRefGoogle Scholar
  5. 5.
    Dobrossy MD, Dunnett SB (2001) The influence of environment and experience on neural grafts. Nat Rev Neurosci 2:871–879PubMedCrossRefGoogle Scholar
  6. 6.
    Faure A, Haberland U, Conde F, El Massioui N (2005) Lesion to the nigrostriatal dopamine system disrupts stimulus-response habit formation. J Neurosci 25:2771–2780PubMedCrossRefGoogle Scholar
  7. 7.
    Rosenkranz JA, Grace AA (2002) Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning. Nature 417:282–287PubMedCrossRefGoogle Scholar
  8. 8.
    Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–184PubMedCrossRefGoogle Scholar
  9. 9.
    Wise RA (1996) Neurobiology of addiction. Curr Opin Neurobiol 6:243–251PubMedCrossRefGoogle Scholar
  10. 10.
    Sawaguchi T, Goldmanrakic PS (1991) D1 dopamine-receptors in prefrontal cortex – involvement in working memory. Science 251:947–950PubMedCrossRefGoogle Scholar
  11. 11.
    Sawaguchi T, Goldmanrakic PS (1994) The role of D1-dopamine receptor in working-memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus-monkeys performing an oculomotor delayed-response task. J Neurophysiol 71:515–528PubMedGoogle Scholar
  12. 12.
    Wilkerson A, Levin ED (1999) Ventral hippocampal dopamine D-1 and D-2 systems and spatial working memory in rats. Neuroscience 89:743–749PubMedCrossRefGoogle Scholar
  13. 13.
    Williams GV, Goldmanrakic PS (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575PubMedCrossRefGoogle Scholar
  14. 14.
    Li D, Sham PC, Owen MJ, He L (2006) Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 15:2276–2284PubMedCrossRefGoogle Scholar
  15. 15.
    Kebabian JW, Greengard P (1971) Dopamine-sensitive adenyl cyclase: possible role in synaptic transmission. Science 174:1346–1349PubMedCrossRefGoogle Scholar
  16. 16.
    Bunzow JR, Van Tol HH, Grandy DK, Albert P, Salon J, Christie M, Machida CA, Neve KA, Civelli O (1988) Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 336:783–787PubMedCrossRefGoogle Scholar
  17. 17.
    Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614PubMedCrossRefGoogle Scholar
  18. 18.
    Oak JN, Oldenhof J, Van Tol HH (2000) The dopamine D(4) receptor: one decade of research. Eur J Pharmacol 405:303–327PubMedCrossRefGoogle Scholar
  19. 19.
    Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V (1992) Multiple dopamine D4 receptor variants in the human population. Nature 358:149–152PubMedCrossRefGoogle Scholar
  20. 20.
    Kamakura S, Iwaki A, Matsumoto M, Fukumaki Y (1997) Cloning and characterization of the 5′-flanking region of the human dopamine D4 receptor gene. Biochem Biophys Res Commun 235:321–326PubMedCrossRefGoogle Scholar
  21. 21.
    Ding YC, Chi HC, Grady DL, Morishima A, Kidd JR, Kidd KK, Flodman P, Spence MA, Schuck S, Swanson JM, Zhang YP, Moyzis RK (2002) Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc Natl Acad Sci USA 99:309–314PubMedCrossRefGoogle Scholar
  22. 22.
    Asghari V, Schoots O, van Kats S, Ohara K, Jovanovic V, Guan HC, Bunzow JR, Petronis A, Van Tol HH (1994) Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes. Mol Pharmacol 46:364–373PubMedGoogle Scholar
  23. 23.
    Lichter JB, Barr CL, Kennedy JL, Van Tol HH, Kidd KK, Livak KJ (1993) A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum Mol Genet 2:767–773PubMedCrossRefGoogle Scholar
  24. 24.
    Livak KJ, Rogers J, Lichter JB (1995) Variability of dopamine D4 receptor (DRD4) gene sequence within and among nonhuman primate species. Proc Natl Acad Sci USA 92:427–431PubMedCrossRefGoogle Scholar
  25. 25.
    Chang FM, Kidd JR, Livak KJ, Pakstis AJ, Kidd KK (1996) The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Hum Genet 98:91–101PubMedCrossRefGoogle Scholar
  26. 26.
    Civelli O, Bunzow JR, Grandy DK (1993) Molecular diversity of the dopamine receptors. Annu Rev Pharmacol Toxicol 33:281–307PubMedCrossRefGoogle Scholar
  27. 27.
    Lanau F, Brockhaus M, Pink JR, Franchet C, Wildt-Perinic D, Goepfert C, Probst A, Hartman DS (1997) Development and characterization of antibodies against the N terminus of the human dopamine D4 receptor. J Neurochem 69:2169–2178PubMedGoogle Scholar
  28. 28.
    Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225PubMedGoogle Scholar
  29. 29.
    Van Craenenbroeck K, Clark SD, Cox MJ, Oak JN, Liu F, Van Tol HH (2005) Folding efficiency is rate-limiting in dopamine D4 receptor biogenesis. J Biol Chem 280:19350–19357PubMedCrossRefGoogle Scholar
  30. 30.
    O’Dowd BF, Hnatowich M, Caron MG, Lefkowitz RJ, Bouvier M (1989) Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor. J Biol Chem 264:7564–7569PubMedGoogle Scholar
  31. 31.
    Ovchinnikov YuA, Abdulaev NG, Bogachuk AS (1988) Two adjacent cysteine residues in the C-terminal cytoplasmic fragment of bovine rhodopsin are palmitylated. FEBS Lett 230:1–5PubMedCrossRefGoogle Scholar
  32. 32.
    Grunewald S, Haase W, Reilander H, Michel H (1996) Glycosylation, palmitoylation, and localization of the human D2S receptor in baculovirus-infected insect cells. Biochemistry 35:15149–15161PubMedCrossRefGoogle Scholar
  33. 33.
    Ng GY, O’Dowd BF, Caron M, Dennis M, Brann MR, George SR (1994) Phosphorylation and palmitoylation of the human D2L dopamine receptor in Sf9 cells. J Neurochem 63:1589–1595PubMedCrossRefGoogle Scholar
  34. 34.
    Dohlman HG, Caron MG, DeBlasi A, Frielle T, Lefkowitz RJ (1990) Role of extracellular disulfide-bonded cysteines in the ligand binding function of the beta 2-adrenergic receptor. Biochemistry 29:2335–2342PubMedCrossRefGoogle Scholar
  35. 35.
    Hwa J, Garriga P, Liu X, Khorana HG (1997) Structure and function in rhodopsin: packing of the helices in the transmembrane domain and folding to a tertiary structure in the intradiscal domain are coupled. Proc Natl Acad Sci USA 94:10571–10576PubMedCrossRefGoogle Scholar
  36. 36.
    Pangalos MN, Davies CH (2002) Understanding G protein-coupled receptors and their role in the CNS. In: Molecular and cellular neurobiology. Oxford University Press, LondonGoogle Scholar
  37. 37.
    Helmreich EJ, Hofmann KP (1996) Structure and function of proteins in G-protein-coupled signal transfer. Biochim Biophys Acta 1286:285–322PubMedGoogle Scholar
  38. 38.
    Sidhu A, Niznik HB (2000) Coupling of dopamine receptor subtypes to multiple and diverse G proteins. Int J Dev Neurosci 18:669–677PubMedCrossRefGoogle Scholar
  39. 39.
    Lane JR, Powney B, Wise A, Rees S, Milligan G (2008) G protein coupling and ligand selectivity of the D2L and D3 dopamine receptors. J Pharmacol Exp Ther 325:319–330PubMedCrossRefGoogle Scholar
  40. 40.
    Herve D, Levi-Strauss M, Marey-Semper I, Verney C, Tassin JP, Glowinski J, Girault JA (1993) G(olf) and Gs in rat basal ganglia: possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase. J Neurosci 13:2237–2248PubMedGoogle Scholar
  41. 41.
    Neve KA, Seamans JK, Trantham-Davidson H (2004) Dopamine receptor signaling. J Recept Signal Transduct Res 24:165–205PubMedCrossRefGoogle Scholar
  42. 42.
    Kazmi MA, Snyder LA, Cypess AM, Graber SG, Sakmar TP (2000) Selective reconstitution of human D4 dopamine receptor variants with Gi alpha subtypes. Biochemistry 39:3734–3744PubMedCrossRefGoogle Scholar
  43. 43.
    Oldenhof J, Vickery R, Anafi M, Oak J, Ray A, Schoots O, Pawson T, von Zastrow M, Van Tol HH (1998) SH3 binding domains in the dopamine D4 receptor. Biochemistry 37:15726–15736PubMedCrossRefGoogle Scholar
  44. 44.
    Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH (1995) Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem 65:1157–1165PubMedCrossRefGoogle Scholar
  45. 45.
    Jovanovic V, Guan HC, Van Tol HH (1999) Comparative pharmacological and functional analysis of the human dopamine D4.2 and D4.10 receptor variants. Pharmacogenetics 9:561–568PubMedCrossRefGoogle Scholar
  46. 46.
    Hemmings HC, Greengard P, Tung HYL, Cohen P (1984) Darpp-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. Nature 310:503–505PubMedCrossRefGoogle Scholar
  47. 47.
    Le Novere N, Li L, Girault JA (2008) DARPP-32: molecular integration of phosphorylation potential. Cell Mol Life Sci 65:2125–2127PubMedCrossRefGoogle Scholar
  48. 48.
    Zhen X, Zhang J, Johnson GP, Friedman E (2001) D(4) dopamine receptor differentially regulates Akt/nuclear factor-kappa b and extracellular signal-regulated kinase pathways in D(4)MN9D cells. Mol Pharmacol 60:857–864PubMedGoogle Scholar
  49. 49.
    Sarkar C, Das S, Chakroborty D, Chowdhury UR, Basu B, Dasgupta PS, Basu S (2006) Cutting edge: stimulation of dopamine D4 receptors induce T cell quiescence by up-regulating Kruppel-like factor-2 expression through inhibition of ERK1/ERK2 phosphorylation. J Immunol 177:7525–7529PubMedGoogle Scholar
  50. 50.
    Bitner RS, Nikkel AL, Otte S, Martino B, Barlow EH, Bhatia P, Stewart AO, Brioni JD, Decker MW, Moreland RB (2006) Dopamine D4 receptor signaling in the rat paraventricular hypothalamic nucleus: evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase phosphorylation. Neuropharmacology 50:521–531PubMedCrossRefGoogle Scholar
  51. 51.
    Lavine N, Ethier N, Oak JN, Pei L, Liu F, Trieu P, Rebois RV, Bouvier M, Hebert TE, Van Tol HH (2002) G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels and adenylyl cyclase. J Biol Chem 277:46010–46019PubMedCrossRefGoogle Scholar
  52. 52.
    Pillai G, Brown NA, McAllister G, Milligan G, Seabrook GR (1998) Human D2 and D4 dopamine receptors couple through betagamma G-protein subunits to inwardly rectifying K+ channels (GIRK1) in a Xenopus oocyte expression system: selective antagonism by L-741,626 and L-745,870 respectively. Neuropharmacology 37:983–987PubMedCrossRefGoogle Scholar
  53. 53.
    Werner P, Hussy N, Buell G, Jones KA, North RA (1996) D2, D3, and D4 dopamine receptors couple to G protein-regulated potassium channels in Xenopus oocytes. Mol Pharmacol 49:656–661PubMedGoogle Scholar
  54. 54.
    Wedemeyer C, Goutman JD, Avale ME, Franchini LF, Rubinstein M, Calvo DJ (2007) Functional activation by central monoamines of human dopamine D(4) receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes. Eur J Pharmacol 562:165–173PubMedCrossRefGoogle Scholar
  55. 55.
    Liu LX, Burgess LH, Gonzalez AM, Sibley DR, Chiodo LA (1999) D2S, D2L, D3, and D4 dopamine receptors couple to a voltage-dependent potassium current in N18TG2 x mesencephalon hybrid cell (MES-23.5) via distinct G proteins. Synapse 31:108–118PubMedCrossRefGoogle Scholar
  56. 56.
    Wilke RA, Hsu SF, Jackson MB (1998) Dopamine D4 receptor mediated inhibition of potassium current in neurohypophysial nerve terminals. J Pharmacol Exp Ther 284:542–548PubMedGoogle Scholar
  57. 57.
    Piomelli D, Pilon C, Giros B, Sokoloff P, Martres MP, Schwartz JC (1991) Dopamine activation of the arachidonic acid cascade as a basis for D1/D2 receptor synergism. Nature 353:164–167PubMedCrossRefGoogle Scholar
  58. 58.
    Chio CL, Drong RF, Riley DT, Gill GS, Slightom JL, Huff RM (1994) D4 dopamine receptor-mediated signaling events determined in transfected Chinese hamster ovary cells. J Biol Chem 269:11813–11819PubMedGoogle Scholar
  59. 59.
    Felder CC, Campbell T, Albrecht F, Jose PA (1990) Dopamine inhibits Na(+)-H+ exchanger activity in renal BBMV by stimulation of adenylate cyclase. Am J Physiol 259:F297–F303PubMedGoogle Scholar
  60. 60.
    Coldwell MC, Boyfield I, Brown AM, Stemp G, Middlemiss DN (1999) Pharmacological characterization of extracellular acidification rate responses in human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells. Br J Pharmacol 127:1135–1144PubMedCrossRefGoogle Scholar
  61. 61.
    Lajiness ME, Chio CL, Huff RM (1993) D2 dopamine receptor stimulation of mitogenesis in transfected Chinese hamster ovary cells: relationship to dopamine stimulation of tyrosine phosphorylations. J Pharmacol Exp Ther 267:1573–1581PubMedGoogle Scholar
  62. 62.
    Narkar VA, Hussain T, Pedemonte C, Lokhandwala MF (2001) Dopamine D(2) receptor activation causes mitogenesis via p44/42 mitogen-activated protein kinase in opossum kidney cells. J Am Soc Nephrol 12:1844–1852PubMedGoogle Scholar
  63. 63.
    Oak JN, Lavine N, Van Tol HH (2001) Dopamine D(4) and D(2L) receptor stimulation of the mitogen-activated protein kinase pathway is dependent on trans-activation of the platelet-derived growth factor receptor. Mol Pharmacol 60:92–103PubMedGoogle Scholar
  64. 64.
    Wang C, Buck DC, Yang R, Macey TA, Neve KA (2005) Dopamine D2 receptor stimulation of mitogen-activated protein kinases mediated by cell type-dependent transactivation of receptor tyrosine kinases. J Neurochem 93:899–909PubMedCrossRefGoogle Scholar
  65. 65.
    Gill RS, Hsiung MS, Sum CS, Lavine N, Clark SD, Van Tol HH (2010) The dopamine D4 receptor activates intracellular platelet-derived growth factor receptor beta to stimulate ERK1/2. Cell Signal 22:285–290PubMedCrossRefGoogle Scholar
  66. 66.
    Kotecha SA, Oak JN, Jackson MF, Perez Y, Orser BA, Van Tol HH, MacDonald JF (2002) A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron 35:1111–1122PubMedCrossRefGoogle Scholar
  67. 67.
    Ferguson SS (2003) Receptor tyrosine kinase transactivation: fine-tuning synaptic transmission. Trends Neurosci 26:119–122PubMedCrossRefGoogle Scholar
  68. 68.
    Arnsten AF (2009) Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs 23(Suppl 1):33–41PubMedCrossRefGoogle Scholar
  69. 69.
    de Almeida J, Palacios JM, Mengod G (2008) Distribution of 5-HT and DA receptors in primate prefrontal cortex: implications for pathophysiology and treatment. Prog Brain Res 172:101–115PubMedCrossRefGoogle Scholar
  70. 70.
    Jung MW, Baeg EH, Kim MJ, Kim YB, Kim JJ (2008) Plasticity and memory in the prefrontal cortex. Rev Neurosci 19:29–46PubMedGoogle Scholar
  71. 71.
    Tallon-Baudry C, Bertrand O, Peronnet F, Pernier J (1998) Induced gamma-band activity during the delay of a visual short-term memory task in humans. J Neurosci 18:4244–4254PubMedGoogle Scholar
  72. 72.
    Yuen EY, Yan Z (2009) Dopamine D4 receptors regulate AMPA receptor trafficking and glutamatergic transmission in GABAergic interneurons of prefrontal cortex. J Neurosci 29:550–562PubMedCrossRefGoogle Scholar
  73. 73.
    Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74:1–58PubMedCrossRefGoogle Scholar
  74. 74.
    Mrzljak L, Bergson C, Pappy M, Huff R, Levenson R, Goldman-Rakic PS (1996) Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature 381:245–248PubMedCrossRefGoogle Scholar
  75. 75.
    Wang X, Zhong P, Yan Z (2002) Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex. J Neurosci 22:9185–9193PubMedGoogle Scholar
  76. 76.
    Graziane NM, Yuen EY, Yan Z (2009) Dopamine D4 receptors regulate GABAA receptor trafficking via an actin/cofilin/myosin-dependent mechanism. J Biol Chem 284:8329–8336PubMedCrossRefGoogle Scholar
  77. 77.
    Milligan G, White JH (2001) Protein-protein interactions at G-protein-coupled receptors. Trends Pharmacol Sci 22:513–518PubMedCrossRefGoogle Scholar
  78. 78.
    Bockaert J, Fagni L, Dumuis A, Marin P (2004) GPCR interacting proteins (GIP). Pharmacol Ther 103:203–221PubMedCrossRefGoogle Scholar
  79. 79.
    Hall RA, Lefkowitz RJ (2002) Regulation of G protein-coupled receptor signaling by scaffold proteins. Circ Res 91:672–680PubMedCrossRefGoogle Scholar
  80. 80.
    Sun Y, McGarrigle D, Huang XY (2007) When a G protein-coupled receptor does not couple to a G protein. Mol Biosyst 3:849–854PubMedCrossRefGoogle Scholar
  81. 81.
    Bergson C, Levenson R, Goldman-Rakic PS, Lidow MS (2003) Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling. Trends Pharmacol Sci 24:486–492PubMedCrossRefGoogle Scholar
  82. 82.
    Rondou P, Haegeman G, Vanhoenacker P, Van Craenenbroeck K (2008) BTB protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase. J Biol Chem 283:11083–11096PubMedCrossRefGoogle Scholar
  83. 83.
    Yao WD, Spealman RD, Zhang J (2008) Dopaminergic signaling in dendritic spines. Biochem Pharmacol 75:2055–2069PubMedCrossRefGoogle Scholar
  84. 84.
    Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG (2004) Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci 27:107–144PubMedCrossRefGoogle Scholar
  85. 85.
    Kim KM, Valenzano KJ, Robinson SR, Yao WD, Barak LS, Caron MG (2001) Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. J Biol Chem 276:37409–37414PubMedCrossRefGoogle Scholar
  86. 86.
    Macey TA, Gurevich VV, Neve KA (2004) Preferential Interaction between the dopamine D2 receptor and Arrestin2 in neostriatal neurons. Mol Pharmacol 66:1635–1642PubMedCrossRefGoogle Scholar
  87. 87.
    Vickery RG, von Zastrow M (1999) Distinct dynamin-dependent and -independent mechanisms target structurally homologous dopamine receptors to different endocytic membranes. J Cell Biol 144:31–43PubMedCrossRefGoogle Scholar
  88. 88.
    Spooren A, Rondou P, Debowska K, Lintermans B, Vermeulen L, Samyn B, Skieterska K, Debyser G, Devreese B, Vanhoenacker P, Wojda U, Haegeman G, Van Craenenbroeck K (2010) Resistance of the dopamine D4 receptor to agonist-induced internalization and degradation. Cell Signal 22:600–609PubMedCrossRefGoogle Scholar
  89. 89.
    Cho DI, Beom S, Van Tol HH, Caron MG, Kim KM (2006) Characterization of the desensitization properties of five dopamine receptor subtypes and alternatively spliced variants of dopamine D2 and D4 receptors. Biochem Biophys Res Commun 350:634–640PubMedCrossRefGoogle Scholar
  90. 90.
    Watts VJ, Vu MN, Wiens BL, Jovanovic V, Van Tol HH, Neve KA (1999) Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors. Psychopharmacology (Berl) 141:83–92CrossRefGoogle Scholar
  91. 91.
    Helmeste DM, Tang SW (2000) Dopamine D4 receptors. Jpn J Pharmacol 82:1–14PubMedCrossRefGoogle Scholar
  92. 92.
    Van Craenenbroeck K, Gellynck E, Lintermans B, Leysen JE, Van Tol HH, Haegeman G, Vanhoenacker P (2006) Influence of the antipsychotic drug pipamperone on the expression of the dopamine D4 receptor. Life Sci 80:74–81PubMedCrossRefGoogle Scholar
  93. 93.
    Bartlett SE, Enquist J, Hopf FW, Lee JH, Gladher F, Kharazia V, Waldhoer M, Mailliard WS, Armstrong R, Bonci A, Whistler JL (2005) Dopamine responsiveness is regulated by targeted sorting of D2 receptors. Proc Natl Acad Sci USA 102:11521–11526PubMedCrossRefGoogle Scholar
  94. 94.
    Kim OJ, Ariano MA, Namkung Y, Marinec P, Kim E, Han J, Sibley DR (2008) D2 dopamine receptor expression and trafficking is regulated through direct interactions with ZIP. J Neurochem 106:83–95PubMedCrossRefGoogle Scholar
  95. 95.
    Callier S, Snapyan M, Le Crom S, Prou D, Vincent JD, Vernier P (2003) Evolution and cell biology of dopamine receptors in vertebrates. Biol Cell 95:489–502PubMedCrossRefGoogle Scholar
  96. 96.
    Matsumoto M, Hidaka K, Tada S, Tasaki Y, Yamaguchi T (1995) Full-length cDNA cloning and distribution of human dopamine D4 receptor. Brain Res Mol Brain Res 29:157–162PubMedCrossRefGoogle Scholar
  97. 97.
    Lidow MS, Wang F, Cao Y, Goldman-Rakic PS (1998) Layer V neurons bear the majority of mRNAs encoding the five distinct dopamine receptor subtypes in the primate prefrontal cortex. Synapse 28:10–20PubMedCrossRefGoogle Scholar
  98. 98.
    Meador-Woodruff JH, Grandy DK, Van Tol HH, Damask SP, Little KY, Civelli O, Watson SJ Jr (1994) Dopamine receptor gene expression in the human medial temporal lobe. Neuropsychopharmacology 10:239–248PubMedGoogle Scholar
  99. 99.
    Meador-Woodruff JH, Haroutunian V, Powchik P, Davidson M, Davis KL, Watson SJ (1997) Dopamine receptor transcript expression in striatum and prefrontal and occipital cortex: focal abnormalities in orbitofrontal cortex in schizophrenia. Arch Gen Psychiatry 54:1089–1095PubMedGoogle Scholar
  100. 100.
    Defagot MC, Antonelli MC (1997) Autoradiographic localization of the putative D4 dopamine receptor in rat brain. Neurochem Res 22:401–407PubMedCrossRefGoogle Scholar
  101. 101.
    Defagot MC, Falzone TL, Low MJ, Grandy DK, Rubinstein M, Antonelli MC (2000) Quantitative analysis of the dopamine D4 receptor in the mouse brain. J Neurosci Res 59:202–208PubMedCrossRefGoogle Scholar
  102. 102.
    Primus RJ, Thurkauf A, Xu J, Yevich E, McInerney S, Shaw K, Tallman JF, Gallagher DW (1997) II. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94-1. J Pharmacol Exp Ther 282:1020–1027PubMedGoogle Scholar
  103. 103.
    Tarazi FI, Kula NS, Baldessarini RJ (1997) Regional distribution of dopamine D4 receptors in rat forebrain. Neuroreport 8:3423–3426PubMedCrossRefGoogle Scholar
  104. 104.
    Ariano MA, Wang J, Noblett KL, Larson ER, Sibley DR (1997) Cellular distribution of the rat D4 dopamine receptor protein in the CNS using anti-receptor antisera. Brain Res 752:26–34PubMedCrossRefGoogle Scholar
  105. 105.
    Defagot MC, Malchiodi EL, Villar MJ, Antonelli MC (1997) Distribution of D4 dopamine receptor in rat brain with sequence-specific antibodies. Brain Res Mol Brain Res 45:1–12PubMedCrossRefGoogle Scholar
  106. 106.
    Khan ZU, Gutierrez A, Martin R, Penafiel A, Rivera A, De La Calle A (1998) Differential regional and cellular distribution of dopamine D2-like receptors: an immunocytochemical study of subtype-specific antibodies in rat and human brain. J Comp Neurol 402:353–371PubMedCrossRefGoogle Scholar
  107. 107.
    Mauger C, Sivan B, Brockhaus M, Fuchs S, Civelli O, Monsma F Jr (1998) Development and characterization of antibodies directed against the mouse D4 dopamine receptor. Eur J Neurosci 10:529–537PubMedCrossRefGoogle Scholar
  108. 108.
    Rivera A, Cuellar B, Giron FJ, Grandy DK, de la Calle A, Moratalla R (2002) Dopamine D4 receptors are heterogeneously distributed in the striosomes/matrix compartments of the striatum. J Neurochem 80:219–229PubMedCrossRefGoogle Scholar
  109. 109.
    Bondy B, de Jonge S, Pander S, Primbs J, Ackenheil M (1996) Identification of dopamine D4 receptor mRNA in circulating human lymphocytes using nested polymerase chain reaction. J Neuroimmunol 71:139–144PubMedCrossRefGoogle Scholar
  110. 110.
    O’Malley KL, Harmon S, Tang L, Todd RD (1992) The rat dopamine D4 receptor: sequence, gene structure, and demonstration of expression in the cardiovascular system. New Biol 4:137–146PubMedGoogle Scholar
  111. 111.
    Sun D, Wilborn TW, Schafer JA (1998) Dopamine D4 receptor isoform mRNA and protein are expressed in the rat cortical collecting duct. Am J Physiol 275:F742–F751PubMedGoogle Scholar
  112. 112.
    Cox BA, Henningsen RA, Spanoyannis A, Neve RL, Neve KA (1992) Contributions of conserved serine residues to the interactions of ligands with dopamine D2 receptors. J Neurochem 59:627–635PubMedCrossRefGoogle Scholar
  113. 113.
    Mansour A, Meng F, Meador-Woodruff JH, Taylor LP, Civelli O, Akil H (1992) Site-directed mutagenesis of the human dopamine D2 receptor. Eur J Pharmacol 227:205–214PubMedCrossRefGoogle Scholar
  114. 114.
    Neve KA, Cox BA, Henningsen RA, Spanoyannis A, Neve RL (1991) Pivotal role for aspartate-80 in the regulation of dopamine D2 receptor affinity for drugs and inhibition of adenylyl cyclase. Mol Pharmacol 39:733–739PubMedGoogle Scholar
  115. 115.
    Woodward R, Coley C, Daniell S, Naylor LH, Strange PG (1996) Investigation of the role of conserved serine residues in the long form of the rat D2 dopamine receptor using site-directed mutagenesis. J Neurochem 66:394–402PubMedCrossRefGoogle Scholar
  116. 116.
    Wilson JM, Sanyal S, Van Tol HH (1998) Dopamine D2 and D4 receptor ligands: relation to antipsychotic action. Eur J Pharmacol 351:273–286PubMedCrossRefGoogle Scholar
  117. 117.
    Lanau F, Zenner MT, Civelli O, Hartman DS (1997) Epinephrine and norepinephrine act as potent agonists at the recombinant human dopamine D4 receptor. J Neurochem 68:804–812PubMedCrossRefGoogle Scholar
  118. 118.
    Newman-Tancredi A, Audinot-Bouchez V, Gobert A, Millan MJ (1997) Noradrenaline and adrenaline are high affinity agonists at dopamine D4 receptors. Eur J Pharmacol 319:379–383PubMedCrossRefGoogle Scholar
  119. 119.
    Sokoloff P, Andrieux M, Besancon R, Pilon C, Martres MP, Giros B, Schwartz JC (1992) Pharmacology of human dopamine D3 receptor expressed in a mammalian cell line: comparison with D2 receptor. Eur J Pharmacol 225:331–337PubMedCrossRefGoogle Scholar
  120. 120.
    Bristow LJ, Kramer MS, Kulagowski J, Patel S, Ragan CI, Seabrook GR (1997) Schizophrenia and L-745,870, a novel dopamine D4 receptor antagonist. Trends Pharmacol Sci 18:186–188PubMedGoogle Scholar
  121. 121.
    Kulagowski JJ, Broughton HB, Curtis NR, Mawer IM, Ridgill MP, Baker R, Emms F, Freedman SB, Marwood R, Patel S, Patel S, Ragan CI, Leeson PD (1996) 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. J Med Chem 39:1941–1942PubMedCrossRefGoogle Scholar
  122. 122.
    Patel S, Freedman S, Chapman KL, Emms F, Fletcher AE, Knowles M, Marwood R, McAllister G, Myers J, Curtis N, Kulagowski JJ, Leeson PD, Ridgill M, Graham M, Matheson S, Rathbone D, Watt AP, Bristow LJ, Rupniak NM, Baskin E, Lynch JJ, Ragan CI (1997) Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor. J Pharmacol Exp Ther 283:636–647PubMedGoogle Scholar
  123. 123.
    Vallone D, Picetti R, Borrelli E (2000) Structure and function of dopamine receptors. Neurosci Biobehav Rev 24:125–132PubMedCrossRefGoogle Scholar
  124. 124.
    Usiello A, Baik JH, Rouge-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E (2000) Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408:199–203PubMedCrossRefGoogle Scholar
  125. 125.
    Wang Y, Xu R, Sasaoka T, Tonegawa S, Kung MP, Sankoorikal EB (2000) Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions. J Neurosci 20:8305–8314PubMedGoogle Scholar
  126. 126.
    Lindgren N, Usiello A, Goiny M, Haycock J, Erbs E, Greengard P, Hokfelt T, Borrelli E, Fisone G (2003) Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites. Proc Natl Acad Sci USA 100:4305–4309PubMedCrossRefGoogle Scholar
  127. 127.
    Fernandez J, Alonso JM, Andres JI, Cid JM, Diaz A, Iturrino L, Gil P, Megens A, Sipido VK, Trabanco AA (2005) Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents. J Med Chem 48:1709–1712PubMedCrossRefGoogle Scholar
  128. 128.
    Kongsamut S, Roehr JE, Cai J, Hartman HB, Weissensee P, Kerman LL, Tang L, Sandrasagra A (1996) Iloperidone binding to human and rat dopamine and 5-HT receptors. Eur J Pharmacol 317:417–423PubMedCrossRefGoogle Scholar
  129. 129.
    Sahlholm K, Marcellino D, Nilsson J, Fuxe K, Arhem P (2008) Differential voltage-sensitivity of D2-like dopamine receptors. Biochem Biophys Res Commun 374:496–501PubMedCrossRefGoogle Scholar
  130. 130.
    Sahlholm K, Nilsson J, Marcellino D, Fuxe K, Arhem P (2008) Voltage-dependence of the human dopamine D2 receptor. Synapse 62:476–480PubMedCrossRefGoogle Scholar
  131. 131.
    Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M (2008) How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 29:190–201PubMedCrossRefGoogle Scholar
  132. 132.
    Kuznetsova AY, Deth RC (2008) A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated phospholipid methylation. J Comput Neurosci 24:314–329PubMedCrossRefGoogle Scholar
  133. 133.
    Glickstein SB, Schmauss C (2001) Dopamine receptor functions: lessons from knockout mice [corrected]. Pharmacol Ther 91:63–83PubMedCrossRefGoogle Scholar
  134. 134.
    Dulawa SC, Grandy DK, Low MJ, Paulus MP, Geyer MA (1999) Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J Neurosci 19:9550–9556PubMedGoogle Scholar
  135. 135.
    Sibley DR (1999) New insights into dopaminergic receptor function using antisense and genetically altered animals. Annu Rev Pharmacol Toxicol 39:313–341PubMedCrossRefGoogle Scholar
  136. 136.
    Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH (1996) Population and familial association between the D4 dopamine receptor gene and measures of novelty seeking. Nat Genet 12:81–84PubMedCrossRefGoogle Scholar
  137. 137.
    Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH (1996) Dopamine D4 receptor (D4DR) exon iii polymorphism associated with the human personality trait of novelty seeking. Nat Genet 12:78–80PubMedCrossRefGoogle Scholar
  138. 138.
    Munafo MR, Yalcin B, Willis-Owen SA, Flint J (2008) Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data. Biol Psychiatry 63:197–206PubMedCrossRefGoogle Scholar
  139. 139.
    Rubinstein M, Cepeda C, Hurst RS, Flores-Hernandez J, Ariano MA, Falzone TL, Kozell LB, Meshul CK, Bunzow JR, Low MJ, Levine MS, Grandy DK (2001) Dopamine D4 receptor-deficient mice display cortical hyperexcitability. J Neurosci 21:3756–3763PubMedGoogle Scholar
  140. 140.
    Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G, Fang Y, Larson JL, McDougall JA, Chester JA, Saez C, Pugsley TA, Gershanik O, Low MJ, Grandy DK (1997) Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90:991–1001PubMedCrossRefGoogle Scholar
  141. 141.
    Pauls DL (2005) The genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1310–1312PubMedCrossRefGoogle Scholar
  142. 142.
    Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1313–1323PubMedCrossRefGoogle Scholar
  143. 143.
    Shastry BS (2004) Molecular genetics of attention-deficit hyperactivity disorder (ADHD): an update. Neurochem Int 44:469–474PubMedCrossRefGoogle Scholar
  144. 144.
    LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL (1996) Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry 1:121–124PubMedGoogle Scholar
  145. 145.
    Smalley SL, Bailey JN, Palmer CG, Cantwell DP, McGough JJ, Del’Homme MA, Asarnow JR, Woodward JA, Ramsey C, Nelson SF (1998) Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder. Mol Psychiatry 3:427–430PubMedCrossRefGoogle Scholar
  146. 146.
    Swanson JM, Sunohara GA, Kennedy JL, Regino R, Fineberg E, Wigal T, Lerner M, Williams L, LaHoste GJ, Wigal S (1998) Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach. Mol Psychiatry 3:38–41PubMedCrossRefGoogle Scholar
  147. 147.
    Faraone SV, Biederman J, Weiffenbach B, Keith T, Chu MP, Weaver A, Spencer TJ, Wilens TE, Frazier J, Cleves M, Sakai J (1999) Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder. Am J Psychiatry 156:768–770PubMedGoogle Scholar
  148. 148.
    Castellanos FX, Lau E, Tayebi N, Lee P, Long RE, Giedd JN, Sharp W, Marsh WL, Walter JM, Hamburger SD, Ginns EI, Rapoport JL, Sidransky E (1998) Lack of an association between a dopamine-4 receptor polymorphism and attention-deficit/hyperactivity disorder: genetic and brain morphometric analyses. Mol Psychiatry 3:431–434PubMedCrossRefGoogle Scholar
  149. 149.
    Jonsson EG, Nothen MM, Gustavsson JP, Neidt H, Brene S, Tylec A, Propping P, Sedvall GC (1997) Lack of evidence for allelic association between personality traits and the dopamine D4 receptor gene polymorphisms. Am J Psychiatry 154:697–699PubMedGoogle Scholar
  150. 150.
    Malhotra AK, Virkkunen M, Rooney W, Eggert M, Linnoila M, Goldman D (1996) The association between the dopamine D4 receptor (D4DR) 16 amino acid repeat polymorphism and novelty seeking. Mol Psychiatry 1:388–391PubMedGoogle Scholar
  151. 151.
    Wong AH, Buckle CE, Van Tol HH (2000) Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol 410:183–203PubMedCrossRefGoogle Scholar
  152. 152.
    Okuyama Y, Ishiguro H, Toru M, Arinami T (1999) A genetic polymorphism in the promoter region of DRD4 associated with expression and schizophrenia. Biochem Biophys Res Commun 258:292–295PubMedCrossRefGoogle Scholar
  153. 153.
    Ronai Z, Barta C, Guttman A, Lakatos K, Gervai J, Staub M, Sasvari-Szekely M (2001) Genotyping the -521C/T functional polymorphism in the promoter region of dopamine D4 receptor (DRD4) gene. Electrophoresis 22:1102–1105PubMedCrossRefGoogle Scholar
  154. 154.
    Talkowski ME, Kirov G, Bamne M, Georgieva L, Torres G, Mansour H, Chowdari KV, Milanova V, Wood J, McClain L, Prasad K, Shirts B, Zhang J, O’Donovan MC, Owen MJ, Devlin B, Nimgaonkar VL (2008) A network of dopaminergic gene variations implicated as risk factors for schizophrenia. Hum Mol Genet 17:747–758PubMedCrossRefGoogle Scholar
  155. 155.
    Norton N, Williams HJ, Owen MJ (2006) An update on the genetics of schizophrenia. Curr Opin Psychiatry 19:158–164PubMedCrossRefGoogle Scholar
  156. 156.
    Ross CA, Margolis RL, Reading SAJ, Pletnikov M, Coyle JT (2006) Neurobiology of schizophrenia. Neuron 52:139–153PubMedCrossRefGoogle Scholar
  157. 157.
    Seeman P, Guan HC, Van Tol HH (1993) Dopamine D4 receptors elevated in schizophrenia. Nature 365:441–445PubMedCrossRefGoogle Scholar
  158. 158.
    Jonsson E, Brene S, Geijer T, Terenius L, Tylec A, Persson ML, Sedvall G (1996) A search for association between schizophrenia and dopamine-related alleles. Eur Arch Psychiatry Clin Neurosci 246:297–304PubMedCrossRefGoogle Scholar
  159. 159.
    Tanaka T, Igarashi S, Onodera O, Tanaka H, Kameda K, Takahashi K, Tsuji S, Ihda S (1995) Lack of association between dopamine D4 receptor gene and schizophrenia. Am J Med Genet 60:580–582PubMedCrossRefGoogle Scholar
  160. 160.
    Rao PA, Pickar D, Gejman PV, Ram A, Gershon ES, Gelernter J (1994) Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Arch Gen Psychiatry 51:912–917PubMedGoogle Scholar
  161. 161.
    Shaikh S, Collier D, Kerwin RW, Pilowsky LS, Gill M, Xu WM, Thornton A (1993) Dopamine D4 receptor subtypes and response to clozapine. Lancet 341:116PubMedCrossRefGoogle Scholar
  162. 162.
    Wong AH, Van Tol HH (2003) The dopamine D4 receptors and mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 27:1091–1099PubMedCrossRefGoogle Scholar
  163. 163.
    Sunahara RK, Guan HC, O’Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HH, Niznik HB (1991) Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature 350:614–619PubMedCrossRefGoogle Scholar
  164. 164.
    Freedman SB, Patel S, Marwood R, Emms F, Seabrook GR, Knowles MR, McAllister G (1994) Expression and pharmacological characterization of the human D3 dopamine receptor. J Pharmacol Exp Ther 268:417–426PubMedGoogle Scholar
  165. 165.
    Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O’Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS (1998) Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr 178:440–466PubMedGoogle Scholar
  166. 166.
    Cussac D, Newman-Tancredi A, Sezgin L, Millan MJ (2000) [3H]S33084: a novel, selective and potent radioligand at cloned, human dopamine D3 receptors. Naunyn Schmiedebergs Arch Pharmacol 361:569–572PubMedCrossRefGoogle Scholar
  167. 167.
    Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor, I: a multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 303:791–804PubMedCrossRefGoogle Scholar
  168. 168.
    Seeman P, Van Tol HH (1993) Dopamine D4 receptors bind inactive (+)-aporphines, suggesting neuroleptic role: sulpiride not stereoselective. Eur J Pharmacol 233:173–174PubMedCrossRefGoogle Scholar
  169. 169.
    Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, Nash NR, Olsson R, Davis RE, Hacksell U, Weiner DM, Brann MR (2005) Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. J Pharmacol Exp Ther 315:1278–1287PubMedCrossRefGoogle Scholar
  170. 170.
    Seeman P, Tallerico T (1998) Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 3:123–134PubMedCrossRefGoogle Scholar
  171. 171.
    Vanover KE, Harvey SC, Son T, Bradley SR, Kold H, Makhay M, Veinbergs I, Spalding TA, Weiner DM, Andersson CM, Tolf BR, Brann MR, Hacksell U, Davis RE (2004) Pharmacological characterization of AC-90179 [2-(4-methoxyphenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide hydrochloride]: a selective serotonin 2A receptor inverse agonist. J Pharmacol Exp Ther 310:943–951PubMedCrossRefGoogle Scholar
  172. 172.
    Millan MJ, Cussac D, Gobert A, Lejeune F, Rivet JM, Mannoury La Cour C, Newman-Tancredi A, Peglion JL (2004) S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors, I: cellular, electrophysiological, and neurochemical profile in comparison with ropinirole. J Pharmacol Exp Ther 309:903–920PubMedCrossRefGoogle Scholar
  173. 173.
    Seeman P, Corbett R, Van Tol HH (1997) Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology 16:93–110; discussion 111–135PubMedCrossRefGoogle Scholar
  174. 174.
    Joyce JN, Janowsky A, Neve KA (1991) Characterization and distribution of [125I]epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brain. J Pharmacol Exp Ther 257:1253–1263PubMedGoogle Scholar
  175. 175.
    Tallman JF, Primus RJ, Brodbeck R, Cornfield L, Meade R, Woodruff K, Ross P, Thurkauf A, Gallager DW (1997) I. NGD 94-1: identification of a novel, high-affinity antagonist at the human dopamine D4 receptor. J Pharmacol Exp Ther 282:1011–1019PubMedGoogle Scholar
  176. 176.
    Newman-Tancredi A, Audinot V, Chaput C, Verriele L, Millan MJ (1997) [35S]Guanosine-5′-O-(3-thio)triphosphate binding as a measure of efficacy at human recombinant dopamine D4.4 receptors: actions of antiparkinsonian and antipsychotic agents. J Pharmacol Exp Ther 282:181–191PubMedGoogle Scholar
  177. 177.
    Mamiya T, Matsumura T, Ukai M (2004) Effects of L-745,870, a dopamine D4 receptor antagonist, on naloxone-induced morphine dependence in mice. Ann N Y Acad Sci 1025:424–429PubMedCrossRefGoogle Scholar
  178. 178.
    Moustgaard A, Hau J, Lind NM (2008) Effects of dopamine D4 receptor antagonist on spontaneous alternation in rats. Behav Brain Funct 4:49PubMedCrossRefGoogle Scholar
  179. 179.
    Tanaka K, Okada Y, Kanno T, Otomo A, Yanagisawa Y, Shouguchi-Miyata J, Suga E, Kohiki E, Onoe K, Osuga H, Aoki M, Hadano S, Itoyama Y, Ikeda JE (2008) A dopamine receptor antagonist L-745,870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice. Exp Neurol 211:378–386PubMedCrossRefGoogle Scholar
  180. 180.
    Huang Y, Kegeles LS, Bae S, Hwang D, Roth BL, Savage JE, Laruelle M (2001) Synthesis of potent and selective dopamine D(4) antagonists as candidate radioligands. Bioorg Med Chem Lett 11:1375–1377PubMedCrossRefGoogle Scholar
  181. 181.
    Gazi L, Bobirnac I, Danzeisen M, Schupbach E, Langenegger D, Sommer B, Hoyer D, Tricklebank M, Schoeffter P (1999) Receptor density as a factor governing the efficacy of the dopamine D4 receptor ligands, L-745,870 and U-101958 at human recombinant D4.4 receptors expressed in CHO cells. Br J Pharmacol 128:613–620PubMedCrossRefGoogle Scholar
  182. 182.
    Kramer MS, Last B, Getson A, Reines SA (1997) The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia: D4 dopamine antagonist group. Arch Gen Psychiatry 54:567–572PubMedGoogle Scholar
  183. 183.
    Cao BJ, Rodgers RJ (1997) Dopamine D4 receptor and anxiety: behavioural profiles of clozapine, L-745,870 and L-741,742 in the mouse plus-maze. Eur J Pharmacol 335:117–125PubMedCrossRefGoogle Scholar
  184. 184.
    Brioni JD, Moreland RB, Cowart M, Hsieh GC, Stewart AO, Hedlund P, Donnelly-Roberts DL, Nakane M, Lynch JJ 3rd, Kolasa T, Polakowski JS, Osinski MA, Marsh K, Andersson KE, Sullivan JP (2004) Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats. Proc Natl Acad Sci USA 101:6758–6763PubMedCrossRefGoogle Scholar
  185. 185.
    Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ 3rd, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO (2004) Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction. J Med Chem 47:3853–3864PubMedCrossRefGoogle Scholar
  186. 186.
    Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE (2006) WAY-100635 is a potent dopamine D4 receptor agonist. Psychopharmacology (Berl) 188:244–251CrossRefGoogle Scholar
  187. 187.
    Marona-Lewicka D, Nichols DE (2009) WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D(4) receptor activation. Behav Pharmacol 20:114–118PubMedCrossRefGoogle Scholar
  188. 188.
    Melis MR, Succu S, Sanna F, Melis T, Mascia MS, Enguehard-Gueiffier C, Hubner H, Gmeiner P, Gueiffier A, Argiolas A (2006) PIP3EA and PD-168077, two selective dopamine D4 receptor agonists, induce penile erection in male rats: site and mechanism of action in the brain. Eur J Neurosci 24:2021–2030PubMedCrossRefGoogle Scholar
  189. 189.
    Bernaerts P, Tirelli E (2003) Facilitatory effect of the dopamine D4 receptor agonist PD168,077 on memory consolidation of an inhibitory avoidance learned response in C57BL/6J mice. Behav Brain Res 142:41–52PubMedCrossRefGoogle Scholar
  190. 190.
    Tang AH, Franklin SR, Himes CS, Smith MW, Tenbrink RE (1997) PNU-96415E, a potential antipsychotic agent with clozapine-like pharmacological properties. J Pharmacol Exp Ther 281:440–447PubMedGoogle Scholar
  191. 191.
    Powell SB, Paulus MP, Hartman DS, Godel T, Geyer MA (2003) RO-10-5824 is a selective dopamine D4 receptor agonist that increases novel object exploration in C57 mice. Neuropharmacology 44:473–481PubMedCrossRefGoogle Scholar
  192. 192.
    Jentsch JD, Taylor JR, Redmond DE Jr, Elsworth JD, Youngren KD, Roth RH (1999) Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys. Psychopharmacology (Berl) 142:78–84CrossRefGoogle Scholar
  193. 193.
    De La Garza R, Madras BK 2nd (2000) [(3)H]PNU-101958, a D(4) dopamine receptor probe, accumulates in prefrontal cortex and hippocampus of non-human primate brain. Synapse 37:232–244PubMedCrossRefGoogle Scholar
  194. 194.
    Langer O, Halldin C, Chou Y, Sandell J, Swahn C, Nagren K, Perrone R, Berardi F, Leopoldo M, Farde L (2000) Carbon-11 pb-12: an attempt to visualize the dopamine d(4) receptor in the primate brain with positron emission tomography. Nucl Med Biol 27:707–714PubMedCrossRefGoogle Scholar
  195. 195.
    Belliotti TR, Wustrow DJ, Brink WA, Zoski KT, Shih YH, Whetzel SZ, Georgic LM, Corbin AE, Akunne HC, Heffner TG, Pugsley TA, Wise LD (1999) A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: discovery of a potential atypical antipsychotic agent. J Med Chem 42:5181–5187PubMedCrossRefGoogle Scholar
  196. 196.
    Okuyama S, Kawashima N, Chaki S, Yoshikawa R, Funakoshi T, Ogawa SI, Suzuki Y, Ikeda Y, Kumagai T, Nakazato A, Nagamine M, Tomisawa K (1999) A selective dopamine D4 receptor antagonist, NRA0160: a preclinical neuropharmacological profile. Life Sci 65:2109–2125PubMedCrossRefGoogle Scholar
  197. 197.
    Woolley ML, Waters KA, Reavill C, Bull S, Lacroix LP, Martyn AJ, Hutcheson DM, Valerio E, Bate S, Jones DN, Dawson LA (2008) Selective dopamine D4 receptor agonist (A-412997) improves cognitive performance and stimulates motor activity without influencing reward-related behaviour in rat. Behav Pharmacol 19:765–776PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Pieter Rondou
    • 1
    • 2
  • Guy Haegeman
    • 1
  • Kathleen Van Craenenbroeck
    • 1
    Email author
  1. 1.Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST)Ghent University (UGent)GhentBelgium
  2. 2.Center for Medical Genetics Ghent (CMGG)Ghent University HospitalGhentBelgium

Personalised recommendations