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Revision as of 23:00, 16 February 2014 editSeppi333 (talk | contribs)Autopatrolled, Extended confirmed users, Page movers, New page reviewers, Pending changes reviewers, Template editors35,345 edits might as well make this a drugbox along with norepi since it's also a peripheral injectable  Latest revision as of 21:30, 16 November 2024 edit Slothwizard (talk | contribs)Extended confirmed users1,190 editsm Consistent with other articlesTags: Visual edit Mobile edit Mobile web edit 
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{{Short description|Hormone used as a medication}}
{{Use dmy dates|date=February 2014}}
{{About|the medication|this substance as a natural biological molecule|Dopamine}}
{{Other uses}}
{{Other uses|Dopamine (disambiguation)}}
{{Use dmy dates|date=June 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{drugbox {{drugbox
| Watchedfields = changed
| verifiedrevid = 595793408
| drug_name = Dopamine | drug_name = Dopamine
| image = Dopamine2.svg
| verifiedrevid = 464188976
| alt =
| image =Dopamine2.svg
| caption = ] of dopamine
| width=200px
| image2 = Dopamine-from-xtal-view-1-3D-bs-17.png
| alt =
| alt2 =
| image2=Dopamine-3d-CPK.png
| caption2 = ] of the ]ic form of dopamine found in the ]<ref>{{ cite journal | title = Tautomeric and ionisation forms of dopamine and tyramine in the solid state | vauthors = Cruickshank L, Kennedy AR, Shankland N | journal = ] | volume = 1051 | pages = 132–136 | year = 2013 | doi = 10.1016/j.molstruc.2013.08.002 | bibcode = 2013JMoSt1051..132C }}</ref>
| width2=180px
| alt2 =
| IUPAC_Name=4-(2-aminoethyl)benzene-1,2-diol
| synonyms=2-(3,4-dihydroxyphenyl)ethylamine;<br/> 3,4-dihydroxyphenethylamine;<br/> 3-hydroxytyramine; DA; Intropin; Revivan; Oxytyramine


<!--Clinical data--> <!-- Clinical data -->| tradename = Intropin, Dopastat, Revimine, others
| Drugs.com = {{Drugs.com|monograph|dopamine-hydrochloride}}
| tradename =
| routes_of_administration = ]
| Drugs.com =
| pregnancy_US = | ATC_prefix = C01
| ATC_suffix = CA04
| legal_AU = | legal_AU =
| legal_CA = | legal_CA =
| legal_UK = | legal_UK =
| legal_US = | legal_US =
| licence_US = Dopamine | legal_EU = Rx-only
| legal_EU_comment = <ref name="Neoatricon EPAR" />
| legal_status = Rx-only | legal_status = Rx-only
| dependency_liability =
| routes_of_administration= ] Injection


<!-- Physiological data -->| source_tissues = ]; ]; many others
<!--Pharmacokinetic data-->
| target_tissues = System-wide
| bioavailability =
| receptors = ], ], ], ], ], ]<ref name="DA IUPHAR">{{cite web|title=Dopamine: Biological activity|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=940|work=IUPHAR/BPS guide to pharmacology|publisher=International Union of Basic and Clinical Pharmacology|access-date=29 January 2016|url-status=live|archive-url=https://web.archive.org/web/20160205041409/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=940|archive-date=5 February 2016}}</ref>
| agonists = Direct: ], ]<br />]: ], ], ], ]
| antagonists = ]s, ], ]

<!-- Pharmacokinetic data -->| bioavailability =
| protein_bound = | protein_bound =
| metabolism = ], ], ], ] | metabolism = ], ],<ref name="DA IUPHAR" /> ], ], ], ], ]
| elimination_half-life = | elimination_half-life =
| excretion = Renal | excretion = ]


<!--Identifiers--> <!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 51-61-6
| CAS_supplemental = {{CAS|62-31-7}} (hydrochloride)
| PubChem = 681
| IUPHAR_ligand = 940
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00988
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 661
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = VTD58H1Z2X | UNII = VTD58H1Z2X
| InChI = 1/C8H11NO2/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,5,10-11H,3-4,9H2
| InChIKey = VYFYYTLLBUKUHU-UHFFFAOYAA
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C8H11NO2/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,5,10-11H,3-4,9H2
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = VYFYYTLLBUKUHU-UHFFFAOYSA-N
| CAS_number =51-61-6
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_supplemental ={{CAS|62-31-7}} (hydrochloride)
| PubChem=681
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 59
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 661
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07870 | KEGG = D07870
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00988
| IUPHAR_ligand = 940
| ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 18243 | ChEBI = 18243
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 59
| synonyms = 2-(3,4-Dihydroxyphenyl)ethylamine; 3,4-Dihydroxyphenethylamine; 3-hydroxytyramine; DA; Intropin; Revivan; Oxytyramine; Prolactin inhibiting factor; Prolactin inhibiting hormone

<!-- Chemical data -->| IUPAC_name = 4-(2-Aminoethyl)benzene-1,2-diol
| C = 8
| H = 11
| N = 1
| O = 2
| SMILES = c1cc(c(cc1CCN)O)O | SMILES = c1cc(c(cc1CCN)O)O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| ATC_prefix = C01
| StdInChI = 1S/C8H11NO2/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,5,10-11H,3-4,9H2
| ATC_suffix = CA04
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = VYFYYTLLBUKUHU-UHFFFAOYSA-N
<!--Chemical data-->
| C=8 | H=11 | N=1 | O=2 | density = 1.26
| molecular_weight = 153.18 g/mol
| density = 1.26
| boiling_point = | boiling_point =
| boiling_notes = decomposes | boiling_notes = decomposes
| melting_point = 128 | melting_point = 128
| melting_notes = | melting_notes =
| solubility = <!--60.0 g/100 ml--> | solubility = <!--60.0 g/100 ml-->
}} }}


<!-- Definition and medical uses -->
'''Dopamine''' (or '''3,4-]]]]''') is a neurotransmitter in the ] and ] families that plays a number of important roles in the brains and bodies of animals. Its name derives from its chemical structure: it is an ] that is formed by removing a ] from a molecule of ].
'''Dopamine''', sold under the brand name '''Intropin''' among others, is a medication most commonly used in the treatment of ], a ] that is causing symptoms, and, if ] is not available, ].<ref name=AHSP2016>{{cite web|title=Dopamine Hydrochloride|url=https://www.drugs.com/monograph/dopamine-hydrochloride.html|website=drugs.com|publisher=American Society of Health-System Pharmacists|access-date=15 July 2016|date=29 June 2016|url-status=live|archive-url=https://web.archive.org/web/20160914161247/https://www.drugs.com/monograph/dopamine-hydrochloride.html|archive-date=14 September 2016}}</ref> In ] it continues to be the preferred treatment for very ].<ref name=Bh2016>{{cite journal | vauthors = Bhayat SI, Gowda HM, Eisenhut M | title = Should dopamine be the first line inotrope in the treatment of neonatal hypotension? Review of the evidence | journal = World Journal of Clinical Pediatrics | volume = 5 | issue = 2 | pages = 212–222 | date = May 2016 | pmid = 27170932 | pmc = 4857235 | doi = 10.5409/wjcp.v5.i2.212 | doi-access = free }}</ref> In children ] or ] is generally preferred while in adults norepinephrine is generally preferred for very low blood pressure.<ref name=De2012>{{cite journal | vauthors = De Backer D, Aldecoa C, Njimi H, Vincent JL | title = Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis* | journal = Critical Care Medicine | volume = 40 | issue = 3 | pages = 725–730 | date = March 2012 | pmid = 22036860 | doi = 10.1097/ccm.0b013e31823778ee | s2cid = 24620964 }}</ref><ref name=Del2012>{{cite journal | vauthors = Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R | title = Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 | journal = Critical Care Medicine | volume = 41 | issue = 2 | pages = 580–637 | date = February 2013 | pmid = 23353941 | doi = 10.1097/CCM.0b013e31827e83af | s2cid = 34855187 | doi-access = free }}</ref> It is given ] or ] as a continuous infusion.<ref name=AHSP2016/> Effects typically begin within five minutes.<ref name=AHSP2016/> Doses are then increased to effect.<ref name=AHSP2016/>


<!-- Side effects -->
In the ], dopamine functions as a ]—a chemical released by nerve cells to send signals to other nerve cells. The brain includes several distinct dopamine systems, one of which plays a major role in reward-motivated behavior. Every type of reward that has been studied increases the level of dopamine in the brain, and a variety of addictive drugs, including stimulants such as ], ], and ], act by amplifying the effects of dopamine. Other brain dopamine systems are involved in motor control and in controlling the release of several important hormones.
Common ] include worsening kidney function, an ], ], ], ], or ].<ref name=AHSP2016/> If it ] local ] may occur.<ref name=AHSP2016/> The medication ] can be given to try to decrease this risk.<ref name=AHSP2016/> It is unclear if dopamine is safe to use during ] or ].<ref name=AHSP2016/> At low doses dopamine mainly triggers ]s and ]s while at high doses it works via ]s.<ref name=AHSP2016/>


<!-- Society and culture -->
Several important diseases of the nervous system are associated with dysfunctions of the dopamine system. ], a degenerative condition causing tremor and motor impairment, is caused by loss of dopamine-secreting neurons in the midbrain area called the ]. There is evidence that ] involves altered levels of dopamine activity, and the antipsychotic drugs that are frequently used to treat it have a primary effect of attenuating dopamine activity. ] (ADHD) and ] (RLS) are also believed to be associated with decreased dopamine activity.
Dopamine was first synthesized in a laboratory in 1910 by ] and James Ewens in England.<ref name="pmid18781671">{{cite journal | vauthors = Fahn S | title = The history of dopamine and levodopa in the treatment of Parkinson's disease | journal = Movement Disorders | volume = 23 | issue = Suppl 3 | pages = S497–S508 | year = 2008 | pmid = 18781671 | doi = 10.1002/mds.22028 | quote = According to Hornykiewicz,6 dopamine was first synthesized by George Barger and James Ewens in 1910 at the Wellcome labs in London, England. | s2cid = 45572523 }}</ref> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In ] ] is a ] as well as a ].<ref>{{cite book| vauthors = Millar T |title=Biochemistry explained : a practical guide to learning biochemistry|date=2002|publisher=Routledge|location=London|isbn=9780415299411|page=40|url=https://books.google.com/books?id=WywxhvLh1R8C&pg=PA40|url-status=live|archive-url=https://web.archive.org/web/20160815234209/https://books.google.ca/books?id=WywxhvLh1R8C&pg=PA40|archive-date=15 August 2016}}</ref>


==Medical uses==
Outside the nervous system, dopamine functions in several parts of the body as a local chemical messenger. In the blood vessels, it inhibits norepinephrine release and acts as a vasodilator; in the kidneys, it increases sodium excretion and urine output; in the pancreas, it reduces insulin production; in the digestive system, it reduces ] and protects intestinal mucosa; and in the immune system, it reduces the activity of lymphocytes. With the exception of the blood vessels, dopamine in each of these peripheral systems has a "]" function: it is synthesized locally and exerts its effects on cells that are located near the cells that release it.


===Low blood pressure===
A variety of important drugs work by altering the way the body makes or uses dopamine. Dopamine itself is available for intravenous injection: although it cannot reach the brain from the bloodstream, its peripheral effects make it useful in the treatment of heart failure or shock, especially in newborn babies. ], the metabolic precursor of dopamine, does reach the brain and is the most widely used treatment for Parkinson's disease. Dopamine-activating stimulants such as cocaine, amphetamine, and ] (Ritalin){{citation needed|date=September 2013}} are addictive in high doses, but are used at lower doses to treat ADHD. Conversely, many antipsychotic drugs act by suppressing the effects of dopamine. Drugs that act against dopamine by a different mechanism are also some of the most effective anti-nausea agents.
In ] it continues to be the preferred treatment for very low blood pressure.<ref name=Bh2016/> In children ] or ] is generally preferred while in adults norepinephrine is generally preferred for very low blood pressure.<ref name=De2012/><ref name=Del2012/>


In those with ] or ], this should be corrected with ] before dopamine is considered.<ref name=AHSP2016/>
==Dopaminergic systems of the body==


===In the brain=== ===Kidney function===
Low-dosage dopamine has been routinely used for the treatment and prevention of ]. However, since 1999 a number of reviews have concluded that doses at such low levels are not effective and may sometimes be harmful.<ref>{{cite journal | vauthors = Karthik S, Lisbon A | title = Low-dose dopamine in the intensive care unit | journal = Seminars in Dialysis | volume = 19 | issue = 6 | pages = 465–471 | year = 2006 | pmid = 17150046 | doi = 10.1111/j.1525-139X.2006.00208.x | s2cid = 22538344 }}</ref><ref>{{cite journal | vauthors = Power DA, Duggan J, Brady HR | title = Renal-dose (low-dose) dopamine for the treatment of sepsis-related and other forms of acute renal failure: ineffective and probably dangerous | journal = Clinical and Experimental Pharmacology & Physiology. Supplement | volume = 26 | pages = S23–S28 | date = April 1999 | pmid = 10386250 }}</ref>
]


===Administration===
{{Main|Dopaminergic pathways}}
Since the ] of dopamine in ] is short—approximately one minute in adults, two minutes in newborn babies and up to five minutes in ]—it is usually given as a continuous ] rather than a single injection.<ref name=BhattMehta>{{cite journal | vauthors = Bhatt-Mehta V, Nahata MC | title = Dopamine and dobutamine in pediatric therapy | journal = Pharmacotherapy | volume = 9 | issue = 5 | pages = 303–314 | year = 1989 | pmid = 2682552 | doi = 10.1002/j.1875-9114.1989.tb04142.x | s2cid = 25614283 }}</ref>


===Other===
Inside the brain, dopamine plays important roles in ], ], ], cognition, and ], as well as a number of basic lower-level functions including ], ], and ].
A ] form of ] known as ] is available for use in ] to assess the function of the ].<ref name="Deng_2002">{{cite journal |vauthors=Deng WP, Wong KA, Kirk KL | title = Convenient syntheses of 2-, 5- and 6-fluoro- and 2,6-difluoro-L-DOPA | journal = Tetrahedron: Asymmetry | volume = 13 | issue = 11 | pages = 1135–1140 | year = 2002 | doi = 10.1016/S0957-4166(02)00321-X}}</ref>


==Contraindications==
] neurons (i.e., neurons whose primary neurotransmitter is dopamine) are comparatively few in number — a total of around 400,000 in the human brain<ref name=SchultzAnnRev>{{cite journal |author=Schultz W |title=Multiple dopamine functions at different time courses |journal=Annu. Rev. Neurosci. |volume=30 |issue= |pages=259–88 |year=2007 |pmid=17600522 |doi=10.1146/annurev.neuro.28.061604.135722}}</ref> — and their cell bodies are confined to a few relatively small brain areas, but they send projections to many other brain areas and exert powerful effects on their targets. These ] were first mapped in 1964 by Annica Dahlström and Kjell Fuxe, who assigned them labels starting with the letter "A" (for "aminergic").<ref>{{cite journal |title=Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons |journal=Acta physiologica Scandinavica. Supplementum |year=1964 |volume=232 |pages=1–55 |pmid=14229500 |author=A. Dahlström and K. Fuxe}}</ref> In their scheme, areas A1 through A7 contain the neurotransmitter ], whereas A8 through A14 contain dopamine. Here is a list of the dopaminergic areas they identified:
Dopamine should generally not be given to people who have a ] or uncorrected ].<ref name=AHSP2016/>


==Side effects==
*The ], a small midbrain area that forms a component of the ]. The dopamine neurons are found mainly in a part of this structure called the ''pars compacta'' (cell group A8) and nearby (group A9).<ref name=Bjorklund>{{cite journal |author=Björklund A, Dunnett SB |title=Dopamine neuron systems in the brain: an update |journal=Trends Neurosci. |volume=30 |issue=5 |pages=194–202 |date=May 2007 |pmid=17408759 |doi=10.1016/j.tins.2007.03.006}}</ref> In rodents, their most important projections go to the ], ], and ], all of which also belong to the basal ganglia, and play important roles in motor control. The name ''substantia nigra'' is Latin for "dark substance", and refers to the fact that the dopaminergic neurons there are darkly pigmented. These neurons are especially vulnerable to damage. When a large fraction of them die, the result is a ].<ref>{{cite journal |author=Christine CW, Aminoff MJ |title=Clinical differentiation of parkinsonian syndromes: prognostic and therapeutic relevance |journal=Am. J. Med. |volume=117 |issue=6 |pages=412–9 |date=September 2004 |pmid=15380498 |doi=10.1016/j.amjmed.2004.03.032}}</ref>
The ], or dose which is expected to prove lethal in 50% of the population, has been found to be: 59&nbsp;mg/kg (mouse; administered ]); 950&nbsp;mg/kg (mouse; administered ]); 163&nbsp;mg/kg (rat; administered intraperitoneally); 79&nbsp;mg/kg (dog; administered intravenously).<ref>{{cite book | vauthors = Lewis RJ | year = 2004 |title=Sax's Dangerous Properties of Industrial Materials, 11th Ed. |page=1552 |publisher=Wiley & Sons |location=Hoboken, NJ. |isbn=978-0-471-47662-7}}</ref>


===Extravasation===
*The ] (VTA), another midbrain area. This cell group (A10) is the largest group of dopaminergic cells in the human brain, though still quite small in absolute terms. Projections from these dopaminergic neurons go to the ] and the ] as well as several other areas.<ref name=Bjorklund/> These neurons play a central role in reward and other aspects of motivation. The nucleus accumbens is often considered to be the "limbic" part of the ]. As such, it is the part of the striatum involved in the highest level aspects of motor control, which include motivation and decision-making. Thus, the role of the VTA in motivation and decision-making is structurally analogous to the role of the substantia nigra in low-level motor control.<ref name=DeLong>{{cite journal |author=DeLong M, Wichmann T |title=Changing views of basal ganglia circuits and circuit disorders |journal=Clin EEG Neurosci |volume=41 |issue=2 |pages=61–7 |date=April 2010 |pmid=20521487 |doi=10.1177/155005941004100204 |url=}}</ref> In primates (i.e. monkeys and humans), the dopamine neurons from the regions of the substantia nigra and VTA project throughout most of the cortical mantle, with particularly dense innervation of the motor and premotor cortices. Thus, there are major species differences in cortical dopamine projections.<ref>{{cite journal |author=Robbins TW, Arnsten AF. |title=The neuropsychopharmacology of fronto-executive function: monoaminergic modulation |journal=Annu Rev Neurosci. |volume=32 |pages=267–87 |year=2009 |doi=10.1146/annurev.neuro.051508.135535 |pmid=19555290 |pmc=2863127}}</ref>
If ] occurs local ] may result.<ref name=AHSP2016/> The medication ] can be injected at the site to try to decrease the risk of tissue death.<ref name=AHSP2016/>


==Mechanism of action==
*The posterior ]. These dopaminergic cells (group A11) project to the spinal cord, and their function is not well established. There is some evidence that pathology in this area plays a role in ], a condition in which people have difficulty sleeping due to an overwhelming compulsion to constantly move parts of the body, especially the legs.<ref>{{cite journal |author=Paulus W, Schomburg ED |title=Dopamine and the spinal cord in restless legs syndrome: does spinal cord physiology reveal a basis for augmentation? |journal=Sleep Med Rev |volume=10 |issue=3 |pages=185–96 |date=June 2006 |pmid=16762808 |doi=10.1016/j.smrv.2006.01.004}}</ref>
Its effects, depending on dosage, include an increase in sodium excretion by the kidneys, an increase in urine output, an increase in ], and an increase in ].<ref name=BhattMehta/> At low doses it acts through the ] to increase ] and heart rate, thereby increasing ] and blood pressure.<ref name="BryantKnights2010"/> Higher doses also cause ] that further increases blood pressure.<ref name="BryantKnights2010">{{cite book | vauthors = Bronwen JB, Knights KM |title=Pharmacology for Health Professionals |edition=2nd |year=2009 |publisher=Elsevier Australia |isbn=978-0-7295-3929-6 |page=192}}</ref><ref>{{cite journal | vauthors = De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL | title = Comparison of dopamine and norepinephrine in the treatment of shock | journal = The New England Journal of Medicine | volume = 362 | issue = 9 | pages = 779–789 | date = March 2010 | pmid = 20200382 | doi = 10.1056/NEJMoa0907118 | s2cid = 2208904 | doi-access = free }}</ref>


While some effects result from stimulation of dopamine receptors, the prominent cardiovascular effects result from dopamine acting at ], ], and ] ]s.<ref>{{Cite web|title = Dopamine|url = http://www.fpnotebook.com/cv/pharm/Dpmn.htm|website = Family Practice Notebook|access-date = 1 February 2016| vauthors = Moses S |quote = Dopamine binds to alpha-1 and beta-1 adrenergic receptors. Mediated through myocardial beta-1 adrenergic receptors, dopamine increase heart rate and force, thereby increasing cardiac output. Alpha-1 adrenergic receptor stimulation on vascular smooth muscle, leads to vasoconstriction and results in an increase in systemic vascular resistance|url-status = live|archive-url = https://web.archive.org/web/20160201191128/http://www.fpnotebook.com/cv/pharm/Dpmn.htm|archive-date = 1 February 2016}}</ref><ref>{{Cite book|title = Clinical Cardiology: Current Practice Guidelines|url = https://books.google.com/books?id=YytoAgAAQBAJ|publisher = OUP Oxford|date = 19 September 2013|isbn = 9780191508516|language = en| vauthors = Katritsis DG, Gersh BJ, Camm AJ |quote = Dopamine binds to beta-1, beta-2, alpha-1 and dopaminergic receptors.|page = 314|url-status = live|archive-url = https://web.archive.org/web/20160506100008/https://books.google.com/books?id=YytoAgAAQBAJ|archive-date = 6 May 2016}}</ref>
*The ] (cell group A12) and ] (cell group A14) of the hypothalamus. An important projection from these dopaminergic neurons goes to the ], where it influences the secretion of the hormone ]. Dopamine is the primary ] inhibitor of the secretion of ] from the ] gland. Dopamine produced by neurons in the arcuate nucleus is secreted into the ] of the ], which supply the ]. The lactotrope cells that produce ], in the absence of dopamine, secrete prolactin continuously; dopamine inhibits this secretion. Thus, in the context of regulating prolactin secretion, dopamine is occasionally called prolactin-inhibiting factor (PIF), prolactin-inhibiting hormone (PIH), or prolactostatin.<ref name="prolactininhibition">{{cite journal |author=Ben-Jonathan N, Hnasko R |title=Dopamine as a Prolactin (PRL) Inhibitor |journal=Endocrine Reviews |volume=22 |issue=6 |pages=724–763 |year=2001 |doi=10.1210/er.22.6.724 |url=http://edrv.endojournals.org/cgi/reprint/22/6/724.pdf |format=PDF |pmid=11739329}}</ref>


== Society and culture ==
*The ]. These cells (group A13) project to several areas of the hypothalamus, and participate in the control of ], which is necessary to activate the development of reproductive systems that occurs following puberty, both in males and females.<ref name=prolactininhibition/>
=== Legal status ===

In March 2024, the ] (CHMP) of the ] (EMA) adopted a positive opinion, recommending the granting of a pediatric use marketing authorization (PUMA) for the medicinal product Neoatricon, intended for treatment of hypotension in neonates, infants and children under 18 years of age.<ref name="Neoatricon EPAR" /><ref>{{cite press release | title=Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 18-21 March 2024 | website=European Medicines Agency | date=22 March 2024 | url=https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-18-21-march-2024 | access-date=13 June 2024}}</ref> The applicant for this medicinal product is BrePco Biopharma Limited.<ref name="Neoatricon EPAR">{{cite web | title=Neoatricon EPAR | website=] (EMA) | date=21 March 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/neoatricon | access-date=23 March 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>
An additional group of dopamine-secreting neurons are located in the ] of the eye. These neurons are ]s, meaning that they have no axons. They release dopamine into the extracellular medium, and are specifically active during daylight hours, becoming silent at night. This retinal dopamine acts to enhance the activity of ]s in the retina while suppressing ]s — the result is to increase sensitivity to color and contrast during bright light conditions, at the cost of reduced sensitivity when the light is dim.<ref>{{cite journal |author=Witkovsky P |title=Dopamine and retinal function |journal=Doc Ophthalmol |volume=108 |issue=1 |pages=17–40 |date=January 2004 |pmid=15104164 |doi=10.1023/B:DOOP.0000019487.88486.0a}}</ref>

===Outside the nervous system===

Dopamine does not cross the ], so its synthesis and functions in peripheral areas are to a large degree independent of its synthesis and functions in the brain. A substantial amount of dopamine circulates in the bloodstream, but its functions there are not entirely clear. Dopamine is found in blood plasma at levels comparable to those of ], but in humans, over 95% of the dopamine in the plasma is in the form of dopamine sulphate, a conjugate produced by the enzyme ] acting on free dopamine. The bulk of this dopamine sulphate is produced in the ] that surround parts of the digestive system. The production of dopamine sulphate is thought to be a mechanism for detoxifying dopamine that is ingested as food or produced by the digestive process — plasma levels typically rise more than fifty-fold after a meal. Dopamine sulphate has no known biological functions and is excreted in urine.<ref name=Eisenhofer/>

The relatively small quantity of unconjugated dopamine in the bloodstream may be produced by the ], the digestive system, or possibly other organs. It may act on dopamine receptors in peripheral tissues, or be metabolized, or be converted to ] by the enzyme ], which is released into the bloodstream by the ].<ref name=Eisenhofer/> Some dopamine receptors are located in the walls of arteries, where they act as a ] and an inhibitor of ] release.<ref name=Missale>{{cite journal |last1=Missale |first1=C |author2=Nash, SR; Robinson, SW; Jaber, M; Caron, MG |title=Dopamine receptors: from structure to function |journal=Physiological reviews |year=1998 |volume=78 |issue=1 |pages=189–225 |pmid=9457173}}</ref> These responses might be activated by dopamine released from the ] under conditions of low oxygen, but whether arterial dopamine receptors perform other biologically useful functions is not known.

Beyond its role in modulating blood flow, there are several peripheral systems in which dopamine circulates within a limited area and performs an ] or ] function.<ref name=Eisenhofer>{{cite journal |author=Eisenhofer G, Kopin IJ, Goldstein DS |title=Catecholamine metabolism: a contemporary view with implications for physiology and medicine |journal=Pharmacol. Rev. |volume=56 |issue=3 |pages=331–49 |date=September 2004 |pmid=15317907 |doi=10.1124/pr.56.3.1 |url=http://intl.pharmrev.org/content/56/3/331.full}}</ref> The peripheral systems in which dopamine plays an important role include:

*'''The immune system.''' Dopamine acts upon receptors present on immune cells, especially ]s.<ref name=Buttarelli>{{cite journal |author=Buttarelli FR, Fanciulli A, Pellicano C, Pontieri FE |title=The dopaminergic system in peripheral blood lymphocytes: from physiology to pharmacology and potential applications to neuropsychiatric disorders |journal=Curr Neuropharmacol |volume=9 |issue=2 |pages=278–88 |date=June 2011 |pmid=22131937 |pmc=3131719 |doi=10.2174/157015911795596612}}</ref> Dopamine can also affect immune cells in the ], ], and ].<ref>{{cite journal |doi=10.1016/S0165-5728(99)00176-9 |last1=Basu |first1=S |last2=Dasgupta |first2=PS. |year=2000 |title=Dopamine, a neurotransmitter, influences the immune system |url= |journal=J Neuroimmunol |volume=102 |issue=2 |pages=113–24 |pmid=10636479}}</ref> In addition, dopamine can be synthesized and released by immune cells themselves.<ref name=Buttarelli/> The main effect of dopamine on lymphocytes is to reduce their activation level. The functional significance of this system is unclear, but it afford a possible route for interactions between the nervous system and immune system, and may be relevant to some autoimmune disorders.<ref>{{cite journal |last1=Sarkar |first1=C |last2=Basu |first2=B |last3=Chakroborty |first3=D |last4=Dasgupta |first4=PS |last5=Basu |first5=S |title=The immunoregulatory role of dopamine: an update |journal=Brain, behavior, and immunity |volume=24 |issue=4 |pages=525–8 |year=2010 |doi=10.1016/j.bbi.2009.10.015 |pmc=2856781 |pmid=19896530}}</ref>

*'''The kidneys.''' Multiple types of dopamine receptors are present in cells of the ]s. Dopamine is also synthesized there, by ] cells, and discharged into the ]. Its actions include increasing the blood supply to the kidneys, increasing filtration by the glomeruli, and increasing excretion of sodium in the urine. Defects in renal dopamine function can be produced by high blood pressure or by genetic problems, and can lead to reduced sodium excretion as well as hypertension.<ref>{{cite journal |author=Carey RM |title=Theodore Cooper Lecture: Renal dopamine system: paracrine regulator of sodium homeostasis and blood pressure |journal=Hypertension |volume=38 |issue=3 |pages=297–302 |date=September 2001 |pmid=11566894 |doi=10.1161/hy0901.096422 |url=http://hyper.ahajournals.org/content/38/3/297.long}}</ref>

*'''The pancreas.''' The role of dopamine here is somewhat complex. The ] consists of two parts, known as ] and ]. The exocrine part synthesizes enzymes and other substances, and secretes them into the ], where food is digested. One of the substances synthesized and secreted by the exocrine pancreas is dopamine. The function of this secreted dopamine after it enters the small intestine is not clearly established — the possibilities include protecting the intestinal mucosa from damage and reducing ] (the rate at which food moves through the intestines).<ref name=Rubi>{{cite journal |author=Rubí B, Maechler P |title=Minireview: new roles for peripheral dopamine on metabolic control and tumor growth: let's seek the balance |journal=Endocrinology |volume=151 |issue=12 |pages=5570–81 |date=December 2010 |pmid=21047943 |doi=10.1210/en.2010-0745 |url=http://endo.endojournals.org/content/151/12/5570.long}}</ref>

:The endocrine part of the pancreas, also known as the ], synthesizes a number of hormones, including ], and secretes them into the bloodstream. There is evidence that the ]s that synthesize insulin contain dopamine receptors, and that dopamine acts to reduce the amount of insulin they release. The source of their dopamine input is not clearly established — it may come from dopamine that circulates in the bloodstream and derives from the sympathetic nervous system, or it may be synthesized locally by other types of pancreatic cells.<ref name=Rubi/>

==Cellular effects==
{{Main|Dopamine receptor}}

{| class="wikitable" style="float: right; text-align: center" border="10"
<caption>Dopamine receptors in the mammal brain</caption>
|-
! Family
! Receptor
! Gene
! Type
! Mechanism
|-
| rowspan=2 | ]
| ]
| {{Gene|DRD1}}
| rowspan=2 | ]-coupled.
| rowspan=2 | Increase intracellular levels of ]<br> by activating ].
|-
| ]
| {{Gene|DRD5}}
|-
| rowspan=3 | ]
| ]
| {{Gene|DRD2}}
| rowspan=3 | ]-coupled.
| rowspan=3 | Decrease intracellular levels of ]<br> by inhibiting ].
|-
| ]
| {{Gene|DRD3}}
|-
| ]
| {{Gene|DRD4}}
|}

Like many other biologically active substances, dopamine exerts its effects by binding to and activating ]s located on the surface of cells. In mammals, five subtypes of dopamine receptors have been identified, labeled D1 through D5. All of them function as ]s, meaning that they exert their effects via a complex ]. Glossing over the details, dopamine receptors in mammals can be divided into two families, known as ] and ]. The ultimate effect of D1-like receptors (D1 and D5) can be excitation (via opening of sodium channels) or inhibition (via opening of potassium channels); the ultimate effect of D2-like receptors (D2, D3, and D4) is usually inhibition of the target neuron. Consequently, it is incorrect to describe dopamine itself as either excitatory or inhibitory. Its effect on a target neuron depends on which types of receptors are present on the membrane of that neuron and on the internal responses of that neuron to cyclic AMP. D1 receptors are the most numerous dopamine receptors in the central nervous system; D2 receptors are next; D3, D4, and D5 receptors are present at significantly lower levels.

The level of extracellular dopamine is modulated by two mechanisms: tonic and phasic dopamine transmission. Tonic dopamine transmission occurs when small amounts of dopamine are released independently of neuronal activity, and is regulated by the activity of other neurons and neurotransmitter reuptake.<ref>{{Cite journal |author=Grace AA, |title=Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the eitiology of schizophrenia |journal=Neuroscience |volume=41 |issue=1 |pages=1–24 |year=1991 |pmid=1676137 |doi=10.1016/0306-4522(91)90196-U}}</ref> Phasic dopamine release results from the activity of the dopamine-containing cells themselves. This activity is characterized by irregular ] activity of single spikes, and rapid bursts of typically 2-6 spikes in quick succession.<ref>{{Cite journal |author=Grace AA, Bunney BS |title=The control of firing pattern in nigral dopamine neurons: single spike firing |url=http://www.jneurosci.org/cgi/reprint/4/11/2866 |format=PDF |journal=Journal of Neuroscience |volume=4 |issue=11 |pages=2866–2876 |year=1984 |pmid=6150070}}</ref><ref>{{Cite journal |author=Grace AA, Bunney BS |title=The control of firing pattern in nigral dopamine neurons: burst firing |url=http://www.jneurosci.org/cgi/reprint/4/11/2877 |format=PDF |journal=Journal of Neuroscience |volume=4 |issue=11 |pages=28677–2890 |year=1984 |pmid=6150071}}</ref>

==The substantia nigra dopamine system and motor control==

]. The dopaminergic pathway from the ] to the ] is shown in light blue.]]

The ] is a component of the ], a group of interconnected structures in the forebrain and midbrain that play a central role in motor control. The precise nature of that role has been difficult to work out, but one popular line of thought describes it as "response selection". The response selection theory proposes that when a person or animal is in a situation where several behaviors are possible, activity in the basal ganglia determines which of them is executed, by releasing that response from inhibition. Thus the basal ganglia are responsible for initiating behaviors but not for determining the details of how they are carried out.

Dopamine is thought to modulate the response selection process in at least two important ways. First, dopamine sets the "effort threshold" for initiating behaviors. The higher the level of dopamine activity, the lower the impetus required to evoke a given behavior. As a consequence, high levels of dopamine lead to high levels of motor activity and "impulsive" behavior; low levels of dopamine lead to torpor and slowed reactions. ], in which dopamine levels in the ''substantia nigra'' circuit are greatly reduced, is characterized by stiffness and greatly reduced movement—however, when people with the disease are confronted with strong stimuli such as a serious threat, their reactions can be as vigorous as those of a healthy person. In the opposite direction, drugs that increase the effects of dopamine, such as cocaine or amphetamine, produce heightened levels of activity, including at the highest levels ] and stereotyped movements.

The second important effect of dopamine is as a "teaching" signal. When a motor response is followed by an increase in dopamine activity, the basal ganglia circuit is altered in a way that makes the same response easier to evoke when similar situations arise in the future. This is a form of ], in which dopamine plays the role of a reward signal.

===Anatomy and physiology===

The anatomy of the basal ganglia is extraordinarily complex, and the role of dopamine there is correspondingly complex. On a macroscopic scale there is only one major dopamine projection, from the ] to the ], but the dopamine inputs contact multiple types of neurons and have several distinct effects on their targets, activating some via D1 receptors while inhibiting others via D2 receptors. A substantial number of dopamine inputs are delivered to the necks of ]s, where they are well-placed to exert a gating effect on specific synaptic connections, often arising from the cerebral cortex. There are two distinct pathways of signal flow arising from the striatum, known as the ] and ]. Dopamine is thought to promote action by upregulating the direct pathway while suppressing the indirect pathway.

Many theoreticians believe that the mechanism underlying motor learning in the basal ganglia involves a form of ] that occurs in the ] and is strongly modulated by dopamine—in other words, a mechanism by which dopamine activity induces strengthening or weakening of synaptic connections inside the striatum.<ref>{{cite journal |author=Calabresi P, Picconi B, Tozzi A, Di Filippo M |title=Dopamine-mediated regulation of corticostriatal synaptic plasticity |journal=Trends Neurosci. |volume=30 |issue=5 |pages=211–9 |date=May 2007 |pmid=17367873 |doi=10.1016/j.tins.2007.03.001}}</ref>

==The ventral tegmental area, reward, and cognition==

The ] (VTA) contains the largest group of dopamine neurons in the human brain. They project to numerous brain areas, but the two largest projections are the ], which targets the ] and other ] structures, and the ], which targets the ] and ] parts of the cerebral cortex.

===Reward===
The VTA dopamine system is strongly associated with the ] of the brain. Dopamine is released in areas such as the ] and ] as a result of rewarding experiences such as food, sex, and ] that become ] with them.<ref name="fn5">{{cite journal |author=Arias-Carrión O, Pöppel E |title=Dopamine, learning and reward-seeking behavior |journal=Act Neurobiol Exp |volume=67 |issue=4 |pages=481–488 |year=2007}}</ref> The source of this dopamine is primarily the VTA, although the substantia nigra may also contribute. Electrical ] can itself serve as a potent reward: animals will quickly learn to press a lever if it results in stimulation of dopamine release, and often will continue pressing the lever for a long time, at steadily increasing rates.<ref name="Wise" /> A variety of drugs that increase dopamine levels are intrinsically rewarding and increase the effects of other types of reward.<ref name="Wise">{{cite journal |author=Wise RA |title=Addictive drugs and brain stimulation reward |journal=Annu. Rev. Neurosci. |volume=19 |issue= |pages=319–40 |year=1996 |pmid=8833446 |doi=10.1146/annurev.ne.19.030196.001535 |url=}}</ref>

In spite of the overwhelming evidence showing a strong association between dopamine and reward, there has been a great deal of dispute about whether the function of dopamine should be described as reward ''per se'', or as some more complex construct that relates strongly to reward. The difficulty arises mainly from two observations: (1) in addition to being rewarding, dopamine is also arousing — it produces a general increase in movement of all sorts; (2) dopamine release can be caused by events that do not seem to have anything to do with reward, most notably pain. One of the most popular alternatives to the reward theory is the "]" theory, which argues that the function of dopamine is to increase the effects of motivators of all sorts, both positive and negative.<ref name=Schultz>{{cite journal |author=Schultz W |title=Getting formal with dopamine and reward |journal=Neuron |volume=36 |issue=2 |pages=241–263 |year=2002 |pmid=12383780 |doi=10.1016/S0896-6273(02)00967-4}}</ref>

A substantial body of evidence suggests that dopamine encodes not reward itself, but rather ''reward prediction error'', that is, the degree to which reward is surprising. According to this hypothesis, which derives initially from recordings made by ], rewards that are expected do not produce any activation of dopamine cells, but rewards that are greater than expected produce a short-lasting increase in dopamine, whereas the omission of an expected reward actually causes dopamine release to drop below its ordinary background level. The "prediction error" hypothesis has drawn particular interest from computational neuroscientists, because an influential computational-learning method known as ] makes heavy use of a signal that encodes prediction error. This confluence of theory and data has led to a fertile interaction between theoretical and empirical neuroscientists.<ref name=Schultz/>

Recent research finds that while some dopaminergic neurons react in the way expected of reward neurons, others do not and seem to respond in regard to salience, including aversive stimuli.<ref name="Matsumoto">{{cite journal |doi=10.1038/nature08028 |author=Matsumoto M, Hikosaka O. |title=Two types of dopamine neuron distinctly convey positive and negative motivational signals |journal=Nature |volume=459 |issue=7248 |pages=837–41 |year=2009 |pmid=19448610 |pmc=2739096}}</ref> This research finds the reward neurons predominate in the ventromedial region of the ], as well as in the ]. Neurons in these areas project mainly to the ] and thus might transmit value-related information in regard to reward values.<ref name="Matsumoto"/> The salience neurons are predominate in the dorsolateral area of the substantia nigra pars compacta which projects to the dorsal ] and may relate to orienting behaviour.<ref name="Matsumoto"/> It has been suggested that the difference between these two types of dopaminergic neurons arises from their input: reward-linked ones have input from the ], while the salience-related ones from the ].<ref name="Matsumoto"/> In primates, neurons from the regions of both the substantia nigra and VTA project to the prefrontal cortex;<ref name="Williams">{{cite journal |author=Williams SM, Goldman-Rakic PS. |title=Widespread origin of the primate mesofrontal dopamine system |journal=Cereb Cortex. |volume=8 |issue=4 |pages=321–45 |year=1998 |doi=10.1093/cercor/8.4.321 |pmid=9651129}}</ref> the origins of the dopamine innervation of other cortical areas in primate have not been studied. It has been appreciated for many years that exposure to even mild, uncontrollable stress increases dopamine release in the rodent prefrontal cortex, e.g. reviewed in,<ref name="Deutch">{{cite journal |author=Deutch AY, Roth RH. |title=The determinants of stress-induced activation of the prefrontal cortical dopamine system |journal=Prog Brain Res. |volume=85 |pages=367–402 |year=1990 |doi=10.1016/S0079-6123(08)62691-6 |pmid=2094906 |series=Progress in Brain Research |isbn=9780444811240}}</ref> suggesting that dopamine salience cells have a large influence on this cortical region.

===="Seeking" versus "liking"====
] and other researchers have argued for a distinction between reward, which is defined in terms of motivation, and pleasure, which is defined in terms of emotional expression. A simpler way of describing this is as a distinction between "seeking" and "liking". "Seeking" occurs when an animal, given access to some stimulus such as food, executes some type of active behavior in order to acquire it. "Liking" occurs when an animal shows expressions of happiness or satisfaction while consuming something. There is considerable evidence that the dopamine system is part of the brain system that mediates seeking but not part of the system that mediates liking. Drugs that increase the effects of dopamine (most notably stimulants such as methamphetamine or cocaine) produce corresponding increases in seeking behaviors, but do not greatly alter expressions of pleasure. Conversely, opiate drugs such as heroin or morphine produce increases in expressions of pleasure but do not greatly alter seeking behaviors. Animals in which the VTA dopamine system has been rendered inactive do not seek food, and will starve to death if left to themselves, but if food is placed in their mouths they will consume it and show facial expressions indicative of pleasure.<!--
--><ref name="fn5">{{cite journal |author=Berridge K, Robinson T |title=What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? |journal=Brain Res Brain Res Rev |volume=28 |issue=3 |pages=309–69 |year=1998 |pmid=9858756 |doi=10.1016/S0165-0173(98)00019-8}}</ref><!--
-->

===Role in cognition===
Dopamine's effects on higher cognitive function have been studied in monkeys and rodents. This work began with the landmark study of Brozoski et al., 1979 showing that depletion of catecholamines from the dorsolateral prefrontal cortex in monkeys impaired spatial working memory to the same degree as removing the cortex itself.<ref name="Brozoski">{{cite journal |author=Brozoski TJ, Brown RM, Rosvold HE, Goldman PS. |title=Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey |journal=Science |volume=205 |issue=4409 |pages=929–32 |year=1979 |bibcode=1979Sci...205..929B |doi=10.1126/science.112679 |pmid=112679}}</ref> It is now known that both dopamine and norepinephrine have essential actions on prefrontal cortical function, and help coordinate cognitive state with arousal state.<ref name="Arnsten">{{cite journal |author=Arnsten AF, Wang MJ, Paspalas CD. |title=Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses |journal=Neuron |volume=76 |issue=1 |pages=223–39 |year=2012 |doi=10.1016/j.neuron.2012.08.038 |pmid=23040817 |pmc=3488343}}</ref> Dopamine has an "inverted U" influence on prefrontal function through its actions on D1 receptors, where either too little or too much impairs working memory function.<ref name="Vijayraghavan">{{cite journal |author=Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF. |title=Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory |journal=Nat Neurosci. |volume=10 |issue=3 |pages=376–84 |year=2007 |doi=10.1038/nn1846 |pmid=17277774}}</ref> In the primate prefrontal cortex, dopamine D1 receptor stimulation selectively influences the firing of "Delay" cells (also called "Memory" cells), while dopamine D2 receptors selectively alter the firing of "Response cells".<ref name="Wang">{{cite journal |author1=Wang M, Vijayraghavan S, Goldman-Rakic PS. |title=Selective D2 receptor actions on the functional circuitry of working memory |journal=Science |volume=303 |issue=5659 |pages=853–6 |year=2004 |bibcode=2004Sci...303..853W |doi=10.1126/science.1091162 |pmid=14764884}}</ref>

==Diseases and disorders==

The dopamine system plays a central role in a number of important medical conditions, including Parkinson's disease, attention deficit hyperactivity disorder, schizophrenia, and drug addiction.

===Parkinson's disease===

] is a disorder characterized by stiffness of the body, slowing of movement, and trembling of limbs when they are not in use. In advanced stages it progresses to dementia and eventually death. The main symptoms are caused by massive loss of dopamine-secreting cells in the ]. These dopamine cells are especially vulnerable to damage, and a variety of insults, including ] (as depicted in the book and movie "]"), repeated sports-related ]s, and some forms of chemical poisoning (ex. ]), can lead to substantial cell loss, producing a ] that is similar in its main features to Parkinson's disease. Most cases of Parkinson's disease, however, are "idiopathic", meaning that the cause of cell death cannot be identified.

The most widely used treatment for Parkinsonism is administration of ], the metabolic precursor for dopamine. This treatment cannot restore the dopamine cells that have been lost, but it causes the remaining cells to produce more dopamine, thereby compensating for the loss to at least some degree. In advanced stages the treatment begins to fail because the cell loss is so severe that the remaining ones cannot produce enough dopamine regardless of L-DOPA levels. As this stage is approached, the metabolic regulatory mechanisms in the dopamine cells, operating far above their normal level, become erratic, producing ], in which patients fluctuate unpredictably between states of hyperactivity and paralysis.<ref name="pmid17988927">{{cite journal |author=Merims D, Giladi N |title=Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson's disease |journal=Parkinsonism & Related Disorders |volume=14 |issue=4 |pages=273–80 |year=2008 |pmid=17988927 |doi=10.1016/j.parkreldis.2007.09.007 |url=http://linkinghub.elsevier.com/retrieve/pii/S1353-8020(07)00208-8}}</ref>

===Attention deficit hyperactivity disorder===

Altered dopamine neurotransmission is implicated in ] (ADHD), a condition associated with impaired ability to regulate attention, behavior, and/or impulses. There are some genetic links between dopamine receptors, the dopamine transporter and ADHD,<ref>{{cite journal |authors=Wu J, Xiao H, Sun H, Zou L, Zhu LQ. |title=Role of dopamine receptors in ADHD: a systematic meta-analysis |journal=Mol Neurobiol. |volume=45 |year=2012 |pages=605-20}}</ref> in addition to links to other neurotransmitter receptors and transporters. The most important relationship between dopamine and ADHD involves the drugs that are used to treat ADHD. Some of the most effective therapeutic agents for ADHD are psychostimulants such as ] (Ritalin) and ], drugs that increase both dopamine and norepinephrine levels in brain.<ref>{{cite journal |authors=Berridge CW, Devilbiss DM. |title=Psychostimulants as cognitive enhancers: the prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder |journal=Biol Psychiatry |volume=69 |issue=12 |year=2011 |pages=e101-11}}</ref>

===Drug addiction===

A variety of addictive drugs produce an increase in reward-related dopamine activity. For some addictive drugs such as alcohol or ], activation of the reward system may play only a minor role in addiction, with suppression of suffering being the dominant mechanism, but for other drugs, including ] and ] such as ] and ], increased postsynaptic dopamine receptor activation or increased levels of synaptic dopamine appear to be the primary factor. When people addicted to stimulants go through withdrawal, they do not experience the physical suffering associated with withdrawal from alcohol or opiates; instead they experience apathy, boredom, restlessness, and most importantly an overwhelming urge to consume more of the drug.{{mcn|date=January 2014}}

The addiction potential for stimulants is strongly dependent on the level of dopamine increase they produce.{{mcn|date=January 2014}}

Treatment of stimulant addiction is very difficult, because even if consumption ceases, the "craving" that comes with psychological withdrawal does not. Even still, when the craving seems to be extinct, it may reemerge when the individual experiences environmental stiumli (friends, locations, situations, etc.) that are associated with the drug. The brain mechanisms underlying these cravings have been a topic of extensive research. There is evidence that they are associated with long-lasting changes in the density of dopamine receptors in parts of the brain.{{mcn|date=September 2013}}

===Pain===
Dopamine has been demonstrated to play a role in ] processing in multiple levels of the ] including the ], ] (PAG), ], ], and ]. Accordingly, decreased levels of dopamine have been associated with painful symptoms that frequently occur in ]. Abnormalities in dopaminergic neurotransmission have also been demonstrated in painful clinical conditions, including ],<ref>{{cite journal |doi=10.1016/S0304-3959(00)00409-7 |last1=Jääskeläinen |first1=SK |last2=Rinne |first2=JO |last3=Forssell |first3=H |last4=Tenovuo |first4=O |last5=Kaasinen |first5=V |last6=Sonninen |first6=P |last7=Bergman |first7=J. |year=2001 |title=Role of the dopaminergic system in chronic pain -- a fluorodopa-PET study |url= |journal=Pain |volume=90 |issue=3 |pages=257–60 |pmid=11207397}}</ref> ], and ]. In general, the analgesic capacity of dopamine occurs as a result of dopamine D2 receptor activation; however, exceptions to this exist in the PAG, in which dopamine D1 receptor activation attenuates pain presumably ''via'' activation of neurons involved in descending inhibition.<ref>{{cite journal |doi=10.1586/14737175.8.5.781 |last1=Wood |first1=PB. |year=2008 |title=Role of central dopamine in pain and analgesia |url= |journal=Expert Rev Neurother |volume=8 |issue=5 |pages=781–97 |pmid=18457535}}</ref> In addition, D1 receptor activation in the insular cortex appears to attenuate subsequent pain-related behavior.

===Nausea===
Nausea and vomiting are largely determined by activity in a brainstem area known as the ]. This area contains a large population of type D2 dopamine receptors. Consequently, drugs that activate D2 receptors have a high potential to cause nausea. This group includes some medications that are administered for ], as well as other dopamine agonists such as ]. In many cases, D2-receptor antagonists such as ] are useful as anti-nausea drugs.

===Psychosis===
{{Main|Dopamine hypothesis of schizophrenia}}
Abnormally high dopaminergic transmission has been linked to ] and ].<ref>{{cite web |publisher=St. Jude Children's Research Hospital |title=Disruption of gene interaction linked to schizophrenia |accessdate=6 July 2006 |url=http://www.innovations-report.com/html/reports/life_sciences/report-52499.html}}</ref> However, clinical studies relating schizophrenia to brain dopamine metabolism have ranged from controversial to negative, with HVA levels in the CSF the same for schizophrenics and controls.<ref>{{cite journal |last1=Maas |first1=J.W. |author2=Bowden CL, Miller AL, Javors MA, Funderburg LG, Berman N, Weintraub ST. |title=Schizophrenia, psychosis, and cerebral spinal fluid homovanillic acid concentrations |journal=Schizophrenia Bulletin. |volume=23 |issue=1 |pages=147–154 |year=1997 |pmid=9050120 |doi=10.1093/schbul/23.1.147}}</ref> Increased dopaminergic functional activity, specifically in the ], is found in schizophrenic individuals. However, decreased activity in another dopaminergic pathway, the ], may also be involved. The two pathways are thought to be responsible for differing sets of symptoms seen in schizophrenia.{{Citation needed|date=June 2011}}

] ]s act largely as dopamine antagonists, inhibiting dopamine at the ] level, and thereby blocking the effects of the neurochemical in a dose-dependent manner. The older, so-called ] most commonly act on D2 receptors,<ref>http://www.williams.edu/imput/synapse/pages/IIIB5.htm</ref> while the ] also act on D1, D3 and D4 receptors, though they have a lower affinity for dopamine receptors in general.<ref>http://bjp.rcpsych.org/cgi/content/full/181/4/271</ref><ref>{{cite journal |last1=Durcan |first1=M |last2=Rigdon |first2=GC |last3=Norman |first3=MH |last4=Morgan |first4=PF |title=Is clozapine selective for the dopamine D4 receptor? |journal=Life Sciences |volume=57 |issue=18 |pages=PL275–83 |year=1995 |pmid=7475902 |doi=10.1016/0024-3205(95)02151-8}}</ref> The finding that drugs such as amphetamines, methamphetamine and cocaine, which can increase dopamine levels by more than tenfold,<ref></ref> can temporarily cause psychosis, provides further evidence for this link.<ref>{{cite journal |last1=Lieberman |first1=J.A. |author2=JM Kane, J. Alvir |title=Provocative tests with psychostimulant drugs in schizophrenia |journal=Psychopharmacology (Berl). |volume=91 |issue=4 |pages=415–433 |publisher= |year=1997 |doi=10.1007/BF00216006 |pmid=2884687}}</ref> However, many non-dopaminergic drugs can induce acute and chronic ].<ref name="Cardinal_2011_diagnosis_psychosis">Cardinal, R.N. & Bullmore, E.T., ''The Diagnosis of Psychosis'', ], 2011, ISBN 978-0-521-16484-9</ref> The NMDA antagonists Ketamine and PCP both are used in research to reproduce the positive and negative symptoms commonly associated with schizophrenia.<ref>{{cite doi|10.1016/S0893-133X(98)00060-8}}</ref><ref>{{cite journal |last1=Abi-Saab |first1=WM |author2=D'Souza DC, Moghaddam B, Krystal JH |title=The NMDA antagonist model for schizophrenia: promise and pitfalls |journal=Pharmacopsychiatry |volume=31 |issue=2 |pages=104–109 |year=1998 |pmid=9754841 |doi=10.1055/s-2007-979354}}</ref>

Dopaminergic dysregulation has also been linked to depressive disorders.<ref>{{cite journal |last1=Galani |first1=VJ |author2=Rana DG |title=Depression and antidepressants with dopamine hypothesis-A review |journal=IJPFR |year=2011 |volume=1 |issue=2 |pages=45–60}}</ref> Early research in humans used various methods of analyzing dopamine levels and function in depressed patients. Studies have reported that there is decreased concentration of ], a precursor to dopamine, in the blood plasma, ventricular spinal fluid, and lumbar spinal fluid of depressed patients compared to control subjects.<ref>{{cite journal |last1=Denkert |first1=O |author2=Renz A, Marano C, Matussek N. |title=Altered tyrosine daytime plasma levels in edogenous depressed patients |journal=Arch gen Psychiat |year=1971 |volume=25 |pages=359–363 |doi=10.1001/archpsyc.1971.01750160071013 |pmid=5116991 |issue=4}}</ref><ref>{{cite journal |last1=Birkmayer |first1=W |author2=Linauer W, Storung D |title=Tyrosin and tryptophan- metabolisms in depression patients |journal=Arch Psychiar Nervenkr |year=1970 |volume=213 |pages=377–387 |doi=10.1007/BF00341554 |issue=4}}</ref> One study measured the amount of ], the major metabolite of dopamine in the CSF, as a marker for the dopamine pathway turnover rate, and found decreased concentrations of homovanillic acid in the CSF of depressed patients.<ref>{{cite journal |last1=Bowers |first1=MB |author2=Heninger GR, Gerbode F. |title=Cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid in psychiatric patients |journal=Int J Neuropharmacol |year=1969 |volume=8 |pages=255–262 |doi=10.1016/0028-3908(69)90046-X |pmid=5796265 |issue=3}}</ref> Postmordem real time ] (RT-PCR) has also been used to find that gene expression of a specific subtype of dopamine receptor was elevated in the ] of people suffering from depression as compared to control subjects.<ref>{{cite journal |last1=Lianbin |first1=X |author2=Katalin S, Attila S, Violetta K, Craig A, Stockmeier C, Beata K, John K, Gregory A, Ordwaya |title=Dopamine receptor gene expression in human amygdaloid nuclei: Elevated D4 receptor mRNA in major depression |journal=Brain Res |year=2008 |volume=1207 |pages=214–224 |doi=10.1016/j.brainres.2008.02.009 |pmid=18371940 |pmc=2577810}}</ref>

The action of commonly used antidepressant drugs also has yielded information about possible alterations of the dopaminergic pathway in treating depression. It has been reported that many antidepressant drugs increase extracellular dopamine concentrations in the rat prefrontal cortex,<ref>{{cite journal |last1=Carlson |first1=JN |author2=Visker KE, Nielsen DM, Keller RW, Glick SD |title=Chronic antidepressant drug treatment reduces turning behavior and increases dopamine levels in the medial prefrontal cortex |journal=Brain Res |year=1996 |volume=707 |pages=122–126 |doi=10.1016/0006-8993(95)01341-5 |pmid=8866721 |issue=1}}</ref> but vary greatly in their effects on the ] and ].<ref>{{cite journal |last1=Ainsworth |first1=K |author2=Smith SE, Zetterstrom TS, Pei Q, Franklin M, Sharp T |title=Effect of antidepressant drugs on dopamine D1 and D2 receptor expression and dopamine release in the nucleus accumbens of the rat |journal=Psychopharmacology |year=1998 |volume=140 |pages=470–477 |doi=10.1007/s002130050791 |pmid=9888623 |issue=4}}</ref><ref>{{cite journal |last1=Meltzer |first1=TL |author2=Wiley JN, Williams AE, Heffner TG |title=Evidence for postsynaptic dopamine effects of B-HT 920 in the presence of the dopamine D1 agonist SKF 38393 |journal=Psychopharmacology |year=1988 |volume=95 |pages=329–332 |doi=10.1007/BF00181942 |pmid=2901126 |issue=3}}</ref> This can be compared to ] (ECT), which has been shown to have a multiple fold increase in striatal dopamine levels in rats.<ref>{{cite journal |last1=Nomikos |first1=GG |author2=Damsma G, Wenkstern D, Fibiger HC |title=Acute effects of bupripion on extracellular dopamine concentration in rat striatum and nucleus accumbens studies by in vivo microdialysis study |journal=Neuropsychopharmacol |year=1989 |volume=4 |pages=65–69}}</ref>

More recent research studies with rodents have found that depression-related behaviors are associated with dopaminergic system dysregulation.<ref name="Tye 2012 537-541">{{cite journal |last1=Deisseroth |author2=Mirzabekov, Warden, Ferenczi, Tsai, Finkelstein, kim, Adhikari, Thompson, Andalman, Gunaydin, Witten & Deisseroth |title=Dopamine neurons modulate neural encoding and expression of depression-related behaviour |journal=Nature |year=2012 |volume=493 |pages=537–541 |bibcode=2013Natur.493..537T |first=Julie J. |doi=10.1038/nature11740 |pmid=23235822 |issue=7433}}</ref> In rodents exposed to chronic mild stress, decreased escape behavior and decreased forced swimming is reversed with activation of the dopaminergic ].<ref name="Tye 2012 537-541"/> Also, rodents that are susceptible to depression-related behavior after ] can have their behavior reversed with dopamine pathway activation.<ref>{{cite journal |last1=Han |first1=D |author2=Walsh, Friedman, Juarez, Ku, Koo, Ferguson, Tsai, Pomeranz, Christoffel, Nectow, Ekstrand, Domingos, Mazei-Robison, Mouzon, Lobo, Neve, Friedman, Russo, Deisseroth, Nestler, Han |title=Rapid regulation of depression-related behaviors by control of midbrain dopamine neurons |journal=Nature |year=2013 |volume=493 |pages=532–536 |bibcode=2013Natur.493..532C |doi=10.1038/nature11713 |pmid=23235832 |issue=7433 |pmc=3554860}}</ref> Depletion of dopamine in the ] and nucleus accumbens has also been reported in cases of ] in animals. These symptoms can be reversed with dopamine agonists and antidepressant administration prior to the learned helplessness protocol.<ref>{{cite journal |last1=Muscat |first1=R |author2=Sampson D, Willner P. |title=Dopaminergic mechanisms of imipramine action in an animal model of depression |journal=Biol Psychiatry |year=1990 |volume=28 |pages=223–230 |doi=10.1016/0006-3223(90)90577-O |pmid=2378927 |issue=3}}</ref>

==Comparative biology and evolution==

===Microorganisms===

There are no reports of dopamine in ], but it has been detected in some types of ] and in a type of protozoan called '']''.<ref>{{cite book |author=Roshchina VV |year=2010 |chapter=Evolutionary considerations of neurotransmitters in microbial, plant, and animal cells |title=Microbial Endocrinology |pages=17–52 |editors=Lyte M, Primrose PEPE |publisher=Springer |location=New York |isbn=978-1-4419-5576-0}}</ref> Perhaps more importantly, there are types of bacteria that contain homologs of all the enzymes that animals use to synthesize dopamine. It has even been proposed that animals derived their dopamine-synthesizing machinery from bacteria, via ] that may have occurred relatively late in evolutionary time, perhaps as a result of the symbiotic incorporation of bacteria into ] cells that gave rise to ].<ref>{{cite journal |author=Iyer LM, Aravind L, Coon SL, Klein DC, Koonin EV |title=Evolution of cell-cell signaling in animals: did late horizontal gene transfer from bacteria have a role? |journal=Trends Genet. |volume=20 |issue=7 |pages=292–9 |date=July 2004 |pmid=15219393 |doi=10.1016/j.tig.2004.05.007}}</ref>

===Animals===

Dopamine is used as an intercellular messenger in virtually all multicellular animals. In sponges only a single report exists of the presence of dopamine, with no indication of its function;<ref>{{cite journal |year=2004 |title=Isolation of Araguspongine M, a new stereoisomer of an Araguspongine/Xestospongin alkaloid, and dopamine from the marine sponge ''Neopetrosia exigua'' collected in Palau |journal=Marine Drugs |volume=2 |issue=4 |pages=154–163 |author=Liu H, Mishima Y, Fujiwara T, Nagai H, Kitazawa A, Mine Y, ''et al.'' |doi=10.3390/md204154}}</ref> however, dopamine has been reported in the nervous systems of numerous radially symmetric species, including ] (jellyfish, hydra, corals, etc.).<ref>{{cite journal |author=Kass-Simon G, Pierobon P |title=Cnidarian chemical neurotransmission, an updated overview |journal=Comp. Biochem. Physiol., Part a Mol. Integr. Physiol. |volume=146 |issue=1 |pages=9–25 |date=January 2007 |pmid=17101286 |doi=10.1016/j.cbpa.2006.09.008}}</ref> This dates the emergence of dopamine as a neurotransmitter back to the earliest appearance of the nervous system, over 500 million years ago in the ]. Among existing species, dopamine functions as a neurotransmitter in vertebrates, ]s, ]s, ]s, and several types of worms.<ref>{{cite journal |author=Cottrell GA |title=Occurrence of dopamine and noradrenaline in the nervous tissue of some invertebrate species |journal=Br J Pharmacol Chemother |volume=29 |issue=1 |pages=63–9 |date=January 1967 |pmid=19108240 |pmc=1557178 |doi=10.1111/j.1476-5381.1967.tb01939.x}}</ref><ref>{{cite journal |author=Kindt KS, Quast KB, Giles AC, ''et al.'' |title=Dopamine mediates context-dependent modulation of sensory plasticity in C. elegans |journal=Neuron |volume=55 |issue=4 |pages=662–76 |date=August 2007 |pmid=17698017 |doi=10.1016/j.neuron.2007.07.023}}</ref>

In every type of animal that has been examined, dopamine acts to modify motor behavior.<ref name=Barron>{{cite journal |author=Barron AB, Søvik E, Cornish JL |title=The roles of dopamine and related compounds in reward-seeking behavior across animal phyla |journal=Front Behav Neurosci |volume=4 |issue= |pages=163 |year=2010 |pmid=21048897 |pmc=2967375 |doi=10.3389/fnbeh.2010.00163}}</ref> In the much-studied nematode worm '']'', it reduces locomotion and increases food-exploratory movements; in ]n worms it produces "screw-like" movements; in ]es it inhibits swimming and promotes crawling; etc. Across a wide range of vertebrates, dopamine has an "activating" effect on behavior-switching and response selection, comparable to its effect in mammals.<ref name=Barron/>

Dopamine also consistently plays a role in reward learning, in all animal groups that have been examined except arthropods. In nematodes, planarians, molluscs, and vertebrates, animals can be trained to repeat an action if it is consistently followed by an increase in dopamine levels.<ref name=Barron/> Arthropods are an exception, though. In these species — insects, crustaceans, etc. — dopamine has an aversive effect, and reward is instead mediated by ], a neurotransmitter that is not found in vertebrates but is thought to be closely related to ]. In insects, dopamine increases aversion learning for olfactory stimuli as well as visual stimuli, and reduces approach learning for stimuli that are followed by rewards. It also improves recall for aversive memories and reduces recall for positive memories.<ref name=Barron/> The origin of the striking reversal between dopamine's effects in arthropods versus all other types of animals has not been explained.

===Plants===

] and fruit pulp of ]]]

Many plants synthesize dopamine to varying degrees, including a variety of food plants. The highest concentrations have been observed in bananas — the fruit pulp of red and yellow bananas contains dopamine at levels of 40 to 50 parts per million by weight. Potatoes, avocados, broccoli, and ]s may also contain dopamine at levels of 1 part per million or more; oranges, tomatoes, spinach, beans, and other plants contain measurable concentrations less than 1 part per million.<ref name=Kulma>{{cite journal |author=Kulma A, Szopa J |title=Catecholamines are active compounds in plants |journal=Plant Science |year=2007 |volume=172 |pages=433–440 |doi=10.1016/j.plantsci.2006.10.013 |issue=3}}</ref> The dopamine in plants is synthesized from the amino acid tyrosine, by biochemical mechanisms similar to those that animals use. It can be metabolized in a number of ways, producing ] and a variety of alkaloids as byproducts.<ref name=Kulma/> The functions of plant catecholamines have not been clearly established, but there is evidence that they play a role in the response to stressors such as bacterial infection, act as growth-promoting factors in some situations, and modify the way that sugars are metabolized. The receptors that mediate these actions have not yet been identified, nor have the intracellular mechanisms that they activate.<ref name=Kulma/>

Dopamine consumed in food cannot act on the brain, because it cannot cross the ]. However, there are also a variety of plants that contain ], the metabolic precursor of dopamine.<ref name=Ingle>{{cite journal |author=Ingle PK |year=2003 |title=L-DOPA bearing plants |journal=Natural Product Radiance |volume=2 |pages=126–133 |url=http://nopr.niscair.res.in/bitstream/123456789/12261/1/NPR%202%283%29%20126-133.pdf |format=PDF |deadurl=no |accessdate=3 February 2014}}</ref> The highest concentrations are found in the leaves and bean pods of plants of the genus '']'', especially in '']'' (velvet beans), which have been used as a source for L-DOPA as a drug.<ref>{{cite journal |year=1993 |title=Occurrence of L-DOPA and dopamine in plants and cell cultures of ''Mucuna pruriens'' and effects of 2, 4-d and NaCl on these compounds |journal=Plant Cell, Tissue and Organ Culture |volume=33 |issue=3 |pages=259–264 |doi=10.1007/BF02319010 |author=Wichers HJ, Visser JF, Huizing HJ, Pras N}}</ref> Another plant containing substantial amounts of L-DOPA is '']'', the plant that produces fava beans (also known as "broad beans"). The level of L-DOPA in the beans, however, is much lower than in the pod shells and other parts of the plant.<ref>{{cite journal |author=Longo R |year=1974 |title=Distribution of L-dopa and related amino acid in ''Vicia'' |journal=Phytochemistry |volume=13 |pages=167–171 |doi=10.1016/S0031-9422(00)91287-1 |first2=Aldo |first3=Piero |first4=Marcellino}}</ref> The seeds of '']'' and '']'' trees also contain substantial amounts of L-DOPA.<ref name=Ingle/>

In the marine green alga ], which is a major component of some ]s, dopamine is present in very high concentrations, estimated at 4.4% of dry weight. There is evidence that this dopamine functions as an anti-] defense, reducing consumption by snails and ]s.<ref>{{Cite journal |title=Dopamine functions as an antiherbivore defense in the temperate green alga ''Ulvaria obscura'' |first1=Kathryn L. |last1=Van Alstyne |first2=Amorah V. |last2=Nelson |first3=James R. |last3=Vyvyan |first4=Devon A. |last4=Cancilla |journal=Oecologia |volume=148 |issue=2 |pages=304–311 |doi=10.1007/s00442-006-0378-3 |year=2006 |pmid=16489461}}</ref>

===As a precursor for melanin===

]s are a family of dark-pigmented substances that are found in a wide range of organisms. Their physical properties make them difficult to work with experimentally, and consequently a number of aspects of their biochemistry are not well understood. Chemically they are closely related to dopamine, and there is a type of melanin, known as "dopamine-melanin", that can be synthesized by oxidation of dopamine via the enzyme ].<ref>{{cite journal |author=Simon JD, Peles D, Wakamatsu K, Ito S |title=Current challenges in understanding melanogenesis: bridging chemistry, biological control, morphology, and function |journal=Pigment Cell Melanoma Res |volume=22 |issue=5 |pages=563–79 |date=October 2009 |pmid=19627559 |doi=10.1111/j.1755-148X.2009.00610.x}}</ref> The melanin that darkens human skin is not of this type: it is synthesized by a pathway that uses ] as a precursor but not dopamine. However, there is substantial evidence that the "neuromelanin" that gives a dark color to the brain's ] is at least in part dopamine-melanin.<ref>{{cite journal |author=Fedorow H, Tribl F, Halliday G, Gerlach M, Riederer P, Double KL |title=Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson's disease |journal=Prog. Neurobiol. |volume=75 |issue=2 |pages=109–24 |date=February 2005 |pmid=15784302 |doi=10.1016/j.pneurobio.2005.02.001}}</ref>

Dopamine-derived melanin probably appears in at least some other biological systems as well. Some of the dopamine in plants is likely to be used as a precursor for dopamine-melanin.<ref>{{cite journal |year=1967 |title=Melanins from DOPA-containing plants |journal=Phytochemistry |volume=6 |issue=1 |pages=13–18 |doi=10.1016/0031-9422(67)85002-7 |author=Andrews RS, Pridham JB}}</ref> The complex patterns that appear on butterfly wings, as well as black-and-white stripes on the bodies of insect larvae, are also thought to be caused by spatially structured accumulations of dopamine-melanin.<ref>{{cite journal |author=Beldade P, Brakefield PM |title=The genetics and evo-devo of butterfly wing patterns |journal=Nature Reviews Genetics |volume=3 |issue=6 |pages=442–52 |date=June 2002 |pmid=12042771 |doi=10.1038/nrg818}}</ref>

==Pharmacology==

===Dopamine as an injectable drug===

Under the trade names '''Intropin''', '''Dopastat''', '''Revimine''', or other names, dopamine can be used as a ] in ] form. It is most commonly used in the treatment of severe ], ] (slow heart rate), ], or ], especially in newborn infants. Its effects, depending on dosage, include an increase in sodium excretion by the kidneys, an increase in urine output, an increase in heart rate, and an increase in blood pressure. At a "cardiac dose" of 5 to 10 μg/kg/min, dopamine acts through the ] to increase heart muscle contraction force and heart rate, thereby increasing cardiac output and blood pressure. At a "pressor dose" of 10 to 20 μg/kg/min, dopamine also causes ] that further increases blood pressure, but can produce negative side effects such as an impairment of kidney function and ].<ref name="BryantKnights2010">{{cite book |author1=Bronwen Jean Bryant |author2=Kathleen Mary Knights |title=Pharmacology for Health Professionals |url=http://books.google.com/books?id=TQV6sLzYsOYC&pg=PA119 |accessdate=9 June 2011 |edition=2nd |date=15 November 2009 |publisher=Elsevier Australia |isbn=978-0-7295-3929-6 |page=192}}</ref><ref>{{cite journal |title=Comparison of Dopamine and Norepinephrine in the Treatment of Shock |journal=New Engl. J. Med. |volume=362 |pages=779–789 |year=2010 |doi=10.1056/NEJMoa0907118 |author=de Backer D, Biston P, Devriendt J, ''et al.'' |issue=9 |pmid=20200382}}</ref> Older literature also describes a so-called "renal dose" of 2 to 5 μg/kg/min thought to improve kidney function without other consequences, but recent reviews have concluded that doses at this low level are not clinically effective and may sometimes be harmful.<ref>{{cite journal |title=Low-dose dopamine in the intensive care unit |journal=Semin Dial |volume=19 |issue=6 |pages=465–71 |year=2006 |pmid=17150046 |doi=10.1111/j.1525-139X.2006.00208.x |author=Karthik S, Lisbon A}}</ref>

===L-DOPA===

] is a dopamine precursor used in various forms to treat ] and dopa-responsive ]. It is typically co-administered with an inhibitor of peripheral decarboxylation (DDC, ]), such as ] or ]. Inhibitors of alternative metabolic route for dopamine by ] are also used. These include ] and ].

===Psychomotor stimulants===
Cocaine and amphetamines inhibit the ] of dopamine; however, they influence separate mechanisms of action. Cocaine is a ] and ] blocker that competitively inhibits dopamine uptake to increase the lifetime of dopamine and augments an overabundance of dopamine (an increase of up to 150 percent) within the parameters of the dopamine neurotransmitters. Like cocaine, amphetamines increase the concentration of dopamine in the ] gap, but by a different mechanism. Amphetamine and ] are similar in structure to dopamine, and so can enter the terminal bouton of the presynaptic neuron via its dopamine transporters as well as by diffusing through the neural membrane directly.<ref name=Miller>{{cite journal |last=Miller |first=GM |title=The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity |journal=Journal of Neurochemistry |date=January 2011 |volume=116 |issue=2 |pages=164–76 |pmid=21073468 |doi=10.1111/j.1471-4159.2010.07109.x |pmc=3005101}}</ref> Upon entering the presynaptic neuron, amphetamines activate ] which, through ] and ] signaling, induces dopamine efflux and non-competitive reuptake inhibition.<ref name=Miller/> Since amphetamines are structurally similar to ], they are also substrates for monoamine transporters; consequently, they competitively inhibit the reuptake of dopamine and other monoamines as well.<ref name=Miller/>

===Antipsychotic drugs===

A range of drugs that reduce dopamine activity have been found useful in the treatment of ] and other disorders that produce ]. These ] drugs are also sometimes known as neuroleptics or "major tranquilizers", in contrast to "minor tranquilizers" such as ] that are used to treat anxiety or sleep disorders. These drugs have a broadly suppressive effect on most types of active behavior, and particularly reduce the delusional and agitated behavior characteristic of overt psychosis. The introduction of the first widely used antipsychotic drug, ] (Thorazine), in the 1950s, led to the release of many schizophrenia patients from institutions in the years that followed.

Even so, the widespread use of antipsychotic drugs has long been controversial. There are several reasons for this. First, these drugs are perceived as very aversive by people who have to take them, because they produce a general dullness of thought and suppress the ability to experience pleasure.<ref name="fn2">{{cite journal |author=Lambert M, Schimmelmann B, Karow A, Naber D |title=Subjective well-being and initial dysphoric reaction under antipsychotic drugs - concepts, measurement and clinical relevance |journal=Pharmacopsychiatry |volume=36 |issue=Suppl 3 |pages=S181–90 |year=2003 |pmid=14677077 |doi=10.1055/s-2003-45128}}</ref> Second, it is difficult to show that they act specifically against psychotic behaviors rather than merely suppressing all types of active behavior. Third, they can produce a range of serious side effects, including weight gain, diabetes, fatigue, sexual dysfunction, hormonal changes, and a type of movement disorder known as ]. Some of these side effects may continue long after the cessation of drug use, or even permanently.

The first drugs introduced specifically for the treatment of psychosis all had strong direct effects on multiple aspects of dopamine function. Drugs of this type are known as "typical antipsychotics". Because of the problems they cause, there has been wide interest in newer types of drugs known as "atypical antipsychotics" or "second-generation antipsychotics", which aim to target the specific types of dopamine receptors involved in psychosis, and thereby reduce psychotic symptoms without producing as many undesirable side effects. There remains substantial dispute, however, about how much of an improvement in the patient experience these drugs produce.

===Toxicity===
The LD<sub>50</sub>, or dose which is expected to be lethal in 50% of the population, has been found to be: 59&nbsp;mg/kg (mouse; administered i.v.); 950&nbsp;mg/kg (mouse; administered i.p.); 163&nbsp;mg/kg (rat; administered i.p.); 79&nbsp;mg/kg (dog; administered i.v.)<ref>R. J. Lewis (Ed.) (2004), Sax's Dangerous Properties of Industrial Materials, 11th Ed., p. 1552, Wiley & Sons, Hoboken, NJ.</ref>{{clarify|date=October 2012}}

'''<big>Binding profile of dopamine</big>'''<ref>{{cite web |title=PDSP K<sub>i</sub> Database |work=Psychoactive Drug Screening Program (PDSP) |author=Roth, BL; Driscol, J |url=http://pdsp.med.unc.edu/pdsp.php |publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health |accessdate=15 November 2013 |date=12 January 2011}}</ref>

{| class="wikitable"
! Macromolecule !! K<sub>i</sub> (nM)
|-
| ] || 8248
|-
| ] || >10000
|-
| ] || 130
|-
| ] || 598
|-
| ] || 32.5
|-
| ] || 182.6
|-
| ] || 228
|-
| ] || 67
|-
| ] || 323
|-
| ] || 422
|}

==Biochemical mechanisms==

Structurally, dopamine belongs to the ] and ] classes. In biological systems, dopamine is synthesized in brain cells and adrenal cells from the precursor ]. In brain cells, it is transported to ] sites and packaged into vesicles for release, which occurs during synaptic transmission. After release, free dopamine is either reabsorbed into the presynaptic terminal for reuse, or broken down by the enzymes ] or COMT, producing a variety of degradation metabolites.

===Biosynthesis===

Dopamine is ] in a restricted set of cell types, mainly ]s and cells in the ] of the ]s. This is the ]:

* <small>L</small>-Phenylalanine → <small>L</small>-Tyrosine → <small>L</small>-DOPA → Dopamine

Thus the direct precursor of dopamine is ], but this itself can be synthesized from the essential amino acid ] or the non-essential amino acid ]. These amino acids are found in nearly every protein and as such are provided from ingestion of protein-containing food, with tyrosine being the most common. Although dopamine itself is also found in many types of food, it is incapable of crossing the ] that surrounds and protects the brain. It must therefore be synthesized inside the brain in order to perform its neural actions.

<small>L</small>-Phenylalanine is converted into <small>L</small>-tyrosine by the enzyme ] (TH) (also known as phenylalanine hydroxylase), with molecular ] (O<sub>2</sub>) and ] (THB) as ]s. <small>L</small>-Tyrosine is converted into <small>L</small>-DOPA by the enzyme ] (TH), with ] (THB), O<sub>2</sub>, and ] ] (Fe<sup>2+</sup>) as cofactors. <small>L</small>-DOPA is converted into dopamine by the enzyme ] (AAAD; also known as DOPA decarboxylase (DDC)), with ] (PLP) as the cofactor.

Dopamine itself is also used as precursor in the synthesis of the neurotransmitters ] and ]. Dopamine is converted into norepinephrine by the enzyme ] (DBH), with O<sub>2</sub> and ] as cofactors. Norepinephrine is converted into epinephrine by the enzyme ] (PNMT) with ] (SAMe) as the cofactor.

It should be noted that some of the cofactors also require their own synthesis. Deficiency in any required amino acid or cofactor will result in subsequent dopamine, norepinephrine, and epinephrine biosynthesis impairment and deficiency.
{{Phenylalanine biosynthesis|caption=This is the biosynthesis of catecholamines, including dopamine, as well as phenethylaminergic trace amines from the amino acid phenylalanine. Abbreviations used:<br />{{nowrap|DBH: Dopamine β-hydroxylase;}}<br />{{nowrap|AADC:Aromatic L-amino acid decarboxylase;}}<br />{{nowrap|AAAH: (Biopterin-dependent) aromatic amino acid hydroxylase;}}<br /> {{nowrap|COMT: Catechol O-methyltransferase;}}<br />{{nowrap|PNMT: Phenylethanolamine N-methyltransferase}}}}

===Storage, release, and reuptake===
Inside the brain dopamine functions as a ], and is controlled by a set of mechanisms that are common to all neurotransmitters. After synthesis, dopamine is transported from the ]{{Citation needed|date=November 2013}} into ]s by the ] (VMAT2). Dopamine is stored in and remains in these vesicles until an ] occurs and causes the contents of the vesicles to be ejected into the ].

Once in the synapse, dopamine binds to and activates ]s, which can be located either on ] target cells or on the membrane of the dopamine-releasing cell itself (i.e., ]s).

After an action potential, the dopamine molecules quickly become unbound from their receptors. They are then absorbed back into the presynaptic cell, via ] mediated either by the high-affinity ] (DAT) or by the low-affinity ] (PMAT). Once back in the cytosol, dopamine is subsequently repackaged into vesicles by VMAT2, making it available for future release.

===Degradation===
]

Dopamine is broken down into inactive metabolites by a set of enzymes, ] (MAO), ] (ALDH), and ] (COMT), acting in sequence. Both ]s of MAO, ] and ], are equally effective.

The metabolites produced by these processes are:
*DOPAL (])
*DOPAC (])
*DOPET (3,4-dihydroxyphenylethanol, also known as ])
*MOPET (3-methoxy-4-hydroxyphenylethanol, also known as ])
*3-MT (])
*HVA (])

All of these are intermediate metabolites except MOPET and HVA, which are filtered from the bloodstream by the kidneys and then excreted in the urine.

The specific reactions that make up these pathways are:
* Dopamine → DOPAL, mediated by MAO
* DOPAL → DOPAC, mediated by ]
* DOPAL → DOPET, mediated by ] (minor pathway)
* DOPAC → HVA, mediated by COMT
* DOPET → MOPET, mediated by COMT
* Dopamine → 3-MT, mediated by COMT
* 3-MT → HVA, mediated by MAO

In most areas of the brain, including the ] and ], dopamine is inactivated by reuptake via the DAT, then enzymatic breakdown by MAO into DOPAC. In the ], however, there are very few DAT proteins, and dopamine is inactivated instead by reuptake via the ] (NET), presumably on neighboring norepinephrine neurons, then enzymatic breakdown by COMT into 3-MT.<ref>{{cite journal |last1=Morón |first1=JA |last2=Brockington |first2=A |last3=Wise |first3=RA |last4=Rocha |first4=BA |last5=Hope |first5=BT |title=Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines |url=http://www.jneurosci.org/cgi/content/abstract/22/2/389 |journal=Journal of Neuroscience |volume=22 |issue=2 |pages=389–95 |year=2002 |pmid=11784783}}</ref> The DAT pathway is roughly an order of magnitude faster than the NET pathway: in mice, dopamine concentrations decay with a half-life of 200 milliseconds in the ] (which uses the DAT pathway) versus 2,000 milliseconds in the prefrontal cortex.<ref>{{cite journal |doi=10.1523/JNEUROSCI.0665-07.2007 |last1=Yavich |first1=L |last2=Forsberg |first2=MM |last3=Karayiorgou |first3=M |last4=Gogos |first4=JA |last5=Männistö |first5=PT |title=Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum |url=http://www.jneurosci.org/cgi/content/abstract/27/38/10196 |journal=Journal of Neuroscience |volume=27 |issue=38 |pages=10196–209 |year=2007 |pmid=17881525}}</ref> Dopamine that is not broken down by enzymes is repackaged into vesicles for future release.

==Chemistry==
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|image1=Dopamine2.svg
|caption1=Dopamine structure
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|image2=Fenyloetyloamina.svg
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|alt2=Phenethylamine structure
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|caption3=Catechol structure
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Chemically, a dopamine molecule consists of a ] structure (a ] ring with two ] side groups) with one ] group attached. As such, dopamine is the simplest possible ], a family that also includes the ]s ] and ]. The presence of a benzene ring with an attached amine group makes it a ], a family that includes numerous psychoactive drugs.

Dopamine, like most ]s, is an ]. At neutral or acidic pH levels it is generally ]. The protonated form is highly water-soluble and relatively stable, though it is capable of oxidizing if exposed to oxygen or other oxidants. At basic pH levels, dopamine becomes deprotonated. In this ] form it is less soluble and also highly reactive and easily oxidized. Because of this pH-dependence, dopamine is supplied for chemical or pharmaceutical use in the form of dopamine hydochloride, that is, the ] salt that is created when dopamine is combined with hydrochloric acid. In dry form, dopamine hydrochloride is a fine colorless powder. When dissolved in distilled water it gives a solution that is mildly acidic and therefore relatively stable. It cannot, however, be combined with alkaline solutions such as a ] buffer without being rendered inactive.

===Oxidation===

Dopamine in the body is normally broken down by oxidation catalyzed by the enzyme ]. However, dopamine is also capable of ], that is, direct reaction with oxygen, yielding ]s plus various ]s as products.<ref name=Sulzer>{{cite journal |author=Sulzer D, Zecca L |title=Intraneuronal dopamine-quinone synthesis: a review |journal=Neurotox Res |volume=1 |issue=3 |pages=181–95 |date=February 2000 |pmid=12835101 |doi=10.1007/BF03033289 |url=}}</ref> The rate of autoxidation can be increased by the presence of ferrous iron or other factors. The ability of dopamine autoxidation to produce quinones and free radicals makes it a potent cell toxin, and there is evidence that this mechanism may contribute to cell loss that occurs in ] or other conditions.<ref>{{cite journal |author=Miyazaki I, Asanuma M |title=Dopaminergic neuron-specific oxidative stress caused by dopamine itself |journal=Acta Med. Okayama |volume=62 |issue=3 |pages=141–50 |date=June 2008 |pmid=18596830 |doi= |url=http://www.lib.okayama-u.ac.jp/www/acta/pdf/62_3_141.pdf |format=PDF}}</ref>

=== {{anchor|Polydopamine}} Polydopamine===

Research motivated by mussel adhesive proteins led to the discovery in 2007 that a wide variety of materials, if placed in a solution of dopamine at slightly basic pH, will become coated with a layer of polymerized dopamine, often referred to as '''polydopamine'''.<ref>''Mussel-Inspired Surface Chemistry for Multifunctional Coatings'' Haeshin Lee, Shara M. Dellatore, William M. Miller, Phillip B. Messersmith Science 19 October 2007: Vol. 318 no. 5849 pp.&nbsp;426–430 {{DOI|10.1126/science.1147241}}</ref><ref name=Dreyer>''Perspectives on poly(dopamine)'' Daniel R. Dreyer, Daniel J. Miller, Benny D. Freeman, Donald R. Paul and Christopher W. Bielawski Chem" ''Sci'' 2013, Advance Article {{DOI|10.1039/C3SC51501J}}</ref> This polymerized dopamine forms by a spontaneous oxidation reaction, and is formally a type of ].<ref name=Lynge>{{cite journal |author=Lynge ME, van der Westen R, Postma A, Städler B |title=Polydopamine--a nature-inspired polymer coating for biomedical science |journal=Nanoscale |volume=3 |issue=12 |pages=4916–28 |date=December 2011 |pmid=22024699 |doi=10.1039/c1nr10969c |url=http://www.researchgate.net/publication/51742922_Polydopamine--a_nature-inspired_polymer_coating_for_biomedical_science/file/d912f50318c9e0c7bb.pdf}}</ref> Synthesis usually involves reaction of dopamine hydrochloride with ] as a base in water. The structure of polydopamine is unknown.<ref name=Dreyer />

Polydopamine coatings can form on objects ranging in size from nanoparticles to large surfaces. Polydopamine layers have chemical properties that have the potential to be extremely useful, and numerous studies have examined their possible applications. At the simplest level, they can be used for protection against damage by light, or to form capsules for drug delivery. At a more sophisticated level, their adhesive properties may make them useful as substrates for biosensors or other biologically active macromolecules.<ref name=Lynge/>

==History==
{{Main|History of catecholamine research}}
Dopamine was first synthesized in 1910 by ] and ] at ] Laboratories in London, England.<ref></ref> It was named dopamine because it is a ] whose ] in the Barger-Ewens synthesis is 3,4-''d''ihydr''o''xy''p''henyl''a''lanine (levodopamine or ]). Dopamine's function as a neurotransmitter was first recognized in 1958 by ] and ] at the Laboratory for Chemical Pharmacology of the National Heart Institute of ].<ref>{{cite journal |doi=10.1016/S0165-6147(00)01607-2 |last1=Benes |first1=F.M. |year=2001 |title=Carlsson and the discovery of dopamine |url= |journal=Trends in Pharmacological Sciences |volume=22 |issue=1 |pages=46–47 |pmid=11165672}}</ref> Carlsson was awarded the 2000 ] for showing that dopamine is not only a precursor of ] (noradrenaline) and ] (adrenaline), but also a neurotransmitter.

== See also ==
{{columns-list|3|
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ] (N-methyldopamine)
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
* ]
}}


==References== == References ==
{{Reflist|30em}} {{Reflist}}


{{Cardiac stimulants excluding cardiac glycosides}}
==External links==
{{Adrenergic receptor modulators}}
{{Wiktionary|Dopamine}}
{{Dopamine receptor modulators}}
* {{DrugBank|APRD00085}}
{{Portal bar | Medicine}}
*
{{Authority control}}
* - The Association for Clinical Biochemistry and Laboratory Medicine
{{Neurotransmitters}}
{{Dopaminergics}}
{{Phenethylamines}}
{{TAAR ligands}}


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