dopamine receptor

{{More citations needed|section|date=March 2009}}

The existence of multiple types of receptors for dopamine was first proposed in 1976.{{cite journal | vauthors = Cools AR, Van Rossum JM | author-link1 = Alexander Cools | title = Excitation-mediating and inhibition-mediating dopamine-receptors: a new concept towards a better understanding of electrophysiological, biochemical, pharmacological, functional and clinical data | journal = Psychopharmacologia | volume = 45 | issue = 3 | pages = 243–254 | year = 1976 | pmid = 175391 | doi=10.1007/bf00421135| s2cid = 40366909 }}{{cite journal | vauthors = Ellenbroek BA, Homberg J, Verheij M, Spooren W, van den Bos R, Martens G | title = Alexander Rudolf Cools (1942-2013) | journal = Psychopharmacology | volume = 231 | issue = 11 | pages = 2219–2222 | year = 2014 | pmid = 24770629 | doi = 10.1007/s00213-014-3583-5 | doi-access = free }} There are at least five subtypes of dopamine receptors, D₁, D₂, D₃, D₄, and D₅. The D₁ and D₅ receptors are members of the D₁-like family of dopamine receptors, whereas the D₂, D₃ and D₄ receptors are members of the D₂-like family. There is also some evidence that suggests the existence of possible D₆ and D₇ dopamine receptors, but such receptors have not been conclusively identified.{{cite journal | vauthors = Contreras F, Fouillioux C, Bolívar A, Simonovis N, Hernández-Hernández R, Armas-Hernandez MJ, Velasco M | title = Dopamine, hypertension and obesity | journal = J Hum Hypertens | volume = 16 | pages = S13–7 | year = 2002 | issue = Suppl 1 | pmid = 11986886 | doi = 10.1038/sj.jhh.1001334 | doi-access = }}

At a global level, D₁ receptors have widespread expression throughout the brain. The relative amount of DA receptors is in the following order: D1 > D2 > D3 > D5 > D4.{{Cite journal |last1=Mishra |first1=Akanksha |last2=Singh |first2=Sonu |last3=Shukla |first3=Shubha |date=2018-01-01 |title=Physiological and Functional Basis of Dopamine Receptors and Their Role in Neurogenesis: Possible Implication for Parkinson's disease |journal=Journal of Experimental Neuroscience |language=en |volume=12 |doi=10.1177/1179069518779829 |issn=1179-0695 |pmc=5985548 |pmid=29899667}} D_1-2 receptor subtypes are found at 10–100 times the levels of the D_3-5 subtypes.{{cite journal | vauthors = Hurley MJ, Jenner P | title = What has been learnt from study of dopamine receptors in Parkinson's disease? | journal = Pharmacol. Ther. | volume = 111 | issue = 3 | pages = 715–28 | year = 2006 | pmid = 16458973 | doi = 10.1016/j.pharmthera.2005.12.001 }}

The D₁-like family receptors are coupled to the G protein G_sα. D₁ is also coupled to G_olf.

G_sα subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP).{{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 | s2cid = 12407397 | doi-access = free }}

• D₁ is encoded by the Dopamine receptor D₁ gene ({{Gene|DRD1}}).
• D₅ is encoded by the Dopamine receptor D₅ gene ({{Gene|DRD5}}).

The D₂-like family receptors are coupled to the G protein G_iα, which directly inhibits the formation of cAMP by inhibiting the enzyme adenylyl cyclase.{{cite journal | vauthors = Neves SR, Ram PT, Iyengar R | title = G protein pathways | journal = Science | volume = 296 | issue = 5573 | pages = 1636–9 | year = 2002 | pmid = 12040175 | doi = 10.1126/science.1071550 | bibcode = 2002Sci...296.1636N | s2cid = 20136388 }}

• D₂ is encoded by the Dopamine receptor D₂ gene ({{Gene|DRD2}}), of which there are two forms: D₂Sh (short) and D₂Lh (long):
• The D₂Sh form is pre-synaptically situated, having modulatory functions (viz., autoreceptors, which regulate neurotransmission via feedback mechanisms. It affects synthesis, storage, and release of dopamine into the synaptic cleft).{{Cite web | url=https://books.google.com/books?id=jXnkai44PxYC&q=The+D2Sh+form+is+pre-synaptically+situated,+having+modulatory+functions+(viz.,+autoreceptors,+which+regulate+neurotransmission+by+feed-back+mechanisms,+affecting+synthesis,+storage,+and+release+of+dopamine+into+the+synaptic+cleft&pg=PA90 |title = Introduction to Neuroscience}}
• The D₂Lh form may function as a classical post-synaptic receptor, i.e., transmit information (in either an excitatory or an inhibitory fashion) unless blocked by a receptor antagonist or a synthetic partial agonist.
• D₃ is encoded by the Dopamine receptor D₃ gene ({{Gene|DRD3}}). Maximum expression of dopamine D₃ receptors is noted in the islands of Calleja and nucleus accumbens.{{cite journal | vauthors = Suzuki M, Hurd YL, Sokoloff P, Schwartz JC, Sedvall G | title = D3 dopamine receptor mRNA is widely expressed in the human brain | journal = Brain Res. | volume = 779 | issue = 1–2 | pages = 58–74 | year = 1998 | pmid = 9473588 | doi = 10.1016/S0006-8993(97)01078-0 | s2cid = 46096849 }}
• D₄ is encoded by the Dopamine receptor D₄ gene ({{Gene|DRD4}}). The D₄ receptor gene displays polymorphisms that differ in a variable number tandem repeat present within the coding sequence of exon 3.[https://www.ncbi.nlm.nih.gov/gene/1815?ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum#geneReference%20Sequences NCBI Database] Some of these alleles are associated with greater incidence of certain disorders. For example, the D_4.7 alleles have an established association with attention-deficit hyperactivity disorder.{{cite journal | vauthors = Manor I, Tyano S, Eisenberg J, Bachner-Melman R, Kotler M, Ebstein RP | title = 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) | journal = Mol. Psychiatry | volume = 7 | issue = 7 | pages = 790–4 | year = 2002 | pmid = 12192625 | doi = 10.1038/sj.mp.4001078 | doi-access = }}{{cite journal | vauthors = Langley K, Marshall L, van den Bree M, Thomas H, Owen M, O'Donovan M, Thapar A | s2cid = 25892078 | title = Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD | journal = Am J Psychiatry | volume = 161 | issue = 1 | pages = 133–8 | year = 2004 | pmid = 14702261 | doi = 10.1176/appi.ajp.161.1.133 }}{{cite journal | vauthors = Kustanovich V, Ishii J, Crawford L, Yang M, McGough JJ, McCracken JT, Smalley SL, Nelson SF | title = Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5 | journal = Mol. Psychiatry | volume = 9 | issue = 7 | pages = 711–7 | year = 2004 | pmid = 14699430 | doi = 10.1038/sj.mp.4001466 | doi-access = }}

Dopamine receptors have been shown to heteromerize with a number of other G protein-coupled receptors.{{cite journal | vauthors = Beaulieu JM, Espinoza S, Gainetdinov RR | title = Dopamine receptors – IUPHAR Review 13 | journal = Br. J. Pharmacol. | volume = 172 | issue = 1 | pages = 1–23 | year = 2015 | pmid = 25671228 | doi = 10.1111/bph.12906 | pmc=4280963}} Especially the D2 receptor is considered a major hub within the GPCR heteromer network.{{cite journal |vauthors=Borroto-Escuela DO, Brito I, Romero-Fernandez W, etal |title=The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components |journal=Int J Mol Sci |volume=15 |issue=5 |pages=8570–90 |date=May 2014 |pmid=24830558 |pmc=4057749 |doi=10.3390/ijms15058570 |doi-access=free }} Protomers consist of

Isoreceptors{{cite journal |vauthors=Agnati LF, Guidolin D, Cervetto C, Borroto-Escuela DO, Fuxe K |title=Role of iso-receptors in receptor-receptor interactions with a focus on dopamine iso-receptor complexes |journal=Rev Neurosci |volume=27 |issue=1 |pages=1–25 |date=January 2016 |pmid=26418645 |doi=10.1515/revneuro-2015-0024 |doi-access=free }}

• D₁–D₂
• D₁–D₃
• D₂–D₃
• D₂–D₄
• D₂–D₅

Non-isoreceptors

• D₁–adenosine A₁
• D₂–adenosine A_2A
• D₂–ghrelin receptor
• D_2sh–TAAR1 (an autoreceptor heteromer)
• D₄–adrenoceptor α_1B
• D₄–adrenoceptor β₁

Dopamine receptor D₁ and Dopamine receptor D₅ are G_s coupled receptors that stimulate adenylyl cyclase to produce cAMP, which in turn increases intracellular calcium and mediates a number of other functions. The D2 class of receptors produce the opposite effect, as they are G_αi and/or G_αo coupled receptors, which blocks the activity of adenylyl cyclase. cAMP mediated protein kinase A activity also results in the phosphorylation of DARPP-32, an inhibitor of protein phosphatase 1. Sustained D1 receptor activity is kept in check by Cyclin-dependent kinase 5. Dopamine receptor activation of Ca²⁺/calmodulin-dependent protein kinase II can be cAMP dependent or independent.{{cite journal | vauthors = Beaulieu JM, Espinoza S, Gainetdinov RR | title = Dopamine receptors – IUPHAR Review 13 | journal = British Journal of Pharmacology | volume = 172 | issue = 1 | pages = 1–23 | date = January 2015 | pmid = 25671228 | pmc = 4280963 | doi = 10.1111/bph.12906 }}

The cAMP mediated pathway results in amplification of PKA phosphorylation activity, which is normally kept in equilibrium by PP1. The DARPP-32 mediated PP1 inhibition amplifies PKA phosphorylation of AMPA, NMDA, and inward rectifying potassium channels, increasing AMPA and NMDA currents while decreasing potassium conductance.

D1 receptor agonism and D2 receptor blockade also increases mRNA translation by phosphorylating ribosomal protein s6, resulting in activation of mTOR. The behavioral implications are unknown. Dopamine receptors may also regulate ion channels and BDNF independent of cAMP, possibly through direct interactions. There is evidence that D1 receptor agonism regulates phospholipase C independent of cAMP, however implications and mechanisms remain poorly understood. D2 receptor signaling may mediate protein kinase B, arrestin beta 2, and GSK-3 activity, and inhibition of these proteins results in stunting of the hyperlocomotion in amphetamine treated rats. Dopamine receptors can also transactivate Receptor tyrosine kinases.

Beta Arrestin recruitment is mediated by G-protein kinases that phosphorylate and inactivate dopamine receptors after stimulation. While beta arrestin plays a role in receptor desensitization, it may also be critical in mediating downstream effects of dopamine receptors. Beta arrestin has been shown to form complexes with MAP kinase, leading to activation of extracellular signal-regulated kinases. Furthermore, this pathway has been demonstrated to be involved in the locomotor response mediated by dopamine receptor D1. Dopamine receptor D2 stimulation results in the formation of an Akt/Beta-arrestin/PP2A protein complex that inhibits Akt through PP2A phosphorylation, therefore disinhibiting GSK-3.{{cite journal | vauthors = Del'guidice T, Lemasson M, Beaulieu JM | title = Role of Beta-arrestin 2 downstream of dopamine receptors in the Basal Ganglia | journal = Frontiers in Neuroanatomy | volume = 5 | pages = 58 | date = 2011 | pmid = 21922001 | pmc = 3167352 | doi = 10.3389/fnana.2011.00058 | doi-access = free }}

{{further|Neurotransmitter#Brain neurotransmitter systems}}

{{further|Dopaminergic pathways}}

Dopamine receptors control neural signaling that modulates many important behaviors, such as spatial working memory.{{cite journal | vauthors = Williams GV, Castner SA | title = Under the curve: critical issues for elucidating D1 receptor function in working memory | journal = Neuroscience | volume = 139 | issue = 1 | pages = 263–76 | year = 2006 | pmid = 16310964 | doi = 10.1016/j.neuroscience.2005.09.028 | s2cid = 20906770 }} Dopamine also plays an important role in the reward system, incentive salience, cognition, prolactin release, emesis and motor function.{{cite book |first = Roy | last = Webster |title=Neurotransmitters, drugs and brain function|date=2001|publisher=Wiley|location=Chichester|isbn=978-0-471-97819-0|pages=137|edition=Repr.}}

In humans, the pulmonary artery expresses D₁, D₂, D₄, and D₅ and receptor subtypes, which may account for vasodilatory effects of dopamine in the blood.{{cite journal | vauthors = Ricci A, Mignini F, Tomassoni D, Amenta F | title = Dopamine receptor subtypes in the human pulmonary arterial tree | journal = Autonomic and Autacoid Pharmacology | volume = 26 | issue = 4 | pages = 361–9 | year = 2006 | pmid = 16968475 | doi = 10.1111/j.1474-8673.2006.00376.x }} Such receptor subtypes have also been discovered in the epicardium, myocardium, and endocardium of the heart.{{cite journal | vauthors = Cavallotti C, Massimo M, Paolo B, Maurizio S, Fiorenzo M | title = Dopamine receptor subtypes in the native human heart | journal = Heart and Vessels | volume = 25 | issue = 5 | pages = 432–7 | year = 2010 | doi=10.1007/s00380-009-1224-4 | pmid = 20676967 | hdl = 11573/230067 | s2cid = 36507640 }} In rats, D₁-like receptors are present on the smooth muscle of the blood vessels in most major organs.{{cite journal | vauthors = Hussain T, Lokhandwala MF | title = Renal dopamine receptors and hypertension | journal = Exp. Biol. Med. (Maywood) | volume = 228 | issue = 2 | pages = 134–42 | year = 2003 | pmid = 12563019 | doi=10.1177/153537020322800202| s2cid = 10896819 }}

D₄ receptors have been identified in the atria of rat and human hearts.{{cite journal | vauthors = Ricci A, Bronzetti E, Fedele F, Ferrante F, Zaccheo D, Amenta F | title = Pharmacological characterization and autoradiographic localization of a putative dopamine D4 receptor in the heart | journal = J Auton Pharmacol | volume = 18 | issue = 2 | pages = 115–21 | year = 1998 | pmid = 9730266 | doi = 10.1046/j.1365-2680.1998.1820115.x | hdl = 11573/464054 }} Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signaling through dopamine receptors.

Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density. In rats, D₁-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D₂-like receptors are present on the glomeruli, zona glomerulosa cells of the adrenal cortex, renal tubules, and postganglionic sympathetic nerve terminals. Dopamine signaling affects diuresis and natriuresis.

The role of the pancreas{{Citation |last=Leung |first=Po Sing |title=Overview of the Pancreas |date=2010 |work=The Renin-Angiotensin System: Current Research Progress in The Pancreas |series=Advances in Experimental Medicine and Biology |volume=690 |pages=3–12 |url=http://link.springer.com/10.1007/978-90-481-9060-7_1 |access-date=2024-04-12 |place=Dordrecht |publisher=Springer Netherlands |language=en |doi=10.1007/978-90-481-9060-7_1 |pmid=20700834 |isbn=978-90-481-9059-1|url-access=subscription }} is to secrete digestive enzymes via exocrine glands and hormones via endocrine glands. Pancreatic endocrine glands, composed of dense clusters of cells called the Islets of Langerhans, secrete insulin, glucagon, and other hormones essential for metabolism and glycemic control. Insulin secreting beta cells have been intensely researched due to their role in diabetes.{{Cite journal |last1=Tan |first1=Sin Yee |last2=Mei Wong |first2=Joyce Ling |last3=Sim |first3=Yan Jinn |last4=Wong |first4=Su Sie |last5=Mohamed Elhassan |first5=Safa Abdelgadir |last6=Tan |first6=Sean Hong |last7=Ling Lim |first7=Grace Pei |last8=Rong Tay |first8=Nicole Wuen |last9=Annan |first9=Naveenya Chetty |last10=Bhattamisra |first10=Subrat Kumar |last11=Candasamy |first11=Mayuren |date=January 2019 |title=Type 1 and 2 diabetes mellitus: A review on current treatment approach and gene therapy as potential intervention |url=https://linkinghub.elsevier.com/retrieve/pii/S1871402118304181 |journal=Diabetes & Metabolic Syndrome: Clinical Research & Reviews |language=en |volume=13 |issue=1 |pages=364–372 |doi=10.1016/j.dsx.2018.10.008|pmid=30641727 |url-access=subscription }}

Recent studies have found that beta cells, as well as other endocrine and exocrine pancreatic cells, express D2 receptors{{Cite journal |last1=Rubí |first1=Blanca |last2=Ljubicic |first2=Sanda |last3=Pournourmohammadi |first3=Shirin |last4=Carobbio |first4=Stefania |last5=Armanet |first5=Mathieu |last6=Bartley |first6=Clarissa |last7=Maechler |first7=Pierre |date=November 2005 |title=Dopamine D2-like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion |journal=Journal of Biological Chemistry |language=en |volume=280 |issue=44 |pages=36824–36832 |doi=10.1074/jbc.M505560200|doi-access=free |pmid=16129680 }} and that beta cells co-secrete dopamine along with insulin.{{Cite journal |last1=Rubí |first1=Blanca |last2=Ljubicic |first2=Sanda |last3=Pournourmohammadi |first3=Shirin |last4=Carobbio |first4=Stefania |last5=Armanet |first5=Mathieu |last6=Bartley |first6=Clarissa |last7=Maechler |first7=Pierre |date=November 2005 |title=Dopamine D2-like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion |journal=Journal of Biological Chemistry |language=en |volume=280 |issue=44 |pages=36824–36832 |doi=10.1074/jbc.M505560200|doi-access=free |pmid=16129680 }} Dopamine has been purported to be a negative regulator of insulin,{{Cite journal |last1=Liu |first1=Mengmeng |last2=Ren |first2=Lele |last3=Zhong |first3=Xiangqin |last4=Ding |first4=Yaqin |last5=Liu |first5=Tao |last6=Liu |first6=Zhihong |last7=Yang |first7=Xiaohua |last8=Cui |first8=Lijuan |last9=Yang |first9=Lijun |last10=Fan |first10=Yanying |last11=Liu |first11=Yunfeng |last12=Zhang |first12=Yi |date=2020-04-07 |title=D2-Like Receptors Mediate Dopamine-Inhibited Insulin Secretion via Ion Channels in Rat Pancreatic β-Cells |journal=Frontiers in Endocrinology |volume=11 |page=152 |doi=10.3389/fendo.2020.00152 |doi-access=free |issn=1664-2392 |pmc=7154177 |pmid=32318020}}{{Cite journal |last1=Aslanoglou |first1=Despoina |last2=Bertera |first2=Suzanne |last3=Sánchez-Soto |first3=Marta |last4=Benjamin Free |first4=R. |last5=Lee |first5=Jeongkyung |last6=Zong |first6=Wei |last7=Xue |first7=Xiangning |last8=Shrestha |first8=Shristi |last9=Brissova |first9=Marcela |last10=Logan |first10=Ryan W. |last11=Wollheim |first11=Claes B. |last12=Trucco |first12=Massimo |last13=Yechoor |first13=Vijay K. |last14=Sibley |first14=David R. |last15=Bottino |first15=Rita |date=2021-02-16 |title=Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors |journal=Translational Psychiatry |language=en |volume=11 |issue=1 |page=59 |doi=10.1038/s41398-020-01171-z |issn=2158-3188 |pmc=7884786 |pmid=33589583}} meaning that bound D2 receptors inhibit insulin secretion. The connection between dopamine and beta cells was discovered, in part, due to the metabolic side-effects of certain antipsychotic medications.{{Cite journal |last1=Kaar |first1=Stephen J. |last2=Natesan |first2=Sridhar |last3=McCutcheon |first3=Robert |last4=Howes |first4=Oliver D. |date=August 2020 |title=Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology |url=https://linkinghub.elsevier.com/retrieve/pii/S002839081930262X |journal=Neuropharmacology |language=en |volume=172 |pages=107704 |doi=10.1016/j.neuropharm.2019.107704|pmid=31299229 |url-access=subscription }}{{Cite journal |last1=Muench |first1=John |last2=Hamer |first2=Ann M. |date=2010-03-01 |title=Adverse effects of antipsychotic medications |url=https://pubmed.ncbi.nlm.nih.gov/20187598 |journal=American Family Physician |volume=81 |issue=5 |pages=617–622 |issn=1532-0650 |pmid=20187598}} Traditional/typical antipsychotic medications function by altering the dopamine pathway in the brain, such as blocking D2 receptors.{{Cite journal |last=Nadal |first=Roser |date=September 2001 |title=Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D 2 Receptor Antagonist |journal=CNS Drug Reviews |language=en |volume=7 |issue=3 |pages=265–282 |doi=10.1111/j.1527-3458.2001.tb00199.x |issn=1080-563X |pmc=6741677 |pmid=11607043}} Common side effects of these medications include rapid weight gain and glycemic dysregulation, among others.{{Cite journal |last1=Kane |first1=John M. |last2=Correll |first2=Christoph U. |date=2010-09-15 |title=Past and Present Progress in the Pharmacologic Treatment of Schizophrenia |url=https://www.psychiatrist.com/jcp/past-present-progress-pharmacologic-treatment-schizophrenia |journal=The Journal of Clinical Psychiatry |volume=71 |issue=9 |pages=1115–1124 |doi=10.4088/JCP.10r06264yel |issn=0160-6689 |pmc=3065240 |pmid=20923620}} The effects of these medications are not limited to the brain, so off-target effects in other organs such as the pancreas have been proposed as a possible mechanism.{{Cite journal |last1=Hassanabad |first1=Mortaza Fatehi |last2=Fatehi |first2=Mohammad |date=2019-01-18 |title=Current Views on Dopaminergic Drugs Affecting Glucose Homeostasis |url=http://www.eurekaselect.com/161536/article |journal=Current Diabetes Reviews |language=en |volume=15 |issue=2 |pages=93–99 |doi=10.2174/1573399814666180424123912|pmid=29692257 |url-access=subscription }}

Dopamine receptors D1, D2, D4, and D5 are present in human subcutaneous, visceral, and brown adipose tissue, and have been implicated in lipid and glucose metabolism, and thermogenesis.{{cite journal |last1=Borcherding |first1=Dana C. |last2=Hugo |first2=Eric R. |last3=Idelman |first3=Gila |last4=Silva |first4=Anuradha De |last5=Richtand |first5=Nathan W. |last6=Loftus |first6=Jean |last7=Ben-Jonathan |first7=Nira |title=Dopamine Receptors in Human Adipocytes: Expression and Functions |journal=PLOS ONE |pages=e25537 |language=en |doi=10.1371/journal.pone.0025537 |date=26 September 2011|volume=6 |issue=9 |doi-access=free |pmid=21966540 |pmc=3180449 |bibcode=2011PLoSO...625537B }}{{cite journal |last1=Vranic |first1=Milica |last2=Ahmed |first2=Fozia |last3=Kristófi |first3=Robin |last4=Hetty |first4=Susanne |last5=Mokhtari |first5=Dariush |last6=Svensson |first6=Maria K. |last7=Eriksson |first7=Jan W. |last8=Pereira |first8=Maria J. |title=Subcutaneous adipose tissue dopamine D2 receptor is increased in prediabetes and T2D |journal=Endocrine |pages=378–391 |language=en |doi=10.1007/s12020-023-03525-1 |date=1 February 2024|volume=83 |issue=2 |pmid=37752366 |pmc=10850013 }} Dopamine that reaches dopamine receptors in adipose tissue can originate from multiple sources: from the circulation, sympathetic nerves innervating adipose tissue that release dopamine from nerve terminals, local synthesis, or immune cells{{cite journal |last1=Tavares |first1=Gabriela |last2=Rosendo-Silva |first2=Daniela |last3=Simões |first3=Flávia |last4=Eickhoff |first4=Hans |last5=Marques |first5=Daniela |last6=Sacramento |first6=Joana F. |last7=Capucho |first7=Adriana M. |last8=Seiça |first8=Raquel |last9=Conde |first9=Sílvia V. |last10=Matafome |first10=Paulo |title=Circulating Dopamine Is Regulated by Dietary Glucose and Controls Glucagon-like 1 Peptide Action in White Adipose Tissue |journal=International Journal of Molecular Sciences |pages=2464 |language=en |doi=10.3390/ijms24032464 |date=January 2023|volume=24 |issue=3 |doi-access=free |pmid=36768789 |pmc=9916853 }}{{cite journal |last1=Nguyen |first1=Khoa D. |last2=Qiu |first2=Yifu |last3=Cui |first3=Xiaojin |last4=Goh |first4=Y. P. Sharon |last5=Mwangi |first5=Julia |last6=David |first6=Tovo |last7=Mukundan |first7=Lata |last8=Brombacher |first8=Frank |last9=Locksley |first9=Richard M. |last10=Chawla |first10=Ajay |title=Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis |journal=Nature |pages=104–108 |language=en |doi=10.1038/nature10653 |date=20 November 2011|volume=480 |issue=7375 |pmid=22101429 |pmc=3371761 |bibcode=2011Natur.480..104N }}

Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including social phobia,{{cite journal | vauthors = Schneier FR, Liebowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin SH, Laruelle M | title = Low dopamine D(2) receptor binding potential in social phobia | journal = Am J Psychiatry | volume = 157 | issue = 3 | pages = 457–459 | year = 2000 | pmid = 10698826 | doi = 10.1176/appi.ajp.157.3.457 }} Tourette's syndrome,{{cite journal | vauthors = Kienast T, Heinz A | title = Dopamine and the diseased brain | journal = CNS Neurol Disord Drug Targets | volume = 5 | issue = 1 | pages = 109–31 | year = 2006 | pmid = 16613557 | doi = 10.2174/187152706784111560 }} Parkinson's disease,{{cite book | vauthors = Fuxe K, Manger P, Genedani S, Agnati L | title = Parkinson's Disease and Related Disorders | chapter = The nigrostriatal DA pathway and Parkinson's disease | journal = J. Neural Transm. Suppl. | volume = 70 | issue = 70 | pages = 71–83 | year = 2006 | pmid = 17017512 | doi = 10.1007/978-3-211-45295-0_13 | isbn = 978-3-211-28927-3 | series = Journal of Neural Transmission. Supplementa }} schizophrenia, neuroleptic malignant syndrome,{{cite journal | vauthors = Mihara K, Kondo T, Suzuki A, Yasui-Furukori N, Ono S, Sano A, Koshiro K, Otani K, Kaneko S | title = Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome | journal = Am. J. Med. Genet. B Neuropsychiatr. Genet. | volume = 117B | issue = 1 | pages = 57–60 | year = 2003 | pmid = 12555236 | doi = 10.1002/ajmg.b.10025 | s2cid = 44866985 }} attention-deficit hyperactivity disorder (ADHD),{{cite journal | vauthors = Faraone SV, Khan SA | title = Candidate gene studies of attention-deficit/hyperactivity disorder | journal = J Clin Psychiatry | volume = 67 | pages = 13–20 | year = 2006 | issue = Suppl 8 | pmid = 16961425 }} and drug and alcohol dependence.

{{main|Attention-deficit hyperactivity disorder}}

Dopamine receptors have been recognized as important components in the mechanism of ADHD for many years. Drugs used to treat ADHD, including methylphenidate and amphetamine, have significant effects on neuronal dopamine signaling. Studies of gene association have implicated several genes within dopamine signaling pathways; in particular, the D_4.7 variant of D₄ has been consistently shown to be more frequent in ADHD patients.{{cite journal | vauthors = Gornick MC, Addington A, Shaw P, Bobb AJ, Sharp W, Greenstein D, Arepalli S, Castellanos FX, Rapoport JL | title = Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD): an update | journal = Am. J. Med. Genet. B Neuropsychiatr. Genet. | volume = 144B | issue = 3 | pages = 379–82 | year = 2007 | pmid = 17171657 | doi = 10.1002/ajmg.b.30460 | s2cid = 25065281 | url = https://zenodo.org/record/1229115 }} ADHD patients with the 4.7 allele also tend to have better cognitive performance and long-term outcomes compared to ADHD patients without the 4.7 allele, suggesting that the allele is associated with a more benign form of ADHD.

The D_4.7 allele has suppressed gene expression compared to other variants.{{cite journal | vauthors = Schoots O, Van Tol HH | title = The human dopamine D4 receptor repeat sequences modulate expression | journal = Pharmacogenomics J. | volume = 3 | issue = 6 | pages = 343–8 | year = 2003 | pmid = 14581929 | doi = 10.1038/sj.tpj.6500208 | doi-access = }}

{{main|Addiction}}

Dopamine is the primary neurotransmitter involved in the reward and reinforcement (mesolimbic) pathway in the brain. Although it was a long-held belief that dopamine was the cause of pleasurable sensations such as euphoria, many studies and experiments on the subject have demonstrated that this is not the case; rather, dopamine in the mesolimbic pathway is responsible for behaviour reinforcement ("wanting") without producing any "liking" sensation on its own.{{Cite journal |last1=Berridge |first1=K. C. |last2=Robinson |first2=T. E. |date=1998 |title=What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? |url=https://pubmed.ncbi.nlm.nih.gov/9858756/ |journal=Brain Research. Brain Research Reviews |volume=28 |issue=3 |pages=309–369 |doi=10.1016/s0165-0173(98)00019-8 |pmid=9858756|s2cid=11959878 }}{{Cite journal |last1=Liggins |first1=John |last2=Pihl |first2=Robert O. |last3=Benkelfat |first3=Chawki |last4=Leyton |first4=Marco |date=2012 |title=The dopamine augmenter L-DOPA does not affect positive mood in healthy human volunteers |journal=PLOS ONE |volume=7 |issue=1 |pages=e28370 |doi=10.1371/journal.pone.0028370 |issn=1932-6203 |pmc=3251561 |pmid=22238577|bibcode=2012PLoSO...728370L |doi-access=free }}{{Cite journal |last1=Olney |first1=Jeffrey J. |last2=Warlow |first2=Shelley M. |last3=Naffziger |first3=Erin E. |last4=Berridge |first4=Kent C. |date=2018 |title=Current perspectives on incentive salience and applications to clinical disorders |journal=Current Opinion in Behavioral Sciences |volume=22 |pages=59–69 |doi=10.1016/j.cobeha.2018.01.007 |issn=2352-1546 |pmc=5831552 |pmid=29503841}}{{Cite web |date=2022-03-22 |title=Drugs and the Brain |url=https://nida.nih.gov/publications/drugs-brains-behavior-science-addiction/drugs-brain |access-date=2022-08-21 |website=National Institute on Drug Abuse |language=en}} Mesolimbic dopamine and its related receptors are a primary mechanism through which drug-seeking behaviour develops (Incentive Salience), and many recreational drugs, such as cocaine and substituted amphetamines, inhibit the dopamine transporter (DAT), the protein responsible for removing dopamine from the neural synapse. When DAT activity is blocked, the synapse floods with dopamine and increases dopaminergic signaling. When this occurs, particularly in the nucleus accumbens,{{cite journal | vauthors = Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D | title = Dopamine and drug addiction: the nucleus accumbens shell connection | journal = Neuropharmacology | volume = 47 | pages = 227–41 | year = 2004 | issue = Suppl 1 | pmid = 15464140 | doi = 10.1016/j.neuropharm.2004.06.032 | s2cid = 25983940 }} increased D₁{{cite journal | vauthors = Hummel M, Unterwald EM | title = D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action | journal = J. Cell. Physiol. | volume = 191 | issue = 1 | pages = 17–27 | year = 2002 | pmid = 11920678 | doi = 10.1002/jcp.10078 | s2cid = 40444893 | doi-access = free }} and decreased D₂ receptor signaling mediates the "incentive salience" factor and can significantly increase positive associations with the drug in the brain.

{{main|Problem gambling}}

Pathological gambling is classified as a mental health disorder that has been linked to obsessive-compulsive spectrum disorder and behavioral addiction. Dopamine has been associated with reward and reinforcement in relation to behaviors and drug addiction.{{cite journal | vauthors = Potenza MN | title = Review. The neurobiology of pathological gambling and drug addiction: an overview and new findings | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 363 | issue = 1507 | pages = 3181–9 | date = October 2008 | pmid = 18640909 | pmc = 2607329 | doi = 10.1098/rstb.2008.0100 | doi-access = free }} The role between dopamine and pathological gambling may be a link between cerebrospinal fluid measures of dopamine and dopamine metabolites in pathological gambling.{{cite journal | vauthors = Leibenluft E | title = Gender differences in major depressive disorder and bipolar disorder | journal = CNS Spectrums | volume = 4 | issue = 10 | pages = 25–33 | date = October 1999 | pmid = 18438310 | doi = 10.1017/S1092852900012335 | s2cid = 20594850 }} Molecular genetic study shows that pathological gambling is associated with the TaqA1 allele of the Dopamine Receptor D2 (DRD2) dopamine receptor. Furthermore, TaqA1 allele is associated with other reward and reinforcement disorders, such as substance abuse and other psychiatric disorders. Reviews of these studies suggest that pathological gambling and dopamine are linked; however, the studies that succeed in controlling for race or ethnicity, and obtain DSM-IV diagnoses do not show a relationship between TaqA1 allelic frequencies and the diagnostic of pathological gambling.

{{Main|Dopamine hypothesis of schizophrenia}}

While there is evidence that the dopamine system is involved in schizophrenia, the theory that hyperactive dopaminergic signal transduction induces the disease is controversial. Psychostimulants, such as amphetamine and cocaine, indirectly increase dopamine signaling; large doses and prolonged use can induce symptoms that resemble schizophrenia. Additionally, many antipsychotic drugs target dopamine receptors, especially D₂ receptors.

Dopamine receptor mutations can cause genetic hypertension in humans.{{cite journal | vauthors = Jose PA, Eisner GM, Felder RA | title = Regulation of blood pressure by dopamine receptors | journal = Nephron Physiol | volume = 95 | issue = 2 | pages =19–27 | year = 2003 | pmid = 14610323 | doi = 10.1159/000073676 | s2cid = 28595227 }} This can occur in animal models and humans with defective dopamine receptor activity, particularly D₁.

Parkinson's disease is associated with the loss of cells responsible for dopamine synthesis and other neurodegenerative events. Parkinson's disease patients are treated with medications which help to replenish dopamine availability, allowing relatively normal brain function and neurotransmission.{{cite journal | vauthors = Lang AE, Obeso JA | title = Challenges in Parkinson's disease: restoration of the nigrostriatal dopamine system is not enough | journal = The Lancet. Neurology | volume = 3 | issue = 5 | pages = 309–16 | date = May 2004 | pmid = 15099546 | doi = 10.1016/S1474-4422(04)00740-9 | s2cid = 6551470 }} Research shows that Parkinson's disease is linked to the class of dopamine agonists instead of specific agents. Reviews touch upon the need to control and regulate dopamine doses for Parkinson's patients with a history of addiction, and those with variable tolerance or sensitivity to dopamine.{{cite journal | vauthors = Nestler EJ | title = Molecular mechanisms of drug addiction | journal = Neuropharmacology | volume = 47 | pages = 24–32 | date = 1 January 2004 | issue = Suppl 1 | pmid = 15464123 | doi = 10.1016/j.neuropharm.2004.06.031 | s2cid = 11266116 }}

{{see also|Yerkes–Dodson law}}

Dopamine receptors are typically stable, however sharp (and sometimes prolonged) increases or decreases in dopamine levels can downregulate (reduce the numbers of) or upregulate (increase the numbers of) dopamine receptors.{{cite journal | last = Scheler| first= G. | title = Regulation of neuromodulator receptor efficacy--implications for whole-neuron and synaptic plasticity. | journal = Prog. Neurobiol. | volume = 72 | issue = 6| pages = 399–415 | date = 2004 | pmid = 15177784 | doi = 10.1016/j.pneurobio.2004.03.008 | arxiv = q-bio/0401039 | s2cid= 9353254 }}

Haloperidol, and some other antipsychotics, have been shown to increase the binding capacity of the D₂ receptor when used over long periods of time (i.e. increasing the number of such receptors).{{cite journal | vauthors = Silvestri S, Seeman MV, Negrete JC, Houle S, Shammi CM, Remington GJ, Kapur S, Zipursky RB, Wilson AA, Christensen BK, Seeman P | title = Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study | journal = Psychopharmacology | volume = 152 | issue = 2 | pages = 174–80 | year = 2000 | pmid = 11057521 | doi = 10.1007/s002130000532 | s2cid = 20804595 }} Haloperidol increased the number of binding sites by 98% above baseline in the worst cases, and yielded significant dyskinesia side effects.

Addictive stimuli have variable effects on dopamine receptors, depending on the particular stimulus.{{cite journal | vauthors = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–22 | date = December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from “normal” to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)." }}[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704/table/T1/?report=objectonly Table 1]" According to one study,{{cite journal | vauthors = Fehr C, Yakushev I, Hohmann N, Buchholz HG, Landvogt C, Deckers H, Eberhardt A, Kläger M, Smolka MN, Scheurich A, Dielentheis T, Schmidt LG, Rösch F, Bartenstein P, Gründer G, Schreckenberger M | title = Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse | journal = The American Journal of Psychiatry | volume = 165 | issue = 4 | pages = 507–14 | date = April 2008 | pmid = 18316420 | doi = 10.1176/appi.ajp.2007.07020352 }} cocaine, opioids like heroin, amphetamine, alcohol, and nicotine cause decreases in D₂ receptor quantity. A similar association has been linked to food addiction, with a low availability of dopamine receptors present in people with greater food intake.{{cite web |url=http://www.docshop.com/2007/08/09/food-addiction/ |title=Food Addiction: From Drugs to Donuts, Brain Activity May be the Key | first = Paul | last = Park |date=9 August 2007}}{{cite journal | vauthors = Johnson PM, Kenny PJ | title = Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats | journal = Nature Neuroscience | volume = 13 | issue = 5 | pages = 635–41 | date = May 2010 | pmid = 20348917 | pmc = 2947358 | doi = 10.1038/nn.2519 }} A recent news article{{cite web |url=https://www.sciencedaily.com/releases/2008/04/080416081628.htm |title=Gene Therapy For Addiction: Flooding Brain With 'Pleasure Chemical' Receptors Works On Cocaine, As On Alcohol |date=18 April 2008}} summarized a U.S. DOE Brookhaven National Laboratory study showing that increasing dopamine receptors with genetic therapy temporarily decreased cocaine consumption by up to 75%. The treatment was effective for 6 days. Cocaine upregulates D₃ receptors in the nucleus accumbens, further reinforcing drug seeking behavior.{{cite journal | vauthors = Staley JK, Mash DC | title = Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities | journal = The Journal of Neuroscience | volume = 16 | issue = 19 | pages = 6100–6 | date = October 1996 | pmid = 8815892 | pmc = 6579196 | doi = 10.1523/JNEUROSCI.16-19-06100.1996}} and Caffeine increases striatal dopamine D₂/D₃ receptor availability in the human brain,{{Cite journal |last1=Volkow |first1=N. D. |last2=Wang |first2=G.-J. |last3=Logan |first3=J. |last4=Alexoff |first4=D. |last5=Fowler |first5=J. S. |last6=Thanos |first6=P. K. |last7=Wong |first7=C. |last8=Casado |first8=V. |last9=Ferre |first9=S. |last10=Tomasi |first10=D. |date=2015-04-14 |title=Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain |journal=Translational Psychiatry |volume=5 |issue=4 |pages=e549 |doi=10.1038/tp.2015.46 |issn=2158-3188 |pmc=4462609 |pmid=25871974}} Caffeine, or other more selective adenosine A2A receptor antagonists, causes significantly less motor stimulation in dopamine D₂ receptor.{{Cite journal |last1=Voiculescu |first1=M |last2=Ghiță |first2=I |last3=Segărceanu |first3=A |last4=Fulga |first4=I |last5=Coman |first5=O |date=2014 |title=Molecular and pharmacodynamic interactions between caffeine and dopaminergic system |journal=Journal of Medicine and Life |volume=7 |issue=Spec Iss 4 |pages=30–38 |issn=1844-122X |pmc=4813614 |pmid=27057246}}

Certain stimulants will enhance cognition in the general population (e.g., direct or indirect mesocortical DRD1 agonists as a class), but only when used at low (therapeutic) concentrations.{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = J. Cogn. Neurosci. | volume = 27| issue = 6| pages = 1069–1089 | date = January 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | s2cid = 15788121 | quote = The present meta-analysis was conducted to estimate the magnitude of the effects of methylphenidate and amphetamine on cognitive functions central to academic and occupational functioning, including inhibitory control, working memory, short-term episodic memory, and delayed episodic memory. In addition, we examined the evidence for publication bias. Forty-eight studies (total of 1,409 participants) were included in the analyses. We found evidence for small but significant stimulant enhancement effects on inhibitory control and short-term episodic memory. Small effects on working memory reached significance, based on one of our two analytical approaches. Effects on delayed episodic memory were medium in size. However, because the effects on long-term and working memory were qualified by evidence for publication bias, we conclude that the effect of amphetamine and methylphenidate on the examined facets of healthy cognition is probably modest overall. In some situations, a small advantage may be valuable, although it is also possible that healthy users resort to stimulants to enhance their energy and motivation more than their cognition. ... Earlier research has failed to distinguish whether stimulants’ effects are small or whether they are nonexistent (Ilieva et al., 2013; Smith & Farah, 2011). The present findings supported generally small effects of amphetamine and methylphenidate on executive function and memory. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ...

The results of this meta-analysis cannot address the important issues of individual differences in stimulant effects or the role of motivational enhancement in helping perform academic or occupational tasks. However, they do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.| url = https://repository.upenn.edu/cgi/viewcontent.cgi?article=1141&context=neuroethics_pubs | url-access = subscription }}{{cite journal |vauthors=Wood S, Sage JR, Shuman T, Anagnostaras SG |title=Psychostimulants and cognition: a continuum of behavioral and cognitive activation |journal=Pharmacol. Rev. |volume=66 |issue=1 |pages=193–221 |date=January 2014 |pmid=24344115 |doi=10.1124/pr.112.007054 |pmc=3880463}} Relatively high doses of dopaminergic stimulants will result in cognitive deficits.{{cite book|vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-148127-4 | page = 318 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control | quote=Mild dopaminergic stimulation of the prefrontal cortex enhances working memory. ...
Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spatial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors.}}

{{FOSB addiction table|Table title=Summary of addiction-related plasticity}}

• D2 short (presynaptic)
• :Category:Dopamine agonists
• :Category:Dopamine antagonists

{{Reflist|30em}}

• {{cite web | url = http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1282 | title = Dopamine Receptors | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 20 July 2006 | archive-date = 1 February 2017 | archive-url = https://web.archive.org/web/20170201103523/http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1282 | url-status = dead }}
• Zimmerberg, B., [http://www.williams.edu/imput/IIIB1.html "Dopamine receptors: A representative family of metabotropic receptors], Multimedia Neuroscience Education Project (2002)
• [http://www.scholarpedia.org/article/Dopamine_anatomy#Dopamine_receptors Scholarpedia article on Dopamine anatomy]

{{G protein-coupled receptors|g1}}

{{Dopaminergics}}

{{Authority control}}

{{DEFAULTSORT:Dopamine Receptor}}

Category:Dopamine receptors