View source for Biology:Dopamine receptor D4

{{short description|Protein-coding gene in the species Homo sapiens}}
{{DISPLAYTITLE:Dopamine receptor D<sub>4</sub>}}
{{Infobox_gene}}
The '''dopamine receptor D<sub>4</sub>''' is a dopamine [[Biology:D2-like receptor|D2-like]] [[Biology:G protein-coupled receptor|G protein-coupled receptor]] encoded by the {{gene|DRD4}} gene on chromosome 11 at 11p15.5.<ref name="pmid1840645">{{cite journal | vauthors = Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O | title = Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine | journal = Nature | volume = 350 | issue = 6319 | pages = 610–4 | date = April 1991 | pmid = 1840645 | doi = 10.1038/350610a0 | bibcode = 1991Natur.350..610V | s2cid = 4244670 }}</ref>

The structure of DRD4 was recently reported in complex with the antipsychotic drug [[Chemistry:Nemonapride|nemonapride]].<ref>{{cite journal | vauthors = Wang S, Wacker D, Levit A, Che T, Betz RM, McCorvy JD, Venkatakrishnan AJ, Huang XP, Dror RO, Shoichet BK, Roth BL | title = D4 dopamine receptor high-resolution structures enable the discovery of selective agonists | journal = Science | volume = 358 | issue = 6361 | pages = 381–386 | date = October 2017 | pmid = 29051383 | pmc = 5856174 | doi = 10.1126/science.aan5468 | bibcode = 2017Sci...358..381W }}</ref>

As with other [[Biology:Dopamine receptor|dopamine receptor]] subtypes, the  D<sub>4</sub> receptor is activated by the [[Biology:Neurotransmitter|neurotransmitter]] [[Biology:Dopamine|dopamine]]. It is linked to many neurological and psychiatric conditions<ref>{{cite journal | vauthors = Ptácek R, Kuzelová H, Stefano GB | title = Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders | journal = Medical Science Monitor | volume = 17 | issue = 9 | pages = RA215–20 | date = September 2011 | pmid = 21873960 | pmc = 3560519 | doi = 10.12659/MSM.881925 }}</ref> including [[Medicine:Schizophrenia|schizophrenia]] and [[Medicine:Bipolar disorder|bipolar disorder]],<ref>{{cite journal | vauthors = Domschke K | title = Clinical and molecular genetics of psychotic depression | journal = Schizophrenia Bulletin | volume = 39 | issue = 4 | pages = 766–75 | date = July 2013 | pmid = 23512949 | pmc = 3686457 | doi = 10.1093/schbul/sbt040 }}</ref> ADHD,<ref>{{cite journal | vauthors = LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL | title = Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder | journal = Molecular Psychiatry | volume = 1 | issue = 2 | pages = 121–4 | date = May 1996 | pmid = 9118321 }}</ref><ref>{{cite journal | vauthors = Smalley SL, Bailey JN, Palmer CG, Cantwell DP, McGough JJ, Del'Homme MA, Asarnow JR, Woodward JA, Ramsey C, Nelson SF | title = Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder | journal = Molecular Psychiatry | volume = 3 | issue = 5 | pages = 427–30 | date = September 1998 | pmid = 9774776 | doi = 10.1038/sj.mp.4000457 | doi-access = free }}</ref> addictive behaviors,<ref>{{cite journal | vauthors = McGeary J | title = The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review | journal = Pharmacology Biochemistry and Behavior | volume = 93 | issue = 3 | pages = 222–9 | date = September 2009 | pmid = 19336242 | pmc = 2706302 | doi = 10.1016/j.pbb.2009.03.010 }}</ref> [[Medicine:Parkinson's disease|Parkinson's disease]],<ref>{{cite journal | vauthors = Cormier F, Muellner J, Corvol JC | title = Genetics of impulse control disorders in Parkinson's disease | journal = Journal of Neural Transmission | volume = 120 | issue = 4 | pages = 665–71 | date = April 2013 | pmid = 23232665 | doi = 10.1007/s00702-012-0934-4 | s2cid = 21967333 }}</ref> and eating disorders such as [[Medicine:Anorexia nervosa|anorexia nervosa]].<ref>{{cite journal | vauthors = Rask-Andersen M, Olszewski PK, Levine AS, Schiöth HB | title = Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake | journal = Brain Research Reviews | volume = 62 | issue = 2 | pages = 147–64 | date = March 2010 | pmid = 19931559 | doi = 10.1016/j.brainresrev.2009.10.007 | s2cid = 37635456 }}</ref>  A weak association has been drawn between DRD4 and [[Medicine:Borderline personality disorder|borderline personality disorder]].

It is also a target for drugs which treat [[Medicine:Schizophrenia|schizophrenia]] and [[Medicine:Parkinson's disease|Parkinson's disease]].<ref>{{cite journal | vauthors = Ptáček R, Kuželová H, Stefano GB, Raboch J, Kream RM | title = Targeted D4 dopamine receptors: implications for drug discovery and therapeutic development | journal = Current Drug Targets | volume = 14 | issue = 4 | pages = 507–12 | date = April 2013 | pmid = 23469923 | doi = 10.2174/1389450111314040012 }}</ref> The D<sub>4</sub> receptor is considered to be [[Biology:Dopamine receptor D2|D<sub>2</sub>-like]] in which the activated receptor inhibits the enzyme adenylate cyclase, thereby reducing the intracellular concentration of the second messenger cyclic AMP.<ref name="pmid15521361">{{cite journal | vauthors = Neve KA, Seamans JK, Trantham-Davidson H | title = Dopamine receptor signaling | journal = Journal of Receptor and Signal Transduction Research | volume = 24 | issue = 3 | pages = 165–205 | date = August 2004 | pmid = 15521361 | doi = 10.1081/RRS-200029981 | citeseerx = 10.1.1.465.5011 | s2cid = 12407397 }}</ref>

== Genetics ==
The human protein is coded by the ''DRD4'' on chromosome 11 located in 11p15.5.<ref name = "Van_Tol_1992">{{cite journal | vauthors = Van Tol HH, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V | title = Multiple dopamine D4 receptor variants in the human population | journal = Nature | volume = 358 | issue = 6382 | pages = 149–52 | date = July 1992 | pmid = 1319557 | doi = 10.1038/358149a0 | bibcode = 1992Natur.358..149T | s2cid = 4345839 }}</ref>

There are slight variations ([[Biology:Mutation|mutation]]s/polymorphisms) in the human gene:
* A 48-base pair VNTR in [[Biology:Exon|exon]] 3
* C-521T in the [[Biology:Promoter (genetics)|promoter]]
* 13-base pair deletion of bases 235 to 247 in exon 1
* 12 base pair repeat in exon 1<ref name="pmid8268330">{{cite journal | vauthors = Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E | title = Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients | journal = Biological Psychiatry | volume = 34 | issue = 7 | pages = 459–64 | date = October 1993 | pmid = 8268330 | doi = 10.1016/0006-3223(93)90236-7 | s2cid = 34841647 }}</ref>
* Val194Gly
* A polymorphic tandem duplication of 48 bp<ref>{{cite journal | vauthors = Rondou P, Haegeman G, Van Craenenbroeck K | title = The dopamine D4 receptor: biochemical and signalling properties | journal = Cellular and Molecular Life Sciences | volume = 67 | issue = 12 | pages = 1971–86 | date = June 2010 | pmid = 20165900 | doi = 10.1007/s00018-010-0293-y | s2cid = 21432517 }}</ref>

Mutations in this gene have been associated with various behavioral phenotypes, including [[Medicine:Dysautonomia|autonomic nervous system dysfunction]], attention deficit/hyperactivity disorder,<ref name="pmid17506925">{{cite journal | vauthors = Thapar A, Langley K, Owen MJ, O'Donovan MC | title = Advances in genetic findings on attention deficit hyperactivity disorder | journal = Psychological Medicine | volume = 37 | issue = 12 | pages = 1681–92 | date = December 2007 | pmid = 17506925 | doi = 10.1017/S0033291707000773 | s2cid = 20556855 }}</ref> [[Medicine:Schizophrenia|schizophrenia]]<ref name="SZGeneD4">[http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=94 Gene Overview of All Published Schizophrenia-Association Studies for DRD4] {{webarchive|url=https://web.archive.org/web/20090221130224/http://schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=94 |date=21 February 2009 }} – SzGene database at Schizophrenia Research Forum.</ref> and the personality trait of novelty seeking.<ref name="pmid17574217">{{cite journal | vauthors = Munafò MR, Yalcin B, Willis-Owen SA, Flint J | title = Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data | journal = Biological Psychiatry | volume = 63 | issue = 2 | pages = 197–206 | date = January 2008 | pmid = 17574217 | doi = 10.1016/j.biopsych.2007.04.006 | s2cid = 28997438 }}</ref>

=== 48-base pair VNTR {{anchor|DRD4-7R|DRD4–7R}}===
The 48-base pair variable number tandem repeat (VNTR) in [[Biology:Exon|exon]] 3 range from 2 to 11 repeats.<ref name = "Van_Tol_1992" /> Dopamine is more potent at the D4 receptor with 2 allelic repeat or 7 allelic repeats than the variant with 4 allelic repeats.<ref>{{cite journal | vauthors = Wedemeyer C, Goutman JD, Avale ME, Franchini LF, Rubinstein M, Calvo DJ | title = Functional activation by central monoamines of human dopamine D(4) receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes | journal = European Journal of Pharmacology | volume = 562 | issue = 3 | pages = 165–73 | date = May 2007 | pmid = 17350612 | doi = 10.1016/j.ejphar.2007.01.055 }}</ref>

'''DRD4-7R'''<!--Do not unbold this; the term redirects here - see MOS:BOLD-->, the 7-repeat (7R) variant of ''DRD4'' (DRD4 7-repeat polymorphism), has been linked to a susceptibility for developing ADHD in several meta-analyses and other psychological traits and disorders.<ref name="pmid22610946">{{cite journal | vauthors = Wu J, Xiao H, Sun H, Zou L, Zhu LQ | title = Role of dopamine receptors in ADHD: a systematic meta-analysis | journal = Molecular Neurobiology | volume = 45 | issue = 3 | pages = 605–20 | date = June 2012 | pmid = 22610946 | doi = 10.1007/s12035-012-8278-5 | s2cid = 895006 }}</ref><ref name="pmid11431226">{{cite journal | vauthors = Faraone SV, Doyle AE, Mick E, Biederman J | title = Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder | journal = The American Journal of Psychiatry | volume = 158 | issue = 7 | pages = 1052–7 | date = July 2001 | pmid = 11431226 | doi = 10.1176/appi.ajp.158.7.1052 }}</ref> Adults and children with the DRD4 7-repeat polymorphism show variations in auditory-evoked [[Medicine:Gamma wave|gamma oscillations]], which may be related to attention processing.<ref>{{cite journal | vauthors = Yordanova J, Banaschewski T, Kolev V, Woerner W, Rothenberger A | title = Abnormal early stages of task stimulus processing in children with attention-deficit hyperactivity disorder--evidence from event-related gamma oscillations | journal = Clinical Neurophysiology | volume = 112 | issue = 6 | pages = 1096–108 | date = June 2001 | pmid = 11377270 | doi=10.1016/s1388-2457(01)00524-7| s2cid = 19789570 }}</ref><ref>{{cite journal | vauthors = Demiralp T, Herrmann CS, Erdal ME, Ergenoglu T, Keskin YH, Ergen M, Beydagi H | title = DRD4 and DAT1 polymorphisms modulate human gamma band responses | journal = Cerebral Cortex | volume = 17 | issue = 5 | pages = 1007–19 | date = May 2007 | pmid = 16751296 | doi = 10.1093/cercor/bhl011 | doi-access = free }}</ref>

The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.<ref name="pmid15077199">{{cite journal | vauthors = Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK | title = The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus | journal = American Journal of Human Genetics | volume = 74 | issue = 5 | pages = 931–44 | date = May 2004 | pmid = 15077199 | pmc = 1181986 | doi = 10.1086/420854 }}</ref> "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.<ref name="pmid7643093">{{cite journal | vauthors = Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH | title = Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants | journal = Journal of Neurochemistry | volume = 65 | issue = 3 | pages = 1157–65 | date = September 1995 | pmid = 7643093 | doi = 10.1046/j.1471-4159.1995.65031157.x | s2cid = 23092115 }}</ref>

The 48-base pair VNTR has been the subject of much speculation about its evolution and role in human behaviors cross-culturally. The 7R allele appears to have been selected for about 40,000 years ago.<ref name="pmid15077199"/> In 1999 Chen and colleagues<ref name="Chen_1999">{{cite journal |vauthors=Chen CS, Burton M, Greenberger E, Dmitrieva J |title=Population Migration and the Variation of Dopamine D4 Receptor (DRD4) Allele Frequencies Around the Globe |journal=Evolution and Human Behavior |volume=20 |issue=5 |year=1999 |pages=309–24 |doi=10.1016/S1090-5138(99)00015-X |s2cid=12754148 |url=http://www.escholarship.org/uc/item/7br14384 }}</ref> observed that populations who migrated farther in the past 30,000 to 1,000 years ago had a higher frequency of 7R/long alleles. They also showed that nomadic populations had higher frequencies of 7R alleles than sedentary ones. More recently it was observed that the health status of nomadic Ariaal men was higher if they had 7R alleles. However, in recently sedentary (non-nomadic) Ariaal those with 7R alleles seemed to have slightly deteriorated health.<ref name="pmid18544160">{{cite journal | vauthors = Eisenberg DT, Campbell B, Gray PB, Sorenson MD | title = 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 | journal = BMC Evolutionary Biology | volume = 8 | pages = 173 | date = June 2008 | pmid = 18544160 | pmc = 2440754 | doi = 10.1186/1471-2148-8-173 | doi-access = free }}</ref>

==Novelty seeking==

Despite early findings of an association between the ''DRD4'' 48bp VNTR and novelty seeking (a normal characteristic of exploratory and excitable people),<ref name="pmid8528256">{{cite journal | vauthors = Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH | title = Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking | journal = Nature Genetics | volume = 12 | issue = 1 | pages = 78–80 | date = January 1996 | pmid = 8528256 | doi = 10.1038/ng0196-78 | s2cid = 27276401 }}</ref><ref name="pmid8528258">{{cite journal | vauthors = Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH | title = Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking | journal = Nature Genetics | volume = 12 | issue = 1 | pages = 81–4 | date = January 1996 | pmid = 8528258 | doi = 10.1038/ng0196-81 | s2cid = 24226671 | url =  https://zenodo.org/record/1233375}}<!--https://zenodo.org/record/1233375--></ref> a 2008 [[Meta-analysis|meta-analysis]] compared 36 published studies of novelty seeking  and the polymorphism and found no effect. Results are consistent with novelty-seeking behavior being a [[Biology:Complex traits|complex trait]] associated with many genes, and the variance attributable to ''DRD4'' by itself being very small. The meta-analysis of 11 studies did find that another polymorphism in the gene, the -521C/T, showed an association with novelty seeking.<ref name="pmid17574217"/> While human results are not strong, research in animals has suggested stronger associations <ref>{{cite journal | vauthors = Fidler AE, van Oers K, Drent PJ, Kuhn S, Mueller JC, Kempenaers B | title = Drd4 gene polymorphisms are associated with personality variation in a passerine bird | journal = Proceedings: Biological Sciences | volume = 274 | issue = 1619 | pages = 1685–91 | date = July 2007 | pmid = 17472912 | pmc = 1914334 | doi = 10.1098/rspb.2007.0337 }}</ref><ref>{{cite journal | vauthors = Mueller JC, Edelaar P, Carrete M, Serrano D, Potti J, Blas J, Dingemanse NJ, Kempenaers B, Tella JL | title = Behaviour-related DRD4 polymorphisms in invasive bird populations | journal = Molecular Ecology | volume = 23 | issue = 11 | pages = 2876–85 | date = June 2014 | pmid = 24750181 | doi = 10.1111/mec.12763 | hdl = 10261/101638 | s2cid = 10576133 }}</ref><ref>{{cite journal | vauthors = Ninomiya S, Anjiki A, Nishide Y, Mori M, Deguchi Y, Satoh T | title = Polymorphisms of the Dopamine D4 Receptor Gene in Stabled Horses are Related to Differences in Behavioral Response to Frustration | journal = Animals | volume = 3 | issue = 3 | pages = 663–9 | date = July 2013 | pmid = 26479526 | pmc = 4494454 | doi = 10.3390/ani3030663 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hori Y, Ozaki T, Yamada Y, Tozaki T, Kim HS, Takimoto A, Endo M, Manabe N, Inoue-Murayama M, Fujita K | title = Breed Differences in Dopamine Receptor D4 Gene (DRD4) in Horses | journal = Journal of Equine Science | volume = 24 | issue = 3 | pages = 31–6 | year = 2013 | pmid = 24833999 | pmc = 4013985 | doi = 10.1294/jes.24.31 }}</ref><ref>{{cite journal | vauthors = Hejjas K, Vas J, Topal J, Szantai E, Ronai Z, Szekely A, Kubinyi E, Horvath Z, Sasvari-Szekely M, Miklosi A | title = Association of polymorphisms in the dopamine D4 receptor gene and the activity-impulsivity endophenotype in dogs | journal = Animal Genetics | volume = 38 | issue = 6 | pages = 629–33 | date = December 2007 | pmid = 17986156 | doi = 10.1111/j.1365-2052.2007.01657.x }}</ref><ref>{{cite journal | author1= Timm, K. |author2= Mägi, M. | author3= Telva, K. | author4= Tilgar, V. | year=2019| title= The behavioural response of Great Tits to novel environment and handling is affected by the DRD4 gene | journal=Ibis| volume=161| pages= 91–100| doi= 10.1111/ibi.12604| issue=2| doi-access= free}}</ref> and new evidence suggests that human encroachment may exert selection pressure in favor of ''DRD4'' variants associated with novelty seeking.<ref name=pmid21942663>{{cite journal | vauthors = Posner MI, Rothbart MK, Sheese BE, Voelker P | title = Control networks and neuromodulators of early development | journal = Developmental Psychology | volume = 48 | issue = 3 | pages = 827–35 | date = May 2012 | pmid = 21942663 | pmc = 3253251 | doi = 10.1037/a0025530 }}</ref>{{Clarify|reason=not clear this reference has anything to do with human-related selection|date=December 2018}}

== Cognition ==
Several studies have shown that [[Biology:Agonist|agonist]]s that activate the D4 receptor increase working memory performance and fear acquisition in monkeys and rodents according to a U-shaped [[Chemistry:Dose–response relationship|dose response curve]].<ref>{{cite journal | vauthors = Bernaerts P, Tirelli E | title = Facilitatory effect of the dopamine D4 receptor agonist PD168,077 on memory consolidation of an inhibitory avoidance learned response in C57BL/6J mice | journal = Behavioural Brain Research | volume = 142 | issue = 1–2 | pages = 41–52 | date = June 2003 | pmid = 12798264 | doi = 10.1016/s0166-4328(02)00371-6 | s2cid = 21960608 }}</ref><ref>{{cite journal | vauthors = Browman KE, Curzon P, Pan JB, Molesky AL, Komater VA, Decker MW, Brioni JD, Moreland RB, Fox GB | title = A-412997, a selective dopamine D4 agonist, improves cognitive performance in rats | journal = Pharmacology Biochemistry and Behavior | volume = 82 | issue = 1 | pages = 148–55 | date = September 2005 | pmid = 16154186 | doi = 10.1016/j.pbb.2005.08.002 | s2cid = 31796938 }}</ref><ref name="Woolley_2008">{{cite journal | vauthors = Woolley ML, Waters KA, Reavill C, Bull S, Lacroix LP, Martyn AJ, Hutcheson DM, Valerio E, Bate S, Jones DN, Dawson LA | title = Selective dopamine D4 receptor agonist (A-412997) improves cognitive performance and stimulates motor activity without influencing reward-related behaviour in rat | journal = Behavioural Pharmacology | volume = 19 | issue = 8 | pages = 765–76 | date = December 2008 | pmid = 19020411 | doi = 10.1097/FBP.0b013e32831c3b06 | s2cid = 36272297 }}</ref> However, [[Biology:Receptor antagonist|antagonists]] of the D4 receptor reverse stress-induced or drug-induced working memory deficits.<ref name="pmid10102786">{{cite journal | vauthors = Jentsch JD, Taylor JR, Redmond DE, Elsworth JD, Youngren KD, Roth RH | title = Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys | journal = Psychopharmacology | volume = 142 | issue = 1 | pages = 78–84 | date = February 1999 | pmid = 10102786 | doi = 10.1007/s002130050865 | s2cid = 24469748 }}</ref><ref name="Arnsten_2000">{{cite journal | vauthors = Arnsten AF, Murphy B, Merchant K | title = The selective dopamine D4 receptor antagonist, PNU-101387G, prevents stress-induced cognitive deficits in monkeys | journal = Neuropsychopharmacology | volume = 23 | issue = 4 | pages = 405–10 | date = October 2000 | pmid = 10989267 | doi = 10.1016/S0893-133X(00)00133-0 | doi-access = free }}</ref> [[Medicine:Gamma wave|Gamma oscillations]], which may be correlated with cognitive processing, can be increased by D4R agonists, but are not significantly reduced by D4R antagonists.<ref name="Furth_2017">{{cite journal | vauthors = Furth KE, McCoy AJ, Dodge C, Walters JR, Buonanno A, Delaville C | title = Neuronal correlates of ketamine and walking induced gamma oscillations in the medial prefrontal cortex and mediodorsal thalamus | journal = PLOS ONE | volume = 12 | issue = 11 | pages = e0186732 | year = 2017 | pmid = 29095852 | pmc = 5667758 | doi = 10.1371/journal.pone.0186732 | bibcode = 2017PLoSO..1286732F | doi-access = free }}</ref><ref name="Kocsis_2014">{{cite journal | vauthors = Kocsis B, Lee P, Deth R | title = Enhancement of gamma activity after selective activation of dopamine D4 receptors in freely moving rats and in a neurodevelopmental model of schizophrenia | journal = Brain Structure & Function | volume = 219 | issue = 6 | pages = 2173–80 | date = November 2014 | pmid = 23839116 | pmc = 3859720 | doi = 10.1007/s00429-013-0607-6 }}</ref><ref name="Nakazawa_2015">{{cite journal | vauthors = Nakazawa S, Murai T, Miyauchi M, Kotani M, Ikeda K | title = Behavioral and neurophysiological effects of Ro 10-5824, a dopamine D4 receptor partial agonist, in common marmosets | journal = Psychopharmacology | volume = 232 | issue = 17 | pages = 3287–95 | date = September 2015 | pmid = 26041337 | doi = 10.1007/s00213-015-3978-y | s2cid = 17141380 }}</ref>

==Cognitive development==
Several studies have suggested that parenting may affect the [[Philosophy:Cognitive development|cognitive development]] of children with the 7-repeat allele of ''DRD4''.<ref name=pmid21942663/> Parenting that has maternal sensitivity, mindfulness, and autonomy–support at 15 months was found to alter children's executive functions at 18 to 20 months.<ref name=pmid21942663/> Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.<ref name=pmid21942663/> Higher quality parenting was associated with better executive control in 4-year-olds.<ref name=pmid21942663/>

==Ligands==
[[Image:D4 ligands.png|thumbnail|right|400px|Chemical structures of representative D<sub>4</sub>-preferring ligands.]]
<!--
{{cite journal | pmid = 10479303 | doi=10.1021/jm990266k | volume=42 | title=Design, synthesis, and evaluation of chromen-2-ones as potent and selective human dopamine D4 antagonists | date=September 1999 | journal=J. Med. Chem. | pages=3718–25 | vauthors=Kesten SR, Heffner TG, Johnson SJ, Pugsley TA, Wright JL, Wise LD }}
{{cite journal | pmid = 9406594 | doi=10.1021/jm970422s | volume=40 | title=(Aryloxy)alkylamines as selective human dopamine D4 receptor antagonists: potential antipsychotic agents | date=December 1997 | journal=J. Med. Chem. | pages=4026–9 | vauthors=Unangst PC, Capiris T, Connor DT | display-authors = etal }}
{{cite journal | pmid = 9276014 | doi=10.1021/jm970170v | volume=40 | title=Chromeno[3,4-c]pyridin-5-ones: selective human dopamine D4 receptor antagonists as potential antipsychotic agents | date=August 1997 | journal=J. Med. Chem. | pages=2688–93 | vauthors=Unangst PC, Capiris T, Connor DT | display-authors = etal }}
{{cite journal | pmid = 8968364 | volume=279 | title=Pharmacological characterization of U-101387, a dopamine D4 receptor selective antagonist | date=December 1996 | journal=J. Pharmacol. Exp. Ther. | pages=1392–403 | vauthors=Merchant KM, Gill GS, Harris DW | display-authors = etal }}
{{cite journal | pmid = 9871530 | volume=8 | title=Synthesis, SAR and pharmacology of CP-293,019: a potent, selective dopamine D4 receptor antagonist | date=April 1998 | journal=Bioorg. Med. Chem. Lett. | pages=725–30 | vauthors=Sanner MA, Chappie TA, Dunaiskis AR | display-authors = etal }}
{{cite journal | pmid = 12362366 | doi=10.1002/1439-7633(20021004)3:10<999::AID-CBIC999>3.0.CO;2-A | volume=3 | title=Synthesis and structure-activity relationship of the isoindolinyl benzisoxazolpiperidines as potent, selective, and orally active human dopamine D4 receptor antagonists | year=2002 | journal=ChemBioChem | pages=999–1009 | vauthors=Hendrix JA, Shimshock SJ, Shutske GM, Tomer , Kapples KJ, Palermo MG, Corbett TJ, Vargas HM, Kafka S, Brooks KM, Laws-Ricker L, Lee DK, de Lannoy I, Bordeleau M, Rizkalla G, Owolabi J, Kamboj RK }}
-->

===Agonists===
* [[Chemistry:WAY-100635|WAY-100635]]: potent full [[Biology:Agonist|agonist]], with 5-HT<sub>1A</sub> antagonistic component<ref name="pmid16915381">{{cite journal| vauthors = Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE | title = WAY-100635 is a potent dopamine D4 receptor agonist | journal = Psychopharmacology | volume = 188 | issue = 2 | pages = 244–51 | date = October 2006 | pmid = 16915381 | doi = 10.1007/s00213-006-0490-4 | s2cid = 24194034 }}</ref>
* A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels<ref name="pmid16153699">{{cite journal | vauthors = Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD | title = A-412997 is a selective dopamine D4 receptor agonist in rats | journal = Pharmacology Biochemistry and Behavior | volume = 82 | issue = 1 | pages = 140–7 | date = September 2005 | pmid = 16153699 | doi = 10.1016/j.pbb.2005.08.001 | s2cid = 10270715 }}</ref>
* [[Chemistry:ABT-724|ABT-724]] - developed for treatment of erectile dysfunction<ref name="pmid15239663">{{cite journal | vauthors = Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO | title = Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 15 | pages = 3853–64 | date = July 2004 | pmid = 15239663 | doi = 10.1021/jm030505a }}</ref>
* [[Chemistry:ABT-670|ABT-670]] - better oral bioavailability than ABT-724<ref>{{cite journal | vauthors = Patel MV, Kolasa T, Mortell K, Matulenko MA, Hakeem AA, Rohde JJ, Nelson SL, Cowart MD, Nakane M, Miller LN, Uchic ME, Terranova MA, El-Kouhen OF, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Chang R, Martino BR, Wetter JM, Marsh KC, Martin R, Darbyshire JF, Gintant G, Hsieh GC, Moreland RB, Sullivan JP, Brioni JD, Stewart AO | title = Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 25 | pages = 7450–65 | date = December 2006 | pmid = 17149874 | doi = 10.1021/jm060662k }}</ref>
* FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes<ref name="pmid11087581">{{cite journal | vauthors = Hübner H, Kraxner J, Gmeiner P | title = Cyanoindole derivatives as highly selective dopamine D(4) receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments | journal = Journal of Medicinal Chemistry | volume = 43 | issue = 23 | pages = 4563–9 | date = November 2000 | pmid = 11087581 | doi = 10.1021/jm0009989 }}</ref>
* FAUC 299: partial agonist<ref name="pmid11087581"/>
* [[Chemistry:F-15063|F-15063]]: antipsychotic with partial D4 agonism
* (''E'')-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes<ref>{{cite journal | vauthors = Kolasa T, Matulenko MA, Hakeem AA, Patel MV, Mortell K, Bhatia P, Henry R, Nakane M, Hsieh GC, Terranova MA, Uchic ME, Miller LN, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino B, El Kouhen O, Marsh KC, Wetter JM, Moreland RB, Brioni JD, Stewart AO | title = 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 | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 17 | pages = 5093–109 | date = August 2006 | pmid = 16913699 | doi = 10.1021/jm060279f }}</ref>
* PIP3EA: partial agonist<ref>{{cite journal | vauthors = Enguehard-Gueiffier C, Hübner H, El Hakmaoui A, Allouchi H, Gmeiner P, Argiolas A, Melis MR, Gueiffier A | title = 2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 13 | pages = 3938–47 | date = June 2006 | pmid = 16789750 | doi = 10.1021/jm060166w }}</ref>
* [[Chemistry:Flibanserin|Flibanserin]] - partial agonist
* [[Chemistry:PD-168,077|PD-168,077]] - D<sub>4</sub> selective but also binds to α1A, α2C and 5HT<sub>1A</sub>
* [[Chemistry:CP-226,269|CP-226,269]] - D<sub>4</sub> selective but also binds to D<sub>2</sub>, D<sub>3</sub>, α2A, α2C and [[Biology:5-HT1A receptor|5HT<sub>1A</sub>]]
* [[Chemistry:Ro10-5824|Ro10-5824]] – partial agonist
* [[Chemistry:Roxindole|Roxindole]] – D<sub>4</sub> selective but also D<sub>2</sub> and D<sub>3</sub> autoreceptor agonist, 5HT<sub>1A</sub> receptor agonist, [[Chemistry:Serotonin reuptake inhibitor|serotonin reuptake inhibitor]])
* [[Chemistry:Apomorphine|Apomorphine]] – D<sub>4</sub> selective but also D<sub>2</sub> and D<sub>3</sub> agonist, α-[[Biology:Adrenergic|adrenergic]] and [[Chemistry:Serotonin|serotonergic]] weak antagonist
* [[Chemistry:Nuciferine|Nuciferine]] - D<sub>4</sub> full selective but also partial D<sub>2</sub> and D<sub>5</sub> agonist

===Antagonists===
* A-381393: potent, subtype selective antagonist (>2700-fold)<ref>{{cite journal | vauthors = Nakane M, Cowart MD, Hsieh GC, Miller L, Uchic ME, Chang R, Terranova MA, Donnelly-Roberts DL, Namovic MT, Miller TR, Wetter JM, Marsh K, Stewart AO, Brioni JD, Moreland RB | title = 2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist | journal = Neuropharmacology | volume = 49 | issue = 1 | pages = 112–21 | date = July 2005 | pmid = 15992586 | doi = 10.1016/j.neuropharm.2005.02.004 | s2cid = 7529599 }}</ref>
* FAUC 213<ref name = "pmid18307287"/>
* [[Chemistry:L-745,870|L-745,870]]<ref>{{cite journal | vauthors = Kulagowski JJ, Broughton HB, Curtis NR, Mawer IM, Ridgill MP, Baker R, Emms F, Freedman SB, Marwood R, Patel S, Patel S, Ragan CI, Leeson PD | title = 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor | journal = Journal of Medicinal Chemistry | volume = 39 | issue = 10 | pages = 1941–2 | date = May 1996 | pmid = 8642550 | doi = 10.1021/jm9600712 }}</ref><ref>{{cite journal | vauthors = Patel S, Freedman S, Chapman KL, Emms F, Fletcher AE, Knowles M, Marwood R, Mcallister G, Myers J, Curtis N, Kulagowski JJ, Leeson PD, Ridgill M, Graham M, Matheson S, Rathbone D, Watt AP, Bristow LJ, Rupniak NM, Baskin E, Lynch JJ, Ragan CI | title = Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 283 | issue = 2 | pages = 636–47 | date = November 1997 | pmid = 9353380 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9353380 }}</ref>
* L-750,667<ref>{{cite journal | vauthors = Patel S, Patel S, Marwood R, Emms F, Marston D, Leeson PD, Curtis NR, Kulagowski JJ, Freedman SB | title = Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor | journal = Molecular Pharmacology | volume = 50 | issue = 6 | pages = 1658–64 | date = December 1996 | pmid = 8967990 | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8967990 }}</ref>
* ML-398<ref name="pmid25221667">{{cite journal | vauthors = Berry CB, Bubser M, Jones CK, Hayes JP, Wepy JA, Locuson CW, Daniels JS, Lindsley CW, Hopkins CR | title = Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity | journal = ACS Medicinal Chemistry Letters | volume = 5 | issue = 9 | pages = 1060–4 | date = September 2014 | pmid = 25221667 | pmc = 4160761 | doi = 10.1021/ml500267c }}</ref>
* S 18126 - also σ<sub>1</sub> affinity<ref name="pmid9765336">{{cite journal | vauthors = Millan MJ, Newman-Tancredi A, Brocco M, Gobert A, Lejeune F, Audinot V, Rivet JM, Schreiber R, Dekeyne A, Spedding M, Nicolas JP, Peglion JL | title = S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl]), a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 287 | issue = 1 | pages = 167–86 | date = October 1998 | pmid = 9765336 | url = http://jpet.aspetjournals.org/cgi/content/abstract/287/1/167 }}</ref>
* [[Chemistry:Fananserin|Fananserin]] – mixed 5-HT<sub>2A</sub> / D<sub>4</sub> antagonist
*[[Chemistry:Olanzapine|Olanzapine]], an atypical antipsychotic
* [[Chemistry:Buspirone|Buspirone]], an anxiolytic

===Inverse agonists===
* FAUC F41: [[Chemistry:Inverse agonist|inverse agonist]], subtype selectivity of more than 3 orders of magnitude over D<sub>2</sub> and D<sub>3</sub><ref name="pmid18307287">{{cite journal | vauthors = Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, Gmeiner P | title = Synthesis, radiofluorination, and in vitro evaluation of pyrazolo[1,5-a]pyridine-based dopamine D4 receptor ligands: discovery of an inverse agonist radioligand for PET | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 6 | pages = 1800–10 | date = March 2008 | pmid = 18307287 | doi = 10.1021/jm701375u }}</ref><ref name="pmid11312915">{{cite journal | vauthors = Lanig H, Utz W, Gmeiner P | title = Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 8 | pages = 1151–7 | date = April 2001 | pmid = 11312915 | doi = 10.1021/jm001055e }}</ref>

== In popular culture ==

Michael Connelly’s 2020 crime novel ''Fair Warning'' (ISBN 978-0-316-53942-5) revolves around a serial killer who uses DNA profiles obtained on the Dark Web to target female victims, specifically those whose DRD4 profiles allegedly make them more susceptible to risk taking and sexual promiscuity.

== See also ==
* Dopamine hypothesis of psychosis

== References ==
{{Reflist|2}}

== External links ==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2258 | title = Dopamine Receptors: D<sub>4</sub> | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology }}
* [https://web.archive.org/web/20110710193406/http://search.engrant.com/sp/DRD4/ Current Research on the DRD<sub>4</sub> Gene]
* {{MeshName|Receptors,+Dopamine+D4}}
* {{cite web | url = http://www.bio.davidson.edu/courses/genomics/2001/wilson/gene.html | title = Are you a thrill seeker?? | access-date = 5 April 2008 | author = Marisa Wilson | publisher = Davidson College }}
* {{cite web | url = http://www.d4dr.net/d4dr_gene.htm | title = The D4DR Gene| access-date = 5 April 2008 | publisher = D4DR Club | archive-url =https://web.archive.org/web/20071013035446/http://www.d4dr.net/d4dr_gene.htm| archive-date =13 October 2007| url-status = dead }}
* {{PDBe-KB2|P21917|D(4) dopamine receptor}}

{{NLM content}}
{{G protein-coupled receptors}}

{{DEFAULTSORT:Dopamine Receptor D4}}
[[Category:Dopamine receptors]]
[[Category:Genes on human chromosome 11]]

{{Sourceattribution|Dopamine receptor D4}}