Gene Symbol: Drd4
Description: dopamine receptor D4
Alias: D4RA, D(4) dopamine receptor, d(2C) dopamine receptor, dopamine D4 receptor, dopamine receptor 4
Species: rat
Products:     Drd4

Top Publications

  1. 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
    ..These findings showed that postsynaptic activation of D4R on the GP neurons reduces GABAergic currents through the suppression of PKA activity. ..
  2. Bai L, Zimmer S, Rickes O, Rohleder N, Holthues H, Engel L, et al. Daily oscillation of gene expression in the retina is phase-advanced with respect to the pineal gland. Brain Res. 2008;1203:89-96 pubmed publisher
    ..nerve growth factor inducible gene-B (NGFI-B), retinoic acid related orphan receptor beta (RORbeta), dopamine D4 receptor, and period2 (Per2) have been simultaneously recorded in the retina and the pineal gland of rats under ..
  3. Klitten L, Rath M, Coon S, Kim J, Klein D, Møller M. Localization and regulation of dopamine receptor D4 expression in the adult and developing rat retina. Exp Eye Res. 2008;87:471-7 pubmed publisher
    ..Dopamine inhibits the synthesis of melatonin in the photoreceptors via Drd4 receptors located on the cell membrane of these cells...
  4. Van Tol H, Bunzow J, Guan H, Sunahara R, Seeman P, Niznik H, et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. 1991;350:610-4 pubmed
    ..Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs. ..
  5. Becker K, Laucht M, El Faddagh M, Schmidt M. The dopamine D4 receptor gene exon III polymorphism is associated with novelty seeking in 15-year-old males from a high-risk community sample. J Neural Transm (Vienna). 2005;112:847-58 pubmed
    In recent years, studies focussing on a possible association between the dopamine D4 receptor (DRD4) gene exon III polymorphism and the personality trait of novelty seeking (NS) have yielded inconsistent results...
  6. Rivera A, Penafiel A, Megias M, Agnati L, López Téllez J, Gago B, et al. Cellular localization and distribution of dopamine D(4) receptors in the rat cerebral cortex and their relationship with the cortical dopaminergic and noradrenergic nerve terminal networks. Neuroscience. 2008;155:997-1010 pubmed publisher
    ..The present findings support a major role of the dopamine D(4) receptor in mediating the transmission of cortical dopamine and noradrenaline nerve terminal plexuses. ..
  7. Faraone S, Doyle A, Mick E, Biederman J. Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry. 2001;158:1052-7 pubmed
    ..several studies have shown an association between ADHD and the 7-repeat allele of the dopamine D(4) receptor gene (DRD4), several studies have not. Thus, the status of the ADHD-DRD4 association is uncertain...
  8. Graziane N, Yuen E, Yan Z. Dopamine D4 Receptors Regulate GABAA Receptor Trafficking via an Actin/Cofilin/Myosin-dependent Mechanism. J Biol Chem. 2009;284:8329-36 pubmed publisher
  9. Kim J, Bailey M, Weller J, Sugden D, Rath M, Møller M, et al. Thyroid hormone and adrenergic signaling interact to control pineal expression of the dopamine receptor D4 gene (Drd4). Mol Cell Endocrinol. 2010;314:128-35 pubmed publisher
    ..through actions mediated by specific G-protein-coupled receptors, one of which is the dopamine receptor D4 (Drd4). Here we present studies on the >100-fold daily rhythm in rat pineal Drd4 expression...

More Information


  1. Beaulieu J, Gainetdinov R. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182-217 pubmed publisher
  2. Nemirovsky S, Avale M, Brunner D, Rubinstein M. Reward-seeking and discrimination deficits displayed by hypodopaminergic mice are prevented in mice lacking dopamine D4 receptors. Synapse. 2009;63:991-7 pubmed publisher
    The dopamine D4 receptor (D4R) is predominantly expressed in the prefrontal cortex, a brain area that integrates motor, rewarding, and cognitive information...
  3. LaHoste G, Swanson J, Wigal S, Glabe C, Wigal T, King N, et al. Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry. 1996;1:121-4 pubmed
    ..The dopamine D4 receptor, which is preferentially distributed in cortical and limbic regions of the brain, is currently of major ..
  4. Kortagere S, Gmeiner P, Weinstein H, Schetz J. Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain. Mol Pharmacol. 2004;66:1491-9 pubmed
    ..The inferences suggest that subtype selectivity involves two different modes of interaction with the microdomain for the D4-selective 1,4-DAPs and a third mode for D2-selective 1,4-DAPs. ..
  5. Dai X, Ma H, Lu Y, Pan X. [Relationship between dopamine D4 receptor gene polymorphisms and primary nocturnal enuresis]. Zhongguo Dang Dai Er Ke Za Zhi. 2008;10:607-10 pubmed
    To study polymorphisms of dopamine D4 receptor (DRD4) in children with primary nocturnal enuresis (PNE) and explore the relationship between DRD4 gene polymorphisms and PNE...
  6. Van Craenenbroeck K, Borroto Escuela D, Romero Fernandez W, Skieterska K, Rondou P, Lintermans B, et al. Dopamine D4 receptor oligomerization--contribution to receptor biogenesis. FEBS J. 2011;278:1333-44 pubmed publisher
    ..In summary, we conclude that D(4)Rs form oligomers with different affinities and that dimerization plays a role in receptor biogenesis. ..
  7. Martina M, Bergeron R. D1 and D4 dopaminergic receptor interplay mediates coincident G protein-independent and dependent regulation of glutamate NMDA receptors in the lateral amygdala. J Neurochem. 2008;106:2421-35 pubmed publisher
    ..The results of our investigation show for the first time a functional interplay between D1R and D4R that mediates coincident G protein-independent and dependent regulation of NMDARs. ..
  8. Zhang K, Zhang M, He H, Zhang J, Chi W, Guo Y, et al. A family-based association study of dopamine receptor D4 and mental retardation in Qinba region of China. Neurosci Lett. 2012;516:1-4 pubmed publisher
    Dopamine receptor D4 (DRD4) is activated by the neurotransmitter dopamine and links to many neurological and psychiatric conditions because of its close relationship with prefrontal cortex and other important brain regions...
  9. Borroto Escuela D, Van Craenenbroeck K, Romero Fernandez W, Guidolin D, Woods A, Rivera A, et al. Dopamine D2 and D4 receptor heteromerization and its allosteric receptor-receptor interactions. Biochem Biophys Res Commun. 2011;404:928-34 pubmed publisher
    ..The bioinformatic predictions suggest the existence of a basic set of common triplets (ALQ and LRA) in the two participating receptors that may contribute to the receptor-receptor interaction interfaces. ..
  10. Birgner C, Kindlundh Högberg A, Alsiö J, Lindblom J, Schioth H, Bergstrom L. The anabolic androgenic steroid nandrolone decanoate affects mRNA expression of dopaminergic but not serotonergic receptors. Brain Res. 2008;1240:221-8 pubmed publisher
    ..The altered mRNA expression of the dopamine receptors may contribute to some of the behavioural changes often reported in AAS abusers of increased impulsivity, aggression and drug-seeking. ..
  11. Taurines R, Grunblatt E, Schecklmann M, Schwenck C, Albantakis L, Reefschläger L, et al. Altered mRNA expression of monoaminergic candidate genes in the blood of children with attention deficit hyperactivity disorder and autism spectrum disorder. World J Biol Psychiatry. 2011;12 Suppl 1:104-8 pubmed publisher
    ..We analyzed mRNA-expression of monoaminergic candidate genes (DRD4, DRD5, TPH1) in peripheral tissue of patients with attention deficit hyperactivity disorder (ADHD) and autism ..
  12. Kumar U, Patel S. Immunohistochemical localization of dopamine receptor subtypes (D1R-D5R) in Alzheimer's disease brain. Brain Res. 2007;1131:187-96 pubmed
    ..These results demonstrate subtype-specific changes in dopamine receptors in AD that may be important in disease pathophysiology and that may also serve as potential targets for therapeutic intervention in AD. ..
  13. Trantham Davidson H, Burnett E, Gass J, Lopez M, Mulholland P, Centanni S, et al. Chronic alcohol disrupts dopamine receptor activity and the cognitive function of the medial prefrontal cortex. J Neurosci. 2014;34:3706-18 pubmed publisher
    ..These studies are consistent with the suggestion that chronic alcohol exposure disrupts cognitive function at least in part through disruption of D2 and D4 receptor signaling in mPFC. ..
  14. Vergara M, Keller V, Fuentealba J, Gysling K. Activation of type 4 dopaminergic receptors in the prelimbic area of medial prefrontal cortex is necessary for the expression of innate fear behavior. Behav Brain Res. 2017;324:130-137 pubmed publisher
    ..Thus, D4R antagonism in the PL decreases the expression of innate fear-behavior indicating that the activation of D4R in the PL is necessary for the expression of innate fear-behavior. ..
  15. 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
  16. Wedzony K, Chocyk A, Mackowiak M, Fijał K, Czyrak A. Cortical localization of dopamine D4 receptors in the rat brain--immunocytochemical study. J Physiol Pharmacol. 2000;51:205-21 pubmed
    Using polyclonal antibody against dopamine D4 receptor we investigated cortical distribution of D4 receptors, with the special emphasis on regions of the prefrontal cortex...
  17. O Malley K, Harmon S, Tang L, Todd R. The rat dopamine D4 receptor: sequence, gene structure, and demonstration of expression in the cardiovascular system. New Biol. 1992;4:137-46 pubmed
    ..However, 20-fold higher levels of D4 mRNA expression were observed in the cardiovascular system. Thus, this receptor appears to mediate dopamine function in the cardiovascular system as well as the central nervous system. ..
  18. 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. ..
  19. Todd R, Neuman R, Lobos E, Jong Y, Reich W, Heath A. Lack of association of dopamine D4 receptor gene polymorphisms with ADHD subtypes in a population sample of twins. Am J Med Genet. 2001;105:432-8 pubmed
    ..transmission distortion genetic studies of ADHD have focused on the possible involvement of polymorphisms of the DRD4 receptor gene...
  20. Zhang K, Tarazi F, Davids E, Baldessarini R. Plasticity of dopamine D4 receptors in rat forebrain: temporal association with motor hyperactivity following neonatal 6-hydroxydopamine lesioning. Neuropsychopharmacology. 2002;26:625-33 pubmed
    ..These results further support the hypothesis that D(4) receptors may play a pivotal role in lesion-induced hyperactivity, and possibly in clinical ADHD. ..
  21. Asghari V, Schoots O, van Kats S, Ohara K, Jovanovic V, Guan H, et al. Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes. Mol Pharmacol. 1994;46:364-73 pubmed
    ..These data suggest that the polymorphic repeat sequence has little influence on D4 binding profiles and might not be essential for G protein interaction. ..
  22. Li Q, Lu G, Antonio G, Mak Y, Rudd J, Fan M, et al. The usefulness of the spontaneously hypertensive rat to model attention-deficit/hyperactivity disorder (ADHD) may be explained by the differential expression of dopamine-related genes in the brain. Neurochem Int. 2007;50:848-57 pubmed
    ..smaller vermis cerebelli and caudate-putamen (CPu), and there was also a significantly lower level of dopamine D4 receptor gene expression and protein synthesis in the prefrontal cortex (PFC) of SHR...
  23. Romo Parra H, Aceves J, Gutierrez R. Tonic modulation of inhibition by dopamine D4 receptors in the rat hippocampus. Hippocampus. 2005;15:254-9 pubmed
    ..c) 2004 Wiley-Liss, Inc. ..
  24. Paredes U, Bubb V, Haddley K, Macho G, Quinn J. An evolutionary conserved region (ECR) in the human dopamine receptor D4 gene supports reporter gene expression in primary cultures derived from the rat cortex. BMC Neurosci. 2011;12:46 pubmed publisher
    ..contained multiple consensus sequences for binding the transcription factor Sp1, a factor previously implicated in DRD4 expression...
  25. Seabrook G, Knowles M, Brown N, Myers J, Sinclair H, Patel S, et al. Pharmacology of high-threshold calcium currents in GH4C1 pituitary cells and their regulation by activation of human D2 and D4 dopamine receptors. Br J Pharmacol. 1994;112:728-34 pubmed
    ..5. These results demonstrate that GH4C1 pituitary cells have at least two types of dihydropyridine sensitive high-threshold calcium currents and that like D2 receptors, human D4 receptors can also regulate calcium channel function. ..
  26. Gonzalez S, Moreno Delgado D, Moreno E, Pérez Capote K, Franco R, Mallol J, et al. Circadian-related heteromerization of adrenergic and dopamine D? receptors modulates melatonin synthesis and release in the pineal gland. PLoS Biol. 2012;10:e1001347 pubmed publisher
    ..The unanticipated heteromerization between adrenergic and dopamine D? receptors provides a feedback mechanism for the neuronal hormone system in the form of dopamine to control circadian inputs...
  27. Comings D, Gonzalez N, Wu S, Gade R, Muhleman D, Saucier G, et al. Studies of the 48 bp repeat polymorphism of the DRD4 gene in impulsive, compulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. Am J Med Genet. 1999;88:358-68 pubmed
    ..the presence of the 7 repeat allele of the 48 bp repeat polymorphism of the third cytoplasmic loop of the dopamine D4 receptor gene (DRD4) and novelty seeking behaviors, attention deficit hyperactivity disorder (ADHD), Tourette ..
  28. Kustanovich V, Ishii J, Crawford L, Yang M, McGough J, McCracken J, et al. Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5. Mol Psychiatry. 2004;9:711-7 pubmed
    ..important for the synthesis, uptake, transport and receptor binding of dopamine in the etiology of ADHD, including DRD4, DAT1, DRD2, and DRD5...
  29. Yuen E, Zhong P, Li X, Wei J, Yan Z. Restoration of glutamatergic transmission by dopamine D4 receptors in stressed animals. J Biol Chem. 2013;288:26112-20 pubmed publisher
    ..The dopamine D4 receptor, which is enriched in PFC, has been implicated in mental disorders, such as attention deficit-hyperactivity ..
  30. Zarei S, Frieden M, Rubi B, Villemin P, Gauthier B, Maechler P, et al. Dopamine modulates von Willebrand factor secretion in endothelial cells via D2-D4 receptors. J Thromb Haemost. 2006;4:1588-95 pubmed
    ..In contrast, D1 and D5 receptors are not functionally expressed in cultured endothelial cells. Dopamine agonists may be useful as inhibitors of endothelial activation in inflammation and cardiovascular disease. ..
  31. Yuen E, Yan Z. Cellular mechanisms for dopamine D4 receptor-induced homeostatic regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. J Biol Chem. 2011;286:24957-65 pubmed publisher
  32. Barr C, Wigg K, Zovko E, Sandor P, Tsui L. No evidence for a major gene effect of the dopamine D4 receptor gene in the susceptibility to Gilles de la Tourette syndrome in five Canadian families. Am J Med Genet. 1996;67:301-5 pubmed
    ..In this paper we test the hypothesis that the dopamine D4 receptor (DRD4) is linked to the genetic susceptibility to TS in five families...
  33. Floran B, Floran L, Erlij D, Aceves J. Dopamine D4 receptors inhibit depolarization-induced [3H]GABA release in the rat subthalamic nucleus. Eur J Pharmacol. 2004;498:97-102 pubmed
    ..3H]GABA release was evoked by high K+ in slices of the nucleus. The selective dopamine D4 receptor agonist PD168,077 (N-[[4-(2-cyanophenyl)-1-piperazynil]methyl]-3-methyl-benzamide) inhibited GABA release ..
  34. Shin Y, Kumar U, Patel Y, Patel S, Sidhu A. Differential expression of D2-like dopamine receptors in the kidney of the spontaneously hypertensive rat. J Hypertens. 2003;21:199-207 pubmed
  35. Chio C, Drong R, Riley D, Gill G, Slightom J, Huff R. D4 dopamine receptor-mediated signaling events determined in transfected Chinese hamster ovary cells. J Biol Chem. 1994;269:11813-9 pubmed
    ..D4 receptors, like other G(i)/G(o)-linked receptors, mediate multiple signaling events, and the pathways activated are similar to those used by D2 and D3 receptors expressed in similar cells. ..
  36. Rivera A, Cuellar B, Girón F, Grandy D, de la Calle A, Moratalla R. Dopamine D4 receptors are heterogeneously distributed in the striosomes/matrix compartments of the striatum. J Neurochem. 2002;80:219-29 pubmed
    ..aspects of striatal function, exploratory behaviour and motor co-ordination, require the integrity of the dopamine D4 receptor subtype. These receptors are also implicated in the pathophysiology of certain neuropsychiatric disorders...
  37. Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z. Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: evidence of linkage and association with the SNP -616. Am J Med Genet B Neuropsychiatr Genet. 2004;131B:33-7 pubmed
    ..Support for this has come from numerous association studies on candidate genes including the dopamine D4 receptor gene (DRD4)...
  38. 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
  39. Wang X, Gu Z, Zhong P, Chen G, Feng J, Yan Z. Aberrant regulation of NMDA receptors by dopamine D4 signaling in rats after phencyclidine exposure. Mol Cell Neurosci. 2006;31:15-25 pubmed
  40. Lanau F, Zenner M, Civelli O, Hartman D. Epinephrine and norepinephrine act as potent agonists at the recombinant human dopamine D4 receptor. J Neurochem. 1997;68:804-12 pubmed
    ..Functional activation of the D4R by multiple neurotransmitters may provide a novel mechanism for integration of catecholamine signaling in the brain and periphery. ..
  41. Marley A, von Zastrow M. DISC1 regulates primary cilia that display specific dopamine receptors. PLoS ONE. 2010;5:e10902 pubmed publisher
    ..Our findings provide new insight to receptor cell biology and suggest a relationship between DISC1 and neural dopamine signaling. ..
  42. Hehar H, Yeates K, Kolb B, Esser M, Mychasiuk R. Impulsivity and Concussion in Juvenile Rats: Examining Molecular and Structural Aspects of the Frontostriatal Pathway. PLoS ONE. 2015;10:e0139842 pubmed publisher
    ..the nucleus accumbens (NAc) and the prefrontal cortex (PFC), the expression patterns of 8 genes (Comt, Drd2, Drd3, Drd4, Maoa, Sert, Tph1, and Tph2) from these two regions were examined...
  43. Cocker P, Hosking J, Murch W, Clark L, Winstanley C. Activation of dopamine D4 receptors within the anterior cingulate cortex enhances the erroneous expectation of reward on a rat slot machine task. Neuropharmacology. 2016;105:186-195 pubmed publisher
    ..The dopamine D4 receptor critically mediates the erroneous reward expectancy generated on such trials...
  44. 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...
  45. 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
  46. Melis M, Succu S, Mascia M, Argiolas A. PD-168077, a selective dopamine D4 receptor agonist, induces penile erection when injected into the paraventricular nucleus of male rats. Neurosci Lett. 2005;379:59-62 pubmed
    ..The present results show that D4 dopamine receptors present in the paraventricular nucleus may influence penile erection by modulating the activity of paraventricular oxytocinergic neurons mediating erectile function. ..
  47. Griffon N, Jeanneteau F, Prieur F, Diaz J, Sokoloff P. CLIC6, a member of the intracellular chloride channel family, interacts with dopamine D(2)-like receptors. Brain Res Mol Brain Res. 2003;117:47-57 pubmed
  48. Wang X, Li F, Jose P, Ecelbarger C. Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II. Am J Physiol Renal Physiol. 2010;299:F1164-70 pubmed publisher
    ..Increased angiotensin II type 1 receptor activity may be mechanistically involved in the decreased expression of D1R and D2R in obese rats. Finally, reduced D1R and D3R in male rats may contribute to sex differences in blood pressure. ..
  49. Svingos A, Periasamy S, Pickel V. Presynaptic dopamine D(4) receptor localization in the rat nucleus accumbens shell. Synapse. 2000;36:222-32 pubmed
    ..These results provide the first ultrastructural evidence for a major presynaptic, and a more minor postsynaptic, involvement of D(4) receptors in dopaminergic modulation of excitatory transmission in the AcbSh. ..
  50. Eisenberg J, Zohar A, Mei Tal G, Steinberg A, Tartakovsky E, Gritsenko I, et al. A haplotype relative risk study of the dopamine D4 receptor (DRD4) exon III repeat polymorphism and attention deficit hyperactivity disorder (ADHD). Am J Med Genet. 2000;96:258-61 pubmed
    ..Several investigations have recently examined the role of the dopamine DRD4 exon III repeat polymorphism in ADHD...
  51. Azdad K, Piet R, Poulain D, Oliet S. Dopamine D4 receptor-mediated presynaptic inhibition of GABAergic transmission in the rat supraoptic nucleus. J Neurophysiol. 2003;90:559-65 pubmed
    ..Therefore dopaminergic facilitation of neurohypophysial hormone release appears to result, at least in part, from disinhibition of magnocellular neurons caused by the depression of GABAergic transmission. ..
  52. Laviolette S, Lipski W, Grace A. A subpopulation of neurons in the medial prefrontal cortex encodes emotional learning with burst and frequency codes through a dopamine D4 receptor-dependent basolateral amygdala input. J Neurosci. 2005;25:6066-75 pubmed
    ..These results demonstrate that individual neurons in the mPFC that receive a functional input from the BLA actively encode emotional learning and that this process depends on DA D4 receptor stimulation in the mPFC. ..
  53. Bellgrove M, Hawi Z, Lowe N, Kirley A, Robertson I, Gill M. DRD4 gene variants and sustained attention in attention deficit hyperactivity disorder (ADHD): effects of associated alleles at the VNTR and -521 SNP. Am J Med Genet B Neuropsychiatr Genet. 2005;136B:81-6 pubmed
    Associations between attention deficit hyperactivity disorder (ADHD) and genetic variants within the dopamine D4 receptor gene have been much reported...