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Gene Review

DRD4  -  dopamine receptor D4

Homo sapiens

Synonyms: D(2C) dopamine receptor, D(4) dopamine receptor, Dopamine D4 receptor
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Disease relevance of DRD4

  • At a theoretic level, the current results suggest a novel link between evolutionary models of seasonal weight gain on the one hand and the DRD4 gene on the other [1].
  • RESULTS: No association was detected using the TDT between DRD3, DRD4, and migraine without aura either in the overall sample or in the subgroup [2].
  • We compared rates of binge eating behavior in the two genotypic groups defined by the presence or absence of the seven-repeat allele of DRD4 [1].
  • In overeating women with SAD, the 7R allele of DRD4 may be associated with a unique developmental trajectory characterized by attentional deficits and dysphoria in childhood and mild to moderate obesity in adulthood [3].
  • OBJECTIVE: This study examined the association of the dopamine receptor D4 (DRD4) gene polymorphism with the temperament dimension of novelty seeking (NS) on cardiovascular heart disease risk factors [the levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides] [4].

Psychiatry related information on DRD4


High impact information on DRD4

  • The dopamine D4 receptor structurally and pharmacologically resembles the dopamine D2 and D3 receptors [11].
  • CONCLUSIONS: Our results provide significant evidence for exclusion for linkage between schizophrenia and the dopamine D4 receptor gene and the TH gene under the models specified [12].
  • With use of polymerase chain reaction amplification, we assessed this variable number of tandem repeats polymorphism in a series of schizophrenic and schizoaffective subjects who had been treated with clozapine, and related genotype with treatment response, to test the hypothesis that DRD4 alleles lead to varying response to clozapine [13].
  • RESULTS: Allelic variation at the DRD4 locus does not predict clinical response to clozapine relative to either fluphenazine hydrochloride or placebo in subjects with treatment-refractory schizophrenia or schizoaffective disorder [13].
  • Recently, on the basis of the unusual DNA sequence organization of the DRD4 7R 48-bp tandem repeat (VNTR), we proposed that the 7R allele originated as a rare mutational event that increased to high frequency by positive selection [14].

Chemical compound and disease context of DRD4


Biological context of DRD4

  • To examine whether this genetic variation might contribute to differences in brain activation within the anterior cingulate cortex, we genotyped 16 subjects for the DRD4 and MAOA genes who had been scanned during the ANT [5].
  • The 7-repeat form of the DRD4 III exon VNTR polymorphism has been associated with childhood ADHD, and recently we have reported its link with attachment disorganization in a nonclinical population of infants [18].
  • These genotype effects were not redundant with the previously reported association between the 7-repeat DRD4 allele and disorganized attachment behavior [18].
  • Several studies have reported an association between clinically defined ADHD and the seven-repeat allele of a 48-bp tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene (DRD4) [19].
  • We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample [20].

Anatomical context of DRD4

  • To test this "peripheral marker hypothesis", we compared mRNA expression of the dopamine receptors D3 (DRD3) and D4 (DRD4) in peripheral blood lymphocytes (PBL) to personality traits assessed with the Temperament and Character Inventory (TCI) in 50 healthy and unmedicated Caucasian individuals [21].
  • As peripheral blood lymphocytes (PBL) may represent a tool for peripheral detection of neuroreceptors, we compared the expression of dopamine D3 (DRD3) and D4 (DRD4) receptors on PBL in migraine patients and in healthy controls using radioligand binding assay techniques in the presence of antidopamine D2-like receptor antibodies [22].
  • RESULTS: Endogenous mRNA expression of the DRD4 gene was demonstrated in two neuroblastoma (SK-N-F1, IMR32) and one retinoblastoma cell line (Y79) by RT-PCR [23].
  • In addition, very low DRD4 mRNA levels were also detected in HeLa cells [23].
  • Low levels of mRNA for dopamine D4 receptor in human cerebral cortex and striatum [24].

Associations of DRD4 with chemical compounds


Physical interactions of DRD4

  • On the whole, our results lend credence to the notion that the relationship between the DRD4 receptor and ADHD is complex and may be reflecting linkage disequilibrium between the 7 or long DRD4 exon III repeats and a 'true' risk allele in this gene or a neighboring locus [29].
  • (pRa,pSb)-(+)-5-(2-Propylidene)-10-(1,2,3,6-tetrahydro-1-met hyl- 4-pyridinyl)-5H-dibenzo[a,d]cycloheptene is 17 times more active in binding to the dopamine D-4 receptor than is its pSa,pRb enantiomer while being only 1.5 times more active in binding to the dopamine D-2 receptor [30].

Regulatory relationships of DRD4


Other interactions of DRD4

  • This provides additional evidence that the DRD4 gene is associated with a refined phenotype of ADHD [33].
  • No significant association was observed for the DRD4, COMT, or MAO(A) polymorphisms [34].
  • Neither the DRD2 S311C polymorphism nor the presence of long alleles for the DRD4 exon III repeat sequence was associated with psychosis or aggression [35].
  • The recently cloned D4 dopamine receptor gene (DRD4) shows considerable homology to the D2 and D3 dopamine receptors (DRD2 and DRD3); pharmacologically, its affinity for the atypical antipsychotic clozapine is much higher than that of these other dopamine receptors [36].
  • The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS [36].

Analytical, diagnostic and therapeutic context of DRD4

  • Four hundred and sixty-one inpatients affected by major psychoses were assessed by the operational criteria checklist for psychotic illness (OPCRIT) and were also typed for the DRD4 and GABRA1 variants using PCR techniques [31].
  • The meta-analysis of DRD4 included data from 13 studies, with a total of 571 informative meioses [37].
  • However, a significantly higher perfusion in the right middle temporal gyrus was found in the group with risk alleles at both DRD4 and DAT1 loci (n = 6) compared to ADHD boys without risk alleles at both loci (n = 28) (P < 0.05) [38].
  • The rCBF was compared between ADHD patients with and without risk alleles at DRD4 (7-repeat allele) and/or at DAT1 (homozygosis for the 10-repeat allele) genes by single photon emission computed tomography (SPECT) during continuous performance test [38].
  • BACKGROUND: We recently described a preliminary association between the hypofunctional seven-repeat allele of the dopamine-4 receptor gene (DRD4) and increased maximal lifetime body mass index in women with seasonal affective disorder (SAD) [1].


  1. The dopamine-4 receptor gene associated with binge eating and weight gain in women with seasonal affective disorder: an evolutionary perspective. Levitan, R.D., Masellis, M., Basile, V.S., Lam, R.W., Kaplan, A.S., Davis, C., Muglia, P., Mackenzie, B., Tharmalingam, S., Kennedy, S.H., Macciardi, F., Kennedy, J.L. Biol. Psychiatry (2004) [Pubmed]
  2. Association between dopamine receptor genes and migraine without aura in a Sardinian sample. Del Zompo, M., Cherchi, A., Palmas, M.A., Ponti, M., Bocchetta, A., Gessa, G.L., Piccardi, M.P. Neurology (1998) [Pubmed]
  3. Childhood inattention and dysphoria and adult obesity associated with the dopamine D4 receptor gene in overeating women with seasonal affective disorder. Levitan, R.D., Masellis, M., Lam, R.W., Muglia, P., Basile, V.S., Jain, U., Kaplan, A.S., Tharmalingam, S., Kennedy, S.H., Kennedy, J.L. Neuropsychopharmacology (2004) [Pubmed]
  4. Relationship between DRD4 polymorphism and lipid metabolism: what is the role of novelty seeking? Elovainio, M., Puttonen, S., Heponiemi, T., Reuter, M., Kivimaki, M., Viikari, J., Keltikangas-Jarvinen, L. Neuropsychobiology (2005) [Pubmed]
  5. Mapping the genetic variation of executive attention onto brain activity. Fan, J., Fossella, J., Sommer, T., Wu, Y., Posner, M.I. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  6. Dopamine D4 receptor and tyrosine hydroxylase genes in bipolar disorder: evidence for a role of DRD4. Muglia, P., Petronis, A., Mundo, E., Lander, S., Cate, T., Kennedy, J.L. Mol. Psychiatry (2002) [Pubmed]
  7. Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. LaHoste, G.J., Swanson, J.M., Wigal, S.B., Glabe, C., Wigal, T., King, N., Kennedy, J.L. Mol. Psychiatry (1996) [Pubmed]
  8. Two dopamine genes related to reports of childhood retrospective inattention and conduct disorder symptoms. Rowe, D.C., Stever, C., Chase, D., Sherman, S., Abramowitz, A., Waldman, I.D. Mol. Psychiatry (2001) [Pubmed]
  9. Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders. Serretti, A., Cristina, S., Lilli, R., Cusin, C., Lattuada, E., Lorenzi, C., Corradi, B., Grieco, G., Costa, A., Santorelli, F., Barale, F., Nappi, G., Smeraldi, E. Am. J. Med. Genet. (2002) [Pubmed]
  10. Interactive effects of a DRD4 polymorphism, lead, and sex on executive functions in children. Froehlich, T.E., Lanphear, B.P., Dietrich, K.N., Cory-Slechta, D.A., Wang, N., Kahn, R.S. Biol. Psychiatry (2007) [Pubmed]
  11. Multiple dopamine D4 receptor variants in the human population. Van Tol, H.H., Wu, C.M., Guan, H.C., Ohara, K., Bunzow, J.R., Civelli, O., Kennedy, J., Seeman, P., Niznik, H.B., Jovanovic, V. Nature (1992) [Pubmed]
  12. Analysis of the D4 dopamine receptor gene variant in an Italian schizophrenia kindred. Macciardi, F., Petronis, A., Van Tol, H.H., Marino, C., Cavallini, M.C., Smeraldi, E., Kennedy, J.L. Arch. Gen. Psychiatry (1994) [Pubmed]
  13. Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Rao, P.A., Pickar, D., Gejman, P.V., Ram, A., Gershon, E.S., Gelernter, J. Arch. Gen. Psychiatry (1994) [Pubmed]
  14. The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Wang, E., Ding, Y.C., Flodman, P., Kidd, J.R., Kidd, K.K., Grady, D.L., Ryder, O.A., Spence, M.A., Swanson, J.M., Moyzis, R.K. Am. J. Hum. Genet. (2004) [Pubmed]
  15. Dopamine receptor D2 and D4 genes, GABA(A) alpha-1 subunit genes and response to lithium prophylaxis in mood disorders. Serretti, A., Lilli, R., Lorenzi, C., Franchini, L., Di Bella, D., Catalano, M., Smeraldi, E. Psychiatry research. (1999) [Pubmed]
  16. Gene-environment interaction in hyperkinetic conduct disorder (HD + CD) as indicated by season of birth variations in dopamine receptor (DRD4) gene polymorphism. Seeger, G., Schloss, P., Schmidt, M.H., Rüter-Jungfleisch, A., Henn, F.A. Neurosci. Lett. (2004) [Pubmed]
  17. 1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction. Kolasa, T., Matulenko, M.A., Hakeem, A.A., Patel, M.V., Mortell, K., Bhatia, P., Henry, R., Nakane, M., Hsieh, G.C., Terranova, M.A., Uchic, M.E., Miller, L.N., Chang, R., Donnelly-Roberts, D.L., Namovic, M.T., Hollingsworth, P.R., Martino, B., El Kouhen, O., Marsh, K.C., Wetter, J.M., Moreland, R.B., Brioni, J.D., Stewart, A.O. J. Med. Chem. (2006) [Pubmed]
  18. Association of D4 dopamine receptor gene and serotonin transporter promoter polymorphisms with infants' response to novelty. Lakatos, K., Nemoda, Z., Birkas, E., Ronai, Z., Kovacs, E., Ney, K., Toth, I., Sasvari-Szekely, M., Gervai, J. Mol. Psychiatry (2003) [Pubmed]
  19. The dopamine D4 receptor and the hyperactivity phenotype: a developmental-epidemiological study. Mill, J.S., Caspi, A., McClay, J., Sugden, K., Purcell, S., Asherson, P., Craig, I., McGuffin, P., Braithwaite, A., Poulton, R., Moffitt, T.E. Mol. Psychiatry (2002) [Pubmed]
  20. High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder. Grady, D.L., Chi, H.C., Ding, Y.C., Smith, M., Wang, E., Schuck, S., Flodman, P., Spence, M.A., Swanson, J.M., Moyzis, R.K. Mol. Psychiatry (2003) [Pubmed]
  21. Dopamine receptor D3 mRNA expression in human lymphocytes is negatively correlated with the personality trait of persistence. Czermak, C., Lehofer, M., Renger, H., Wagner, E.M., Lemonis, L., Rohrhofer, A., Schauenstein, K., Liebmann, P.M. J. Neuroimmunol. (2004) [Pubmed]
  22. Migraine patients show an increased density of dopamine D3 and D4 receptors on lymphocytes. Barbanti, P., Fabbrini, G., Ricci, A., Pascali, M.P., Bronzetti, E., Amenta, F., Lenzi, G.L., Cerbo, R. Cephalalgia : an international journal of headache. (2000) [Pubmed]
  23. No direct effect of the -521 C/T polymorphism in the human dopamine D4 receptor gene promoter on transcriptional activity. Kereszturi, E., Kiraly, O., Barta, C., Molnar, N., Sasvari-Szekely, M., Csapo, Z. BMC Mol. Biol. (2006) [Pubmed]
  24. Low levels of mRNA for dopamine D4 receptor in human cerebral cortex and striatum. Matsumoto, M., Hidaka, K., Tada, S., Tasaki, Y., Yamaguchi, T. J. Neurochem. (1996) [Pubmed]
  25. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Li, D., Sham, P.C., Owen, M.J., He, L. Hum. Mol. Genet. (2006) [Pubmed]
  26. Association analysis of the DRD4 and COMT genes in methamphetamine abuse. Li, T., Chen, C.K., Hu, X., Ball, D., Lin, S.K., Chen, W., Sham, P.C., Loh, e.l.-.W., Murray, R.M., Collier, D.A. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  27. L -dopa-induced adverse effects in PD and dopamine transporter gene polymorphism. Kaiser, R., Hofer, A., Grapengiesser, A., Gasser, T., Kupsch, A., Roots, I., Brockmöller, J. Neurology (2003) [Pubmed]
  28. Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR, and COMT val/met variants. Strobel, A., Lesch, K.P., Jatzke, S., Paetzold, F., Brocke, B. Mol. Psychiatry (2003) [Pubmed]
  29. The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA). Manor, I., Tyano, S., Eisenberg, J., Bachner-Melman, R., Kotler, M., Ebstein, R.P. Mol. Psychiatry (2002) [Pubmed]
  30. Binding of 5H-dibenzo[b,e][1,4]diazepine and chiral 5H-dibenzo[a,d]cycloheptene analogues of clozapine to dopamine and serotonin receptors. Phillips, S.T., de Paulis, T., Baron, B.M., Siegel, B.W., Seeman, P., Van Tol, H.H., Guan, H.C., Smith, H.E. J. Med. Chem. (1994) [Pubmed]
  31. No interaction of GABA(A) alpha-1 subunit and dopamine receptor D4 exon 3 genes in symptomatology of major psychoses. Serretti, A., Macciardi, F., Cusin, C., Lattuada, E., Lilli, R., Di Bella, D., Catalano, M., Smeraldi, E. Am. J. Med. Genet. (1999) [Pubmed]
  32. A dopamine D4 receptor antagonist attenuates ischemia-induced neuronal cell damage via upregulation of neuronal apoptosis inhibitory protein. Okada, Y., Sakai, H., Kohiki, E., Suga, E., Yanagisawa, Y., Tanaka, K., Hadano, S., Osuga, H., Ikeda, J.E. J. Cereb. Blood Flow Metab. (2005) [Pubmed]
  33. Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach. Swanson, J.M., Sunohara, G.A., Kennedy, J.L., Regino, R., Fineberg, E., Wigal, T., Lerner, M., Williams, L., LaHoste, G.J., Wigal, S. Mol. Psychiatry (1998) [Pubmed]
  34. Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism. Arbelle, S., Benjamin, J., Golin, M., Kremer, I., Belmaker, R.H., Ebstein, R.P. The American journal of psychiatry. (2003) [Pubmed]
  35. Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer disease. Sweet, R.A., Nimgaonkar, V.L., Kamboh, M.I., Lopez, O.L., Zhang, F., DeKosky, S.T. Arch. Neurol. (1998) [Pubmed]
  36. The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS. Gelernter, J., Kennedy, J.L., van Tol, H.H., Civelli, O., Kidd, K.K. Genomics (1992) [Pubmed]
  37. Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis. Maher, B.S., Marazita, M.L., Ferrell, R.E., Vanyukov, M.M. Psychiatr. Genet. (2002) [Pubmed]
  38. Brain perfusion and dopaminergic genes in boys with attention-deficit/hyperactivity disorder. Szobot, C., Roman, T., Cunha, R., Acton, P., Hutz, M., Rohde, L.A. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
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