Multiple dopamine D4 receptor variants in the human population

Tol, Hubert H. M. Van; Wu, Caren M.; Guan, Hong-Chang; Ohara, Koichi; Bunzow, James R.; Civelli, Olivier; Kennedy, James; Seeman, Philip; Niznik, Hyman B.; Jovanovic, Vera

doi:10.1038/358149a0

Cited by 961Neurotransmitter Receptor Influence on BehaviorSchizophrenia research and treatmentReceptor Mechanisms and Signaling

Multiple dopamine D4 receptor variants in the human population

Tol, Hubert H. M. Van, Wu, Caren M., Guan, Hong-Chang, Ohara, Koichi, Bunzow, James R., Civelli, Olivier, Kennedy, James, Seeman, Philip +2 more·1992·Nature

DOI 10.1038/358149a0

Open this paper in CoChat — free account

Abstract

The dopamine D4 receptor structurally and pharmacologically resembles the dopamine D2 and D3 receptors. Clozapine, an atypical antipsychotic that is relatively free of the adverse effects of drug-induced parkinsonism and tardive dyskinesia, binds to the D4 receptor with an affinity 10 times higher than to the D2 and D3 receptors. This may explain clozapine's atypical properties. Here we report the existence of at least three polymorphic variations in the coding sequence of the human D4 receptor. A 48-base-pair sequence in the putative third cytoplasmic loop of this receptor exists either as a direct-repeat sequence (D4.2), as a fourfold repeat (D4.4) or as a sevenfold repeat (D4.7). Two more variant alleles were detected in humans. Expression of the complementary DNA for the three cloned receptor variants showed different properties for the long form (D4.7) and the shorter forms (D4.2, D4.4) with respect to clozapine and spiperone binding. To our knowledge, this is the first report of a receptor in the catecholamine receptor family that displays polymorphic variation in the human population. Such variation among humans may underlie individual differences in susceptibility to neuropsychiatric disease and in responsiveness to antipsychotic medication.

Integrity signals

Registry

Crossref · 10.1038/358149a0

Cites

20 of 20 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Functional significance of the DRD4 48-bp exon III VNTR polymorphism has been demonstrated.
“Functional significance of this polymorphism has been demonstrated [70–75].”
From Genetics of child aggression, a systematic review (2024) · cites this paper as [70]

Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate–Phenol–Chloroform Extraction
Chomczynski, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1006/abio.1987.9999 · Cited by 65,240 · see citing works
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
Chomczyński, P., & Sacchi, N. (1987) · Analytical Biochemistry · doi:10.1016/0003-2697(87)90021-2 · Cited by 47,092 · see citing works
A simple and very efficient method for generating cDNA libraries
Gubler, U., & Hoffman, B. J. (1983) · Gene · doi:10.1016/0378-1119(83)90230-5 · Cited by 4,461 · see citing works
Clozapine for the Treatment-Resistant Schizophrenic: A Double-blind Comparison With Chlorpromazine
Kane, J. (1988) · Archives of General Psychiatry · doi:10.1001/archpsyc.1988.01800330013001 · Cited by 4,156 · see citing works
A catalogue of splice junction sequences
Mount, S. M. (1982) · Nucleic Acids Research · doi:10.1093/nar/10.2.459 · Cited by 3,881 · see citing works
Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy
Spada, A. L., Wilson, E. M., Lubahn, D. B., Harding, A., & Fischbeck, K. (1991) · Nature · doi:10.1038/352077a0 · Cited by 2,801 · see citing works
Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member
Brook, J. D., McCurrach, M. E., Harley, H. G., Buckler, A., Church, D. M., Aburatani, H., Hunter, K. W., Stanton, V. P., Thirion, J., Hudson, T. J., et al. (1992) · Cell · doi:10.1016/0092-8674(92)90154-5 · Cited by 2,754 · see citing works
Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics
Sokoloff, P., Bruno Giros, A., Martres, M., Bouthenet, M.-L., & Schwartz, J. (1990) · Nature · doi:10.1038/347146a0 · Cited by 2,608 · see citing works
Analysis of single- and double-stranded nucleic acids on polyacrylamide and agarose gels by using glyoxal and acridine orange.
McMaster, G. K., & Carmichael, G. (1977) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.74.11.4835 · Cited by 2,406 · see citing works
Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine
Tol, H. H. M. V., Bunzow, J. R., Guan, H., Sunahara, R. K., Seeman, P. M., Niznik, H. B., & Civelli, O. (1991) · Nature · doi:10.1038/350610a0 · Cited by 2,015 · see citing works
Self-citation
Instability of a 550-Base Pair DNA Segment and Abnormal Methylation in Fragile X Syndrome
Oberlé, I., Rousseau, F., Heitz, D., Kretz, C., Devys, D., Hanauer, A., Boué, J., Bertheas, M. F., & Mandel, J. L. (1991) · Science · doi:10.1126/science.252.5009.1097 · Cited by 1,499 · see citing works
Cloning and expression of a rat D2 dopamine receptor cDNA
Bunzow, J. R., Tol, H. H. M. V., Grandy, D. K., Albert, P. R., Salon, J. A., Christie, M. J., Machida, C. A., Neve, K. A., & Civelli, O. (1988) · Nature · doi:10.1038/336783a0 · Cited by 1,116 · see citing works
Self-citation
Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes
Bonner, T. I., Young, A. C., Brann, M. R., & Buckley, N. J. (1988) · Neuron · doi:10.1016/0896-6273(88)90190-0 · Cited by 783 · see citing works
The dopamine D2 receptor: two molecular forms generated by alternative splicing.
Toso, R. D., Sommer, B., Ewert, M., Herb, A., Pritchett, D. B., Bach, A., Shivers, B. D., & SEEBURG, P. H. (1989) · The EMBO Journal · doi:10.1002/j.1460-2075.1989.tb08585.x · Cited by 600 · see citing works
Linkage of a Cardiac Arrhythmia, the Long QT Syndrome, and the Harvey ras -1 Gene
Keating, M. T., Atkinson, D. L., Dunn, C., Timothy, K. W., Vincent, G. M., & Leppert, M. (1991) · Science · doi:10.1126/science.1673802 · Cited by 516 · see citing works
Cloning of the cDNA and gene for a human D2 dopamine receptor.
Grandy, D. K., Marchionni, M. A., Makam, H., Stofko, R. E., Alfano, M., Frothingham, L., Fischer, J., Burke-Howie, K. J., Bunzow, J. R., & Server, A. C. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.24.9762 · Cited by 486 · see citing works
Self-citation
Re-evaluation of the linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish
Kelsoe, J. R., Ginns, E. I., Egeland, J. A., Gerhard, D. S., Goldstein, A. M., Bale, S. J., Pauls, D. L., Long, R. T. L., Kídd, K. K., Conte, G. L., et al. (1989) · Nature · doi:10.1038/342238a0 · Cited by 440 · see citing works
A reappraisal of non-consensus mRNA splice sites
Jackson, I. J. (1991) · Nucleic Acids Research · doi:10.1093/nar/19.14.3795 · Cited by 322 · see citing works
Clozapine: neuroleptic-induced EPS and tardive dyskinesia
Casey, D. E. (1989) · Psychopharmacology · doi:10.1007/bf00442559 · Cited by 252 · see citing works
The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS
Gelernter, J. E., Kennedy, J. L., Tol, H. H. M. V., Civelli, O., & Kídd, K. K. (1992) · Genomics · doi:10.1016/0888-7543(92)90222-e · Cited by 128 · see citing works
Self-citation

Flagged first, then by citations

Sorted by citations

A JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Lindemann, L., Jaeschke, G., Michalon, A., Vieira, E., Honer, M., Spooren, W., Porter, R., Hartung, T., Kolczewski, S., Büttelmann, B., et al. (1909) · JAMA · doi:10.1001/jama.1909.02550020033007 · Cited by 7,865 · see citing works
Dopamine receptors: from structure to function
MISSALE, C., NASH, S. R., ROBINSON, S. W., JABER, M., & CARON, M. G. (1998) · Physiological Reviews · doi:10.1152/physrev.1998.78.1.189 · Cited by 3,633 · see citing works
The physiology, signaling, and pharmacology of dopamine receptors
Beaulieu, J.-M., & Gainetdinov, R. R. (2011) · Pharmacological Reviews · doi:10.1124/pr.110.002642 · Cited by 2,763 · see citing works
Molecular genetics of attention-deficit/hyperactivity disorder
Faraone, S. V., Perlis, R. H., Doyle, A. E., Smoller, J. W., Goralnick, J. J., Holmgren, M. A., & Sklar, P. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.11.024 · Cited by 2,357 · see citing works
Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking
Ebstein, R. P., Novick, O., Umansky, R., Priel, B., Osher, Y., Blaine, D., Bennett, E. R., Nemanov, L., Katz, M., & Belmaker, R. H. (1996) · Nature Genetics · doi:10.1038/ng0196-78 · Cited by 1,475 · see citing works
Genetics of attention deficit hyperactivity disorder
Faraone, S. V., & Larsson, H. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0070-0 · Cited by 1,338 · see citing works
Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking
Benjamin, J., Li, L., Patterson, C. A., Greenberg, B. D., Murphy, D. L., & Hamer, D. H. (1996) · Nature Genetics · doi:10.1038/ng0196-81 · Cited by 1,191 · see citing works
Candidate gene studies of ADHD: a meta-analytic review
Gizer, I. R., Ficks, C., & Waldman, I. D. (2009) · Human Genetics · doi:10.1007/s00439-009-0694-x · Cited by 1,020 · see citing works
Are Political Orientations Genetically Transmitted?
Alford, J. R., Funk, C. L., & Hibbing, J. R. (2005) · American Political Science Review · doi:10.1017/s0003055405051579 · Cited by 976 · see citing works
Dopamine receptor pharmacology
Seeman, P. M., & Tol, H. H. M. V. (1994) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(94)90323-9 · Cited by 969 · see citing works
Self-citation
Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder.
Faraone, S., Doyle, A., Mick, E., & Biederman, J. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.7.1052 · Cited by 740 · see citing works
Reward deficiency syndrome: genetic aspects of behavioral disorders
Comings, D. E., & Blum, K. (2000) · Progress in Brain Research · doi:10.1016/s0079-6123(00)26022-6 · Cited by 621 · see citing works
Dopamine D4 receptors elevated in schizophrenia
Seeman, P. M., Guan, H., & Tol, H. H. M. V. (1993) · Nature · doi:10.1038/365441a0 · Cited by 627 · see citing works
Self-citation
Molecular Diversity of the Dopamine Receptors
Civelli, O., Bunzow, J. R., & Grandy, D. K. (1993) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pa.33.040193.001433 · Cited by 623 · see citing works
Self-citation
Dopamine receptors and brain function
Jaber, M., Robinson, S. W., Missale, C., & Caron, M. G. (1996) · Neuropharmacology · doi:10.1016/s0028-3908(96)00100-1 · Cited by 572 · see citing works
A hypervariable segment in the human dopamine receptor D4 (DRD4) gene
Lichter, J. B., Barr, C. L., Kennedy, J. L., Tol, H. H. M. V., Kídd, K. K., & Livak, K. J. (1993) · Human Molecular Genetics · doi:10.1093/hmg/2.6.767 · Cited by 524 · see citing works
Self-citation
Dopamine receptors: Molecular biology, biochemistry and behavioural aspects
Jackson, D. M., & Westlind‐Danielsson, A. (1994) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(94)90041-8 · Cited by 479 · see citing works
Mice Lacking Dopamine D4 Receptors Are Supersensitive to Ethanol, Cocaine, and Methamphetamine
Rubinstein, M., Phillips, T. J., Bunzow, J. R., Falzone, T. L., Dziewczapolski, G., Zhang, G., Fang, Y., Larson, J. L., McDougall, J. A., Chester, J. A., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)80365-7 · Cited by 473 · see citing works
Self-citation
Ultrastructural localization of D2 receptor-like immunoreactivity in midbrain dopamine neurons and their striatal targets
Sesack, Sr., Aoki, C., & Pickel, V. (1994) · The Journal of Neuroscience · doi:10.1523/jneurosci.14-01-00088.1994 · Cited by 461 · see citing works
The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus
Chang, F., Kídd, K. K., Livak, K. J., PAKSTIS, A. J., & Kídd, K. K. (1996) · Human Genetics · doi:10.1007/s004390050166 · Cited by 438 · see citing works
The dopamine D4 receptor: one decade of research
Oak, J. N., Oldenhof, J., & Tol, H. H. M. V. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00562-8 · Cited by 421 · see citing works
Self-citation
Molecular Genetics of Attention Deficit Hyperactivity Disorder
Faraone, S. V., & Mick, E. (2010) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2009.12.004 · Cited by 411 · see citing works
“focused on a tandem repeat polymorphism in exon III of DRD4 because in vitro studies have shown that one variant (the 7-repeat allele) produces a blunted response to dopamine.(26,27) Faraone and colleagues(8) conducted a meta analysis of the 7-repeat allele of the exon III polymorphism and found statistically signific…”
Background
Genetics of dopamine receptors and drug addiction: a comprehensive review
Foll, B. L., Gallo, A., Strat, Y. L., Lü, L., & Gorwood, P. A. P. M. (2009) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e3283242f05 · Cited by 387 · see citing works
The molecular genetic architecture of human personality: beyond self-report questionnaires
Ebstein, R. P. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001814 · Cited by 362 · see citing works
Dopamine, a neurotransmitter, influences the immune system
Basu, S., & Dasgupta, P. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(99)00176-9 · Cited by 335 · see citing works
Association between clozapine response and allelic variation in 5-HT2A receptor gene
Arranz, M. J., Collier, D. A., Sodhi, M., Ball, D., Roberts, G. W., Sham, P. C., Kerwin, R. W., Price, J., & Roberts, G. W. (1995) · The Lancet · doi:10.1016/s0140-6736(95)92168-0 · Cited by 334 · see citing works
Molecular Heterosis: A Review
Comings, D. E., & MacMurray, J. P. (2000) · Molecular Genetics and Metabolism · doi:10.1006/mgme.2000.3015 · Cited by 333 · see citing works
Mechanisms of action of atypical antipsychotic drugs: a critical analysis
Kinon, B. J., & Lieberman, J. A. (1996) · Psychopharmacology · doi:10.1007/bf02245602 · Cited by 317 · see citing works
Dopamine, Immunity, and Disease
Channer, B., Matt, S. M., Nickoloff-Bybel, E. A., Pappa, V., Agarwal, Y., Wickman, J. R., & Gaskill, P. J. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000618 · Cited by 319 · see citing works
The genetic basis for smoking behavior: A systematic review and meta-analysis
Munafo, M. R., Clark, T. G., Johnstone, E. C., Murphy, M., & Walton, R. T. (2004) · Nicotine & Tobacco Research · doi:10.1080/14622200410001734030 · Cited by 312 · see citing works
Pharmacogenetics of Psychotropic Drug Response
Malhotra, A. K., Murphy, G. M., & Kennedy, J. L. (2004) · American Journal of Psychiatry · doi:10.1176/appi.ajp.161.5.780 · Cited by 298 · see citing works
Self-citation
Novel dopamine receptors half a decade later
Sokoloff, P., & Schwartz, J.-C. (1995) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(00)89044-6 · Cited by 295 · see citing works
Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an american indian population
Long, J. C., Knowler, W. C., Hanson, R. L., Robin, R. W., Urbanek, M., Moore, E., Bennett, P. H., & Goldman, D. A. (1998) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19980508)81:3 · Cited by 389 · see citing works
A meta-analysis of the association between DRD4 polymorphism and novelty seeking
Kluger, A. N., Siegfried, Z., & Ebstein, R. P. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4001082 · Cited by 281 · see citing works
Analysis of the monoamine oxidase A (MAOA) gene in bipolar affective disorder by association studies, meta-analyses, and sequencing of the promoter
Furlong, R. A., Ho, L. W., Rubinsztein, J. S., Walsh, C., Paykel, E. S., & Rubinsztein, D. C. (1999) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19990820)88:4 · Cited by 100 · see citing works
Neurobiology of retinal dopamine in relation to degenerative states of the tissue
Djamgoz, M. B. A., Hankins, M. W., Hirano, J., & Archer, S. N. (1997) · Vision Research · doi:10.1016/s0042-6989(97)00129-6 · Cited by 274 · see citing works
Multifinality in the development of personality disorders: A Biology × Sex × Environment interaction model of antisocial and borderline traits
Beauchaine, T. P., Klein, D. N., Crowell, S. E., Derbidge, C. M., & Gatzke‐Kopp, L. M. (2009) · Development and Psychopathology · doi:10.1017/s0954579409000418 · Cited by 263 · see citing works
Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study.
Eisenberg, D. T. A., MacKillop, J., Modi, M. E., Beauchemin, J., Dang, D., Lisman, S. A., Lum, J. K., & Wilson, D. S. (2007) · Behavioral and Brain Functions · doi:10.1186/1744-9081-3-2 · Cited by 257 · see citing works
Population studies of polymorphisms of the serotonin transporter protein gene.
Gelernter, J. E., Cubells, J. F., Kidd, J. R., PAKSTIS, A. J., & Kídd, K. K. (1999) · PubMed · Cited by 256 · see citing works
Animal models of attention-deficit hyperactivity disorder.
Davids, E., Zhang, K., Tarazi, F. I., & Baldessarini, R. J. (2003) · Brain Research Reviews · doi:10.1016/s0165-0173(02)00274-6 · Cited by 250 · see citing works
Association of the Dopamine Transporter Gene (DAT1) With Poor Methylphenidate Response
Winsberg, B. G., & Comings, D. E. (1999) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-199912000-00006 · Cited by 245 · see citing works
Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects.
Strange, P. (2001) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01483-2 · Cited by 249 · see citing works
Atypical Neuroleptics Have Low Affinity for Dopamine D2 Receptors or Are Selective for D4 Receptors
Seeman, P. M. (1997) · Neuropsychopharmacology · doi:10.1016/s0893-133x(96)00187-x · Cited by 236 · see citing works
Self-citation
Genetics of Attention Deficit Hyperactivity Disorder
Mick, E. O., & Faraone, S. V. (2008) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/j.chc.2007.11.011 · Cited by 230 · see citing works
Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior
Strous, R. D., Bark, N. M., Parsia, S. S., Volavka, J., & Lachman, H. M. (1997) · Psychiatry Research · doi:10.1016/s0165-1781(96)03111-3 · Cited by 217 · see citing works
Renal Dopamine Receptors in Health and Hypertension
José, P. A., Eisner, G. M., & Felder, R. A. (1998) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(98)00027-8 · Cited by 216 · see citing works
The human dopamine D4 receptor repeat sequences modulate expression
Schoots, O., & Van Tol, H. H. M. (2003) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500208 · Cited by 213 · see citing works
Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD?
Doyle, A. E., Faraone, S. V., Seidman, L. J., Willcutt, E. G., Nigg, J. T., Waldman, I. D., Pennington, B. F., Peart, J., & Biederman, J. (2005) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2005.01476.x · Cited by 214 · see citing works
Kallmann syndrome gene (KAL-X) is not mutated in schizophrenia
O’Neill, M. J., Brewer, W. J., Thornley, C., Copolov, D., Warne, G. L., Sinclair, A. H., Forrest, S., & Williamson, R. (1999) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19990205)88:1 · Cited by 7 · see citing works
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. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.4.671 · Cited by 202 · see citing works
Localization of serotonin subtype 6 receptor messenger RNA in the rat brain by in situ hybridization histochemistry
Ward, R. P., Hamblin, M. W., Lachowicz, J. E., Hoffman, B. J., Sibley, D. R., & Dorsa, D. M. (1995) · Neuroscience · doi:10.1016/0306-4522(94)00439-c · Cited by 199 · see citing works
Dopamine receptor genetic polymorphisms and body composition in undernourished pastoralists: An exploration of nutrition indices among nomadic and recently settled Ariaal men of northern Kenya
Eisenberg, D. T. A., Campbell, B., Gray, P. B., & Sorenson, M. D. (2008) · BMC Evolutionary Biology · doi:10.1186/1471-2148-8-173 · Cited by 197 · see citing works
Pharmacogenetics and psychopharmacotherapy
Poolsup, Po, A. L. W., & Knight (2000) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1046/j.1365-2710.2000.00281.x · Cited by 197 · see citing works
Dopamine D2 Receptors as Treatment Targets in Schizophrenia
Seeman, P. M. (2010) · Clinical Schizophrenia & Related Psychoses · doi:10.3371/csrp.4.1.5 · Cited by 193 · see citing works
Self-citation
Differential Neural Response to Alcohol Priming and Alcohol Taste Cues Is Associated With DRD4 VNTR and OPRM1 Genotypes
Filbey, F. M., Ray, L. A., Smolen, A., Claus, E. D., Audette, A., & Hutchison, K. E. (2008) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00692.x · Cited by 192 · see citing works
New Insights into the Biology of Schizophrenia through the Mechanism of Action of Clozapine
Brunello, N., MASOTTO, C., Steardo, L., Markstein, R., & Racagni, G. (1995) · Neuropsychopharmacology · doi:10.1016/0893-133x(95)00068-o · Cited by 191 · see citing works
D4 Dopamine-Receptor (DRD4) Alleles and Novelty Seeking in Substance-Dependent, Personality-Disorder, and Control Subjects
Gelernter, J. E., Kranzler, H. R., Coccaro, E. F., Siever, L. J., New, A. S., & Mulgrew, C. L. (1997) · The American Journal of Human Genetics · doi:10.1086/301595 · Cited by 189 · see citing works
Medical therapy for clinically non-functioning pituitary adenomas
Colao, A., Somma, C. D., Pivonello, R., Faggiano, A., Lombardi, G., & Savastano, S. (2008) · Endocrine Related Cancer · doi:10.1677/erc-08-0181 · Cited by 186 · see citing works
Affinity of cyamemazine, an anxiolytic antipsychotic drug, for human recombinant dopamine vs. serotonin receptor subtypes
Hameg, A., Bayle, F., Nuss, P., Dupuis, P., Garay, R. P., & Dib, M. (2003) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01515-0 · Cited by 185 · see citing works
Neurobehavioral foundation of environmental reactivity.
Moore, S. R., & Depue, R. A. (2015) · Psychological Bulletin · doi:10.1037/bul0000028 · Cited by 181 · see citing works
The National Longitudinal Study of Adolescent Health (Add Health) Twin Data
Harris, K. M., Halpern, C. T., Smolen, A., & Haberstick, B. C. (2006) · Twin Research and Human Genetics · doi:10.1375/183242706779462787 · Cited by 178 · see citing works
Can genetic factors influence the likelihood of engaging in entrepreneurial activity?
Nicolaou, N., & Shane, S. A. (2008) · Journal of Business Venturing · doi:10.1016/j.jbusvent.2007.11.003 · Cited by 179 · see citing works
Polymorphisms in dopamine receptors: what do they tell us?
Wong, A. H. C., Buckle, C. E., & Tol, H. H. M. V. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00815-3 · Cited by 176 · see citing works
Self-citation
Attention‐deficit hyperactivity disorder: A study of association with both the dopamine transporter gene and the dopamine D4 receptor gene
Roman, T., Schmitz, M. D., Polanczyk, G. V., Eizirik, M., Rohde, L. A., & Hutz, M. H. (2001) · American Journal of Medical Genetics · doi:10.1002/ajmg.1408 · Cited by 171 · see citing works
The National Longitudinal Study of Adolescent Health (Add Health) Twin Data
Harris, K. M., Halpern, C. T., Smolen, A., & Haberstick, B. C. (2006) · Twin Research and Human Genetics · doi:10.1375/twin.9.6.988 · Cited by 170 · see citing works
Religion priming differentially increases prosocial behavior among variants of the dopamine D4 receptor (DRD4) gene
Sasaki, J. Y., Kim, H. S., Mojaverian, T., Kelley, L. D. S., Park, I. Y., & Janušonis, S. (2011) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsr089 · Cited by 168 · see citing works
Genetics of adult attention-deficit/hyperactivity disorder
Faraone, S. V. (2004) · Psychiatric Clinics of North America · doi:10.1016/s0193-953x(03)00090-x · Cited by 166 · see citing works
Dopamine D4 receptor (DRD4) gene polymorphism is associated with attachment disorganization in infants
Lakatos, K., Tóth, I., Nemoda, Z., Ney, K., Sasvári‐Székely, M., & Gervai, J. (2000) · Molecular Psychiatry · doi:10.1038/sj.mp.4000773 · Cited by 167 · see citing works
Resilience and the brain: a key role for regulatory circuits linked to social stress and support
Holz, N. E., Tost, H., & Meyer-Lindenberg, A. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0551-9 · Cited by 162 · see citing works
Dopamine Receptor Genetic Variation, Psychosis, and Aggression in Alzheimer Disease
Sweet, R. A., Nimgaonkar, V. L., Kamboh, M. I., López, O. L., Zhang, F., & DeKosky, S. T. (1998) · Archives of Neurology · doi:10.1001/archneur.55.10.1335 · Cited by 164 · see citing works
Polypeptide variants of beta-arrestin and arrestin3
Sterne‐Marr, R., Gurevich, V. V., Goldsmith, P. K., Bodine, R. C., Sanders, C. R., Donoso, L. A., & Benovic, J. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82304-3 · Cited by 163 · see citing works
Dopamine D4 Receptor Gene Novelty or Nonsense?
Paterson, A. D. (1999) · Neuropsychopharmacology · doi:10.1016/s0893-133x(98)00115-8 · Cited by 163 · see citing works
The DRD4 VNTR polymorphism moderates craving after alcohol consumption.
Hutchison, K. E., McGeary, J. E., Smolen, A., Bryan, A. D., & Swift, R. M. (2002) · Health Psychology · doi:10.1037/0278-6133.21.2.139 · Cited by 162 · see citing works
Human fear conditioning is related to dopaminergic and serotonergic biological markers.
Garpenstrand, H., Annas, P., Ekblom, J., Oreland, L., & Fredrikson, M. G. (2001) · Behavioral Neuroscience · doi:10.1037//0735-7044.115.2.358 · Cited by 161 · see citing works
A Genetic Polymorphism in the Promoter Region of DRD4 Associated with Expression and Schizophrenia
Okuyama, Y., Ishiguro, H., Toru, M., & Arinami, T. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0630 · Cited by 161 · see citing works
Novel insights in dopamine receptor physiology
Pivonello, R., Ferone, D., Lombardi, G., Colao, A., Lamberts, S. W. J., & Hofland, L. J. (2007) · European Journal of Endocrinology · doi:10.1530/eje.1.02353 · Cited by 160 · see citing works
The New Atypical Antipsychotics
Kerwin, R. W. (1994) · The British Journal of Psychiatry · doi:10.1192/bjp.164.2.141 · Cited by 160 · see citing works
Friendships Moderate an Association Between a Dopamine Gene Variant and Political Ideology
Settle, J. E., Dawes, C. T., Christakis, N., & Fowler, J. H. (2010) · Journal of Politics · doi:10.1017/s0022381610000617 · Cited by 152 · see citing works
Dopamine genes and attention-deficit hyperactivity disorder: a review
DiMaio, S., Grizenko, N., & Joober, R. (2003) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0303 · Cited by 153 · see citing works
The dopamine D4 receptor gene 48-base-pair-repeat polymorphism and mood disorders: A meta-analysis
López‐León, S., Croes, E. A., Sayed‐Tabatabaei, F. A., Claes, S. J., Broeckhoven, C. V., & van Duijn, C. M. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.01.030 · Cited by 156 · see citing works
The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson’s disease
Scheller, D., Ullmer, C., Berkels, R., Gwarek, M., & Lübbert, H. (2008) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-008-0341-4 · Cited by 151 · see citing works
Clinical and Molecular Genetics of ADHD and Tourette Syndrome
Comings, D. E. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb05773.x · Cited by 151 · see citing works
Neurochemistry and Neuroendocrinology of Schizophrenia: A Selective Review
Lieberman, J. A., & Koreen, A. (1993) · Schizophrenia Bulletin · doi:10.1093/schbul/19.2.371 · Cited by 149 · see citing works
Genes Associated With Addiction: Alcoholism, Opiate, and Cocaine Addiction
Kreek, M. J., Nielsen, D. A., & LaForge, K. S. (2004) · NeuroMolecular Medicine · doi:10.1385/nmm:5:1:085 · Cited by 146 · see citing works
The Genetics of Fibromyalgia Syndrome
Buskila, D., Sarzi‐Puttini, P., & Ablin, J. N. (2006) · Pharmacogenomics · doi:10.2217/14622416.8.1.67 · Cited by 146 · see citing works
D4 Dopamine receptor genes of zebrafish and effects of the antipsychotic clozapine on larval swimming behaviour
Boehmler, W., Carr, T., Thisse, C., Thisse, B., Canfield, V. A., & Levenson, R. G. (2006) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2006.00243.x · Cited by 146 · see citing works
rsfMRI effects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts
Blum, K., Liu, Y., Wang, W., Wang, Y., Zhang, Y., Oscar‐Berman, M., Smolen, A., Febo, M., Han, D. C., Simpatico, T. A., et al. (2014) · Postgraduate Medicine · doi:10.1080/00325481.2015.994879 · Cited by 144 · see citing works
The development of psychopathology from infancy to adulthood: The mysterious unfolding of disturbance in time
Fonagy, P. (2003) · Infant Mental Health Journal · doi:10.1002/imhj.10053 · Cited by 143 · see citing works
Serotonin receptor cDNA cloned from Lymnaea stagnalis.
Sugamori, K. S., Sunahara, R. K., Guan, H. C., Bulloch, A. G., Tensen, C. P., Seeman, P. M., Niznik, H. B., & Tol, H. H. M. V. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.1.11 · Cited by 141 · see citing works
Self-citation
Underlying Mechanisms of Gene–Environment Interactions in Externalizing Behavior: A Systematic Review and Search for Theoretical Mechanisms
Weeland, J., Overbeek, G., de Castro, B. O., & Matthys, W. (2015) · Clinical Child and Family Psychology Review · doi:10.1007/s10567-015-0196-4 · Cited by 138 · see citing works
Expression Analysis of Dopamine Receptor Subtypes in Normal Human Pituitaries, Nonfunctioning Pituitary Adenomas and Somatotropinomas, and the Association between Dopamine and Somatostatin Receptors with Clinical Response to Octreotide-LAR in Acromegaly
Neto, L. V., Machado, E. D. O., Luque, R. M., Taboada, G. F., Marcondes, J. B., Chimelli, L. M. C., Quintella, L. P., Niemeyer, P., de Carvalho, D. P., Kineman, R. D., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1826 · Cited by 139 · see citing works
Individual-specific risk factors for anorexia nervosa: a pilot study using a discordant sister-pair design
Karwautz, A. F. K., Rabe‐Hesketh, S., HU, X., Zhao, J., Sham, P. C., Collier, D. A., & Treasure, J. L. (2001) · Psychological Medicine · doi:10.1017/s0033291701003129 · Cited by 139 · see citing works
Full-length cDNA cloning and distribution of human dopamine D4 receptor
Matsumoto, M., Hidaka, K., Tada, S., Tasaki, Y., & Yamaguchi, T. (1995) · Molecular Brain Research · doi:10.1016/0169-328x(94)00245-a · Cited by 139 · see citing works
Dopamine D4 receptor subtypes and response to clozapine
Shaikh, S., Collier, D., Kerwin, R. W., Pilowsky, L. S., Gill, M., Xu, W.-M., & Thornton, A. (1993) · The Lancet · doi:10.1016/0140-6736(93)92594-j · Cited by 138 · see citing works
Depression and self-medication with nicotine: The modifying influence of the dopamine D4 receptor gene.
Lerman, C., Caporaso, N., Main, D., Audrain, J., Boyd, N. R., Bowman, E. D., & Shields, P. G. (1998) · Health Psychology · doi:10.1037//0278-6133.17.1.56 · Cited by 198 · see citing works
The dopaminergic system in hypertension
Zeng, C., Zhang, M., Asico, L. D., Eisner, G. M., & José, P. A. (2007) · Clinical Science · doi:10.1042/cs20070018 · Cited by 137 · see citing works
The DRD4 VNTR polymorphism influences reactivity to smoking cues.
Hutchison, K. E., LaChance, H., NIAURA, R. S., Bryan, A. D., & Smolen, A. (2002) · Journal of Abnormal Psychology · doi:10.1037//0021-843x.111.1.134 · Cited by 134 · see citing works
Variability of dopamine D4 receptor (DRD4) gene sequence within and among nonhuman primate species.
Livak, K. J., Rogers, J., & Lichter, J. B. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.2.427 · Cited by 133 · see citing works
Seeking a mechanism of action for the novel anticonvulsant lacosamide
Errington, A. C., Coyne, L., Stöhr, T., Selve, N., & Lees, G. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.02.002 · Cited by 133 · see citing works
Molecular Characteristics of Mammalian Dopamine Receptors
Lachowicz, J. E., & Sibley, D. R. (1997) · Pharmacology & Toxicology · doi:10.1111/j.1600-0773.1997.tb00039.x · Cited by 132 · see citing works

A hypervariable segment in the human dopamine receptor D4 (DRD4) gene
Lichter, J. B., Barr, C. L., Kennedy, J. L., Tol, H. H. M. V., Kídd, K. K., & Livak, K. J. (1993) · Human Molecular Genetics · doi:10.1093/hmg/2.6.767 · Cited by 524 · see citing works
Self-citation
Polymorphisms of the dopamine D 4 receptor and response to antipsychotic drugs
Cohen, B. M., Ennulat, D. J., Centorrino, F., Matthysse, S., Konieczna, H., Chu, H.-M., & Cherkerzian, S. (1999) · Psychopharmacology · doi:10.1007/s002130050799 · Cited by 80 · see citing works
Allelic Variation in the D4 Dopamine Receptor (DRD4) Gene Does Not Predict Response to Clozapine
Rao, P. A. (1994) · Archives of General Psychiatry · doi:10.1001/archpsyc.1994.03950110072009 · Cited by 113 · see citing works
DOPAMINE D4 RECEPTOR GENE EXON III POLYMORPHISM AND INTERINDIVIDUAL VARIATION IN RESPONSE TO CLOZAPINE
Ai-ling, Z., Zhao, J., Zhang, Y., Xue, Z., Chen, J., & Chen, X. (2005) · International Journal of Neuroscience · doi:10.1080/00207450590957863 · Cited by 49 · see citing works
Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients
Shaikh, S., Collier, D. A., Sham, P. C., Pilowsky, L. S., Sharma, T., Lin, L.-Y., Crocq, M. A., Gill, M., & Kerwin, R. W. (1995) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320600611 · Cited by 65 · see citing works

Authors: Tol, H. H. M. V., Wu, C. M., Guan, H.-C., Ohara, K., Bunzow, J. R., Civelli, O., Kennedy, J., Seeman, P., Niznik, H. B., & Jovanovic, V.
Affiliations: University of Toronto (CA)
Oregon Health & Science University (US)
ORCID: Civelli, Olivier
Seeman, Philip
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1992-07
Volume: 358
Issue: 6382
Pages: 149-152
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/358149a0
OpenAlex: W2026395566
Cited by: 955
References: 20
Citations by year: 2026: 2 · 2025: 5 · 2024: 10 · 2023: 15 · 2022: 10 · 2021: 14 · 2020: 43 · 2019: 15 · 2018: 7 · 2017: 12 · 2016: 32 · 2015: 34 · 2014: 26 · 2013: 23 · 2012: 35
FWCI: 16.03
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: dopamine D4 receptor, genetic polymorphism, receptor isoforms, spiperone binding, direct repeats, cytoplasmic loop, atypical antipsychotics, individual differences in drug response
MeSH terms: Base Sequence, Binding, Competitive, Cell Line, Clozapine, DNA, DNA Restriction Enzymes, Humans, Introns, Molecular Sequence Data, Pituitary Gland, Receptors, Dopamine, Repetitive Sequences, Nucleic Acid, Spiperone, Substantia Nigra, Transfection, Genetic Variation, Gene Expression, Receptors, Dopamine D2, Receptors, Dopamine D4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Multiple dopamine D4 receptor variants in the human population

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks