Gene Symbol: Drd4
Description: dopamine receptor D4
Alias: AW125663, D4R, Drd-4, D(4) dopamine receptor, d(2C) dopamine receptor, dopamine D4 receptor, dopamine receptor 4
Species: mouse
Products:     Drd4

Top Publications

  1. Araki K, Sims J, Bhide P. Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development. Brain Res. 2007;1156:31-45 pubmed
    ..By analyzing D1 receptor protein expression, we show that developmental changes in mRNA expression reliably translate into changes in protein levels, at least for the D1-receptor. ..
  2. Nir I, Harrison J, Haque R, Low M, Grandy D, Rubinstein M, et al. Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. J Neurosci. 2002;22:2063-73 pubmed
    ..morphology, electrophysiology, and regulation of cAMP metabolism in mice with targeted disruption of the dopamine D4 receptor gene...
  3. Gan L, Falzone T, Zhang K, Rubinstein M, Baldessarini R, Tarazi F. Enhanced expression of dopamine D(1) and glutamate NMDA receptors in dopamine D(4) receptor knockout mice. J Mol Neurosci. 2004;22:167-78 pubmed
  4. Helms C, Gubner N, Wilhelm C, Mitchell S, Grandy D. D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking. Pharmacol Biochem Behav. 2008;90:387-93 pubmed publisher
    Alleles of the human dopamine D(4) receptor (D(4)R) gene (DRD4.7) have repeatedly been found to correlate with novelty seeking, substance abuse, pathological gambling, and attention-deficit hyperactivity disorder (ADHD)...
  5. Rubinstein M, Phillips T, Bunzow J, Falzone T, Dziewczapolski G, Zhang G, et al. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell. 1997;90:991-1001 pubmed
    The human dopamine D4 receptor (D4R) has received considerable attention because of its high affinity for the atypical antipsychotic clozapine and the unusually polymorphic nature of its gene...
  6. Jackson C, Chaurasia S, Zhou H, Haque R, Storm D, Iuvone P. Essential roles of dopamine D4 receptors and the type 1 adenylyl cyclase in photic control of cyclic AMP in photoreceptor cells. J Neurochem. 2009;109:148-57 pubmed publisher
    ..Similarly, in mice with disruption of the gene (Drd4) encoding D(4)R, cyclic AMP levels in the dark-adapted retina are significantly lower compared to wild-type retina ..
  7. Chen Y, Palczewska G, Masuho I, Gao S, Jin H, Dong Z, et al. Synergistically acting agonists and antagonists of G protein-coupled receptors prevent photoreceptor cell degeneration. Sci Signal. 2016;9:ra74 pubmed publisher
    ..the combined effects of these drugs were stimulation of Gi/o signaling by activating the dopamine receptors D2R and D4R, as well as inhibition of Gs and Gq signaling by antagonizing D1R and the α1A-adrenergic receptor ADRA1A, ..
  8. Paweł K, Hauser J, Skibinska M, Szczepankiewicz A, Dmitrzak Weglarz M, Gorzkowska K, et al. [Family based association study of DRD1, DRD2, DRD3, DRD4, DAT, COMT gene polymorphism in schizophrenia]. Psychiatr Pol. 2010;44:405-13 pubmed
    ..were the following: DRD1 (polymorphism -48A/G), DRD2 (polymorphism -141C ins/del), DRD3 (polymorphism Ser9Gly), DRD4 (polymorphism -521C/T), DAT (polymorphism VNTR w 3'-UTR), COMT (polymorphism Val108(158)Met). Method...
  9. Rondou P, Haegeman G, Vanhoenacker P, Van Craenenbroeck K. BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase. J Biol Chem. 2008;283:11083-96 pubmed publisher

More Information


  1. Herrmann R, Heflin S, Hammond T, Lee B, Wang J, Gainetdinov R, et al. Rod vision is controlled by dopamine-dependent sensitization of rod bipolar cells by GABA. Neuron. 2011;72:101-10 pubmed publisher
    ..They further reveal a role for GABA in sensitizing the circuitry for dim-light vision, thereby complementing GABA's traditional role in providing dynamic feedforward and feedback inhibition in the retina. ..
  2. Vancura P, Abdelhadi S, Csicsely E, Baba K, Tosini G, Iuvone P, et al. Gnaz couples the circadian and dopaminergic system to G protein-mediated signaling in mouse photoreceptors. PLoS ONE. 2017;12:e0187411 pubmed publisher
    ..The data of the present study suggest that Gnaz links the circadian clockwork-via dopamine acting on D4 receptors-to G protein-mediated signaling in intact but not diabetic retina. ..
  3. Bek M, Wang X, Asico L, Jones J, Zheng S, Li X, et al. Angiotensin-II type 1 receptor-mediated hypertension in D4 dopamine receptor-deficient mice. Hypertension. 2006;47:288-95 pubmed
    ..We conclude that the absence of the D(4) receptor increases blood pressure, possibly via increased angiotensin II type 1 receptor expression. ..
  4. Suzuki T, Kobayashi K, Nagatsu T. Genomic structure and tissue distribution of the mouse dopamine D4 receptor. Neurosci Lett. 1995;199:69-72 pubmed
    The mouse dopamine D4 receptor gene was isolated from a genomic DNA library by plaque hybridization. The D4 receptor gene encoded an open reading frame consisting of 387 amino acids, interrupted by three introns...
  5. Grady D, Thanos P, Corrada M, Barnett J, Ciobanu V, Shustarovich D, et al. DRD4 genotype predicts longevity in mouse and human. J Neurosci. 2013;33:286-91 pubmed publisher
    ..In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health...
  6. Katz J, Chausmer A, Elmer G, Rubinstein M, Low M, Grandy D. Cocaine-induced locomotor activity and cocaine discrimination in dopamine D4 receptor mutant mice. Psychopharmacology (Berl). 2003;170:108-14 pubmed
  7. Zhen X, Zhang J, Johnson G, Friedman E. D(4) dopamine receptor differentially regulates Akt/nuclear factor-kappa b and extracellular signal-regulated kinase pathways in D(4)MN9D cells. Mol Pharmacol. 2001;60:857-64 pubmed
    ..We also demonstrated that D(4) receptor-stimulated cell proliferation is mediated by the Src/SHC/Ras/ERK pathway. ..
  8. Thomas T, Kruzich P, Joyce B, Gash C, Suchland K, Surgener S, et al. Dopamine D4 receptor knockout mice exhibit neurochemical changes consistent with decreased dopamine release. J Neurosci Methods. 2007;166:306-14 pubmed
    b>Dopamine D4 receptor (D4R) knockout mice (D4R-/-) provided for unique neurochemical studies designed to understand D4R contributions to dopamine (DA) regulation...
  9. Dulawa S, Grandy D, Low M, Paulus M, Geyer M. Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J Neurosci. 1999;19:9550-6 pubmed
    ..Some studies have reported that polymorphisms of the human dopamine D4 receptor (D4R) gene are associated with personality inventory measures of the trait called "novelty-seeking&..
  10. Ralph R, Varty G, Kelly M, Wang Y, Caron M, Rubinstein M, et al. The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice. J Neurosci. 1999;19:4627-33 pubmed
    ..Uncovering the neural mechanisms involved in PPI will further our understanding of the substrates of sensorimotor gating and could lead to better therapeutics to treat gating disorders, such as schizophrenia. ..
  11. Gong S, Zheng C, Doughty M, Losos K, Didkovsky N, Schambra U, et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature. 2003;425:917-25 pubmed
    ..The atlas, library of BAC vectors and BAC transgenic mice generated in this screen provide a rich resource that allows a broad array of investigations not previously available to the neuroscience community. ..
  12. Qin L, Liu W, Ma K, Wei J, Zhong P, Cho K, et al. The ADHD-linked human dopamine D4 receptor variant D4.7 induces over-suppression of NMDA receptor function in prefrontal cortex. Neurobiol Dis. 2016;95:194-203 pubmed publisher
    The human dopamine D4 receptor (hD4R) variants with long tandem repeats in the third intracellular loop have been strongly associated with attention deficit hyperactivity disorder (ADHD) and risk taking behaviors...
  13. Tomé M, Jiménez A, Richter H, Vio K, Bermúdez Silva F, Rodriguez E, et al. The subcommissural organ expresses D2, D3, D4, and D5 dopamine receptors. Cell Tissue Res. 2004;317:65-77 pubmed
  14. Wang H, Stanwood G, Grandy D, Deutch A. Dystrophic dendrites in prefrontal cortical pyramidal cells of dopamine D1 and D2 but not D4 receptor knockout mice. Brain Res. 2009;1300:58-64 pubmed publisher
    ..The current data also suggest that caution should be exercised in the interpretation of behavioral, physiological, and biochemical studies of the prefrontal cortex in dopamine receptor knockout mice. ..
  15. Leo D, Gainetdinov R. Transgenic mouse models for ADHD. Cell Tissue Res. 2013;354:259-71 pubmed publisher
    ..New transgenic models mouse models targeting other genes have recently been proposed for ADHD. Here, we discuss the recent advances and pitfalls in modeling ADHD endophenotypes in genetically altered animals. ..
  16. Thanos P, Roushdy K, Sarwar Z, Rice O, Ashby C, Grandy D. The effect of dopamine D4 receptor density on novelty seeking, activity, social interaction, and alcohol binge drinking in adult mice. Synapse. 2015;69:356-64 pubmed publisher
    The dopamine D4 receptor has been postulated to play a role in the pathophysiology of alcoholism...
  17. Zeng C, Armando I, Luo Y, Eisner G, Felder R, Jose P. Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice. Am J Physiol Heart Circ Physiol. 2008;294:H551-69 pubmed
  18. Rao P, Pickar D, Gejman P, Ram A, Gershon E, Gelernter J. Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Arch Gen Psychiatry. 1994;51:912-7 pubmed
    ..interindividual differences in response to clozapine therapy might be attributable to the D4 dopamine receptor (DRD4) alleles they carry...
  19. Gratacos M, Sahún I, Gallego X, Amador Arjona A, Estivill X, Dierssen M. Candidate genes for panic disorder: insight from human and mouse genetic studies. Genes Brain Behav. 2007;6 Suppl 1:2-23 pubmed
    ..The integration of human and animal studies targeting behavioral, systems-level, cellular and molecular levels will most probably help identify new molecules with potential impact on the pathogenetic aspects of the disease. ..
  20. Jackson C, Ruan G, Aseem F, Abey J, GAMBLE K, Stanwood G, et al. Retinal dopamine mediates multiple dimensions of light-adapted vision. J Neurosci. 2012;32:9359-68 pubmed publisher
    ..Together, our data indicate that dopamine is necessary for the circadian nature of light-adapted vision as well as optimal contrast detection and acuity. ..
  21. Rubinstein M, Cepeda C, Hurst R, Flores Hernandez J, Ariano M, Falzone T, et al. Dopamine D4 receptor-deficient mice display cortical hyperexcitability. J Neurosci. 2001;21:3756-63 pubmed
    ..Taken together, these results suggest that the D(4)R can function as an inhibitory modulator of glutamate activity in the FC. ..
  22. Jackson C, Chaurasia S, Hwang C, Iuvone P. Dopamine D? receptor activation controls circadian timing of the adenylyl cyclase 1/cyclic AMP signaling system in mouse retina. Eur J Neurosci. 2011;34:57-64 pubmed publisher
    ..A previous study demonstrated that expression of the gene encoding AC1, Adcy1, is downregulated in mice lacking Drd4, the gene encoding the D?R...
  23. Koch A, Juan T, Jenkins N, Gilbert D, Copeland N, McNiece I, et al. cDNA cloning and chromosomal mapping of mouse fast skeletal muscle troponin T. Mamm Genome. 1997;8:346-8 pubmed
  24. Avale M, Falzone T, Gelman D, Low M, Grandy D, Rubinstein M. The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder. Mol Psychiatry. 2004;9:718-26 pubmed
    The dopamine D4 receptor (D4R) is a candidate gene for attention deficit/hyperactivity disorder (ADHD) based on genetic studies reporting that particular polymorphisms are present at a higher frequency in affected children...
  25. Young J, Powell S, Scott C, ZHOU X, Geyer M. The effect of reduced dopamine D4 receptor expression in the 5-choice continuous performance task: Separating response inhibition from premature responding. Behav Brain Res. 2011;222:183-92 pubmed publisher
    ..Since reduced dopamine D4 receptor (DRD4) function is implicated in several disorders, DRD4 is a potential therapeutic target for cognition ..
  26. Michaelides M, Pascau J, Gispert J, Delis F, Grandy D, Wang G, et al. Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate. Eur J Neurosci. 2010;32:668-76 pubmed publisher
    ..Variable number of tandem repeats polymorphisms in the dopamine D4 receptor (D(4)) gene have been implicated in vulnerability to ADHD and the response to MP...
  27. Pozdeyev N, Tosini G, Li L, Ali F, Rozov S, Lee R, et al. Dopamine modulates diurnal and circadian rhythms of protein phosphorylation in photoreceptor cells of mouse retina. Eur J Neurosci. 2008;27:2691-700 pubmed publisher
    ..In addition, the daytime level of phospho-phosducin was significantly elevated by L-745,870, a dopamine D4 receptor antagonist...
  28. Falzone T, Gelman D, Young J, Grandy D, Low M, Rubinstein M. Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear. Eur J Neurosci. 2002;15:158-64 pubmed
    ..The dopamine D4 receptor (D4R) is expressed at highest levels in the prefrontal cortex and is the predominant D2-like receptor ..
  29. Kruzich P, Suchland K, Grandy D. Dopamine D4 receptor-deficient mice, congenic on the C57BL/6J background, are hypersensitive to amphetamine. Synapse. 2004;53:131-9 pubmed
    Mice lacking the dopamine D4 receptor subtype (D4R-/-) are supersensitive to methamphetamine and cocaine...
  30. Maison S, Liu X, Eatock R, Sibley D, Grandy D, Liberman M. Dopaminergic signaling in the cochlea: receptor expression patterns and deletion phenotypes. J Neurosci. 2012;32:344-55 pubmed publisher
    ..In D4 and D5 knock-outs, the increased noise vulnerability was seen only in ABRs, consistent with a role for dopaminergic signaling in minimizing neural damage. ..
  31. Fishburn C, Carmon S, Fuchs S. Molecular cloning and characterisation of the gene encoding the murine D4 dopamine receptor. FEBS Lett. 1995;361:215-9 pubmed
    ..RT-PCR on mRNA from different brain regions shows that the D4 receptor mRNA is expressed in various areas of the brain, with some differences from the rat and human receptor homologues. ..
  32. Thomas T, Grandy D, Gerhardt G, Glaser P. Decreased dopamine D4 receptor expression increases extracellular glutamate and alters its regulation in mouse striatum. Neuropsychopharmacology. 2009;34:436-45 pubmed publisher
    To better understand the effect of the dopamine D4 receptor (DRD4) on glutamate (Glu) neurotransmission in the brain, we utilized transgenic mice with partial or complete removal of functional DRD4 plasma membrane expression (DRD4+/- and ..
  33. Young J, Kooistra K, Geyer M. Dopamine receptor mediation of the exploratory/hyperactivity effects of modafinil. Neuropsychopharmacology. 2011;36:1385-96 pubmed publisher
    ..Here we examined the effects of modafinil on exploration in C57BL/6J mice, in dopamine drd1, drd2, drd3, and drd4 wild-type (WT), heterozygous (HT), and KO mice, and in 129/SJ mice pretreated with the drd1 antagonist SCH23390 ..
  34. Quach T, Mosinger B, Ricard D, Copeland N, Gilbert D, Jenkins N, et al. Collapsin response mediator protein-3/unc-33-like protein-4 gene: organization, chromosomal mapping and expression in the developing mouse brain. Gene. 2000;242:175-82 pubmed
  35. Kwon O, Paredes D, Gonzalez C, Neddens J, Hernandez L, Vullhorst D, et al. Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. Proc Natl Acad Sci U S A. 2008;105:15587-92 pubmed publisher
    ..dopamine release in the hippocampus and reverses early-phase LTP via activation of D4 dopamine receptors (D4R)...
  36. Kvajo M, McKellar H, Gogos J. Avoiding mouse traps in schizophrenia genetics: lessons and promises from current and emerging mouse models. Neuroscience. 2012;211:136-64 pubmed publisher
    ..Finally, we discuss emerging mouse models, such as second-generation pathophysiology models based on innovative approaches that are facilitated by the information gathered from the current genetic mouse models. ..
  37. Cepeda C, Hurst R, Altemus K, Flores Hernandez J, Calvert C, Jokel E, et al. Facilitated glutamatergic transmission in the striatum of D2 dopamine receptor-deficient mice. J Neurophysiol. 2001;85:659-70 pubmed
    ..These receptors may function as gatekeepers of glutamate release or of its subsequent effects and thus may protect striatal neurons from excessive excitation...
  38. Herwerth M, Jensen V, Novak M, Konopka W, Hvalby O, Köhr G. D4 dopamine receptors modulate NR2B NMDA receptors and LTP in stratum oriens of hippocampal CA1. Cereb Cortex. 2012;22:1786-98 pubmed publisher
    ..Thus, a dopamine hyperfunction in stratum oriens may result in NMDAR hypofunction that could affect both normal and pathological conditions. ..
  39. Ogilvie J, Hakenewerth A, Gardner R, Martak J, Maggio V. Dopamine receptor loss of function is not protective of rd1 rod photoreceptors in vivo. Mol Vis. 2009;15:2868-78 pubmed
    ..The possible role of compensatory effects during retinal development in DA receptor deficient mice is considered. ..
  40. Scott A, Griffin S, Luedtke R. Genetic polymorphisms at the rat and murine loci coding for dopamine D2-like receptors. Brain Res Mol Brain Res. 1995;29:347-57 pubmed
    ..It is anticipated that these genetic polymorphisms will be useful in pharmacogenetic studies to determine the influence of the D2-like receptors in reward and addictive behaviors. ..
  41. Thanos P, Habibi R, Michaelides M, Patel U, Suchland K, Anderson B, et al. Dopamine D4 receptor (D4R) deletion in mice does not affect operant responding for food or cocaine. Behav Brain Res. 2010;207:508-11 pubmed publisher
    In this study we examined the genetic contribution of the D4R in food and cocaine self-administration using D4R mice. Mice were examined for operant responding to food pellets or intravenous cocaine...
  42. Deming J, Shin J, Lim K, Lee E, Van Craenenbroeck K, CRAFT C. Dopamine receptor D4 internalization requires a beta-arrestin and a visual arrestin. Cell Signal. 2015;27:2002-13 pubmed publisher
    The G-protein coupled receptor (GPCR) Dopamine Receptor D4 (DRD4) plays an essential role in cAMP regulation and gap junctional coupling in the photoreceptors, where DRD4 expression is under circadian control...
  43. Fan X, Xu M, Hess E. D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD. Neurobiol Dis. 2010;37:228-36 pubmed publisher
    ..Thus, the D2 dopamine receptor subtype mediates both the hyperactivity and response to amphetamine, suggesting a specific target for novel therapeutics in ADHD. ..
  44. Hohmann S, Becker K, Fellinger J, Banaschewski T, Schmidt M, Esser G, et al. Evidence for epistasis between the 5-HTTLPR and the dopamine D4 receptor polymorphisms in externalizing behavior among 15-year-olds. J Neural Transm (Vienna). 2009;116:1621-9 pubmed publisher
    ..DNA was genotyped for the DRD4 exon III VNTR and the 5-HTTLPR polymorphisms...
  45. Shin R, Masuda M, Miura M, Sano H, Shirasawa T, Song W, et al. Dopamine D4 receptor-induced postsynaptic inhibition of GABAergic currents in mouse globus pallidus neurons. J Neurosci. 2003;23:11662-72 pubmed
    Dopamine D4 receptors (D4R) are localized in the globus pallidus (GP), but their function remains unknown...
  46. Guillemot F, Caspary T, Tilghman S, Copeland N, Gilbert D, Jenkins N, et al. Genomic imprinting of Mash2, a mouse gene required for trophoblast development. Nat Genet. 1995;9:235-42 pubmed
    ..5 days post-coitum. Finally, we have genetically and physically mapped Mash2 to the distal region of chromosome 7, within a cluster of imprinted genes, including insulin-2, insulin-like growth factor-2 and H19. ..
  47. Yuen E, Zhong P, Yan Z. Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors. Proc Natl Acad Sci U S A. 2010;107:22308-13 pubmed publisher
  48. Javitch J, Shi L, Simpson M, Chen J, Chiappa V, Visiers I, et al. The fourth transmembrane segment of the dopamine D2 receptor: accessibility in the binding-site crevice and position in the transmembrane bundle. Biochemistry. 2000;39:12190-9 pubmed
    ..This inference is supported by observed ligand-specific effects of mutations in this region and by the predicted spatial proximity of this segment to known ligand binding sites in other TMs. ..
  49. Seeman P, Weinshenker D, Quirion R, Srivastava L, Bhardwaj S, Grandy D, et al. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005;102:3513-8 pubmed
    ..lesions, antipsychotics, ethanol, amphetamine, phencyclidine, gene knockouts of Dbh (dopamine beta-hydroxylase), Drd4 receptors, Gprk6 (G protein-coupled receptor kinase 6), Comt (catechol-O-methyltransferase), or Th-/-, DbhTh/+ (..
  50. Li Z, Schmauss C, Cuenca A, Ratcliffe E, Gershon M. Physiological modulation of intestinal motility by enteric dopaminergic neurons and the D2 receptor: analysis of dopamine receptor expression, location, development, and function in wild-type and knock-out mice. J Neurosci. 2006;26:2798-807 pubmed
    ..Because motility is abnormal when D2 is absent, the net inhibitory DA effect on motility is physiologically significant. The early expression of DA receptors is also consistent with the possibility that DA affects ENS development. ..
  51. Hwang C, Chaurasia S, Jackson C, Chan G, Storm D, Iuvone P. Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells. J Neurosci. 2013;33:14989-97 pubmed publisher
    ..Hence, we have identified a circadian clock mechanism in a subset of RGCs that modulates an important aspect of retinal physiology and visual processing. ..
  52. Chung W, Goldberg Berman J, Power Kehoe L, Leibel R. Molecular mapping of the tubby (tub) mutation on mouse chromosome 7. Genomics. 1996;32:210-7 pubmed
    ..The gene sulfonylurea receptor was eliminated as a candidate gene for tubby on the basis of its map position, approximately 3.1 +/- 3.1 cM centromeric of tyrosinase and approximately 14.9 +/- 4.8 cM centromeric of Hbb. ..