View source for Dopamine

{{short description|Organic chemical that functions both as a hormone and a neurotransmitter}}
{{About|the neurotransmitter|medical uses|Dopamine (medication)|other uses}}
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{{Good article}}
{{Technical|introduction|date=July 2025}} 
{{Use dmy dates|date=November 2018}}
{{Infobox drug
| drug_name          = 
| IUPAC_name         = 4-(2-Aminoethyl)benzene-1,2-diol
| synonyms           = {{ubl|DA, |2-(3,4-Dihydroxyphenyl)ethylamine, |3,4-Dihydroxyphenethylamine, |3-Hydroxytyramine, |Oxytyramine, | Intropin,| Revivan}}
| image              = Dopamine.svg
| image_class        = skin-invert-image
| alt                = Dopamine structure
| caption            = [[Skeletal formula]] of dopamine
| image2             = Dopamine-based-on-xtal-3D-bs-17.png
| image_class2       = bg-transparent
| caption2           = [[Ball-and-stick model]] of the dopamine molecule as found in solution. In the solid state, dopamine adopts a [[zwitterion]]ic form.<ref>{{cite journal |title=CSD Entry TIRZAX: 5-(2-Ammonioethyl)-2-hydroxyphenolate, Dopamine|journal=Cambridge Structural Database: Access Structures |year=2013|publisher=[[Cambridge Crystallographic Data Centre]]|doi=10.5517/cc10m9nl |doi-access=free |vauthors=Cruickshank L, Kennedy AR, Shankland N}}</ref><ref>{{ cite journal | title = Tautomeric and ionisation forms of dopamine and tyramine in the solid state | vauthors = Cruickshank L, Kennedy AR, Shankland N | journal = [[Journal of Molecular Structure|J. Mol. Struct.]] | volume = 1051 | pages = 132–36 | year = 2013 | doi = 10.1016/j.molstruc.2013.08.002 | bibcode = 2013JMoSt1051..132C }}</ref>
| source_tissues     = [[Substantia nigra]]; [[ventral tegmental area]]; many others
| target_tissues     = System-wide
| receptors          = [[Dopamine receptor D1|D<sub>1</sub>]], [[Dopamine receptor D2|D<sub>2</sub>]], [[Dopamine receptor D3|D<sub>3</sub>]], [[Dopamine receptor D4|D<sub>4</sub>]], [[Dopamine receptor D5|D<sub>5</sub>]], [[TAAR1]]<ref name="DA IUPHAR"/>
| agonists           = Direct: [[apomorphine]], [[bromocriptine]]<br/>[[Indirect agonist|Indirect]]: [[cocaine]], [[amphetamine]], [[methylphenidate]]
| antagonists        = [[Neuroleptic]]s, [[metoclopramide]], [[domperidone]]
| precursor          = [[Phenylalanine]], [[tyrosine]], and [[L-DOPA]]
| biosynthesis       = [[DOPA decarboxylase]]
| metabolism         = [[Monoamine oxidase|MAO]], [[COMT]]<ref name="DA IUPHAR"/>
| CAS_number         = 51-61-6
| CAS_supplemental   = {{CAS|62-31-7}} (hydrochloride)
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = VTD58H1Z2X
| PubChem            = 681
| ChemSpiderID       = 661
| IUPHAR_ligand      = 940
| KEGG               = C03758
| DrugBank           = DB00988
| C                  = 8
| H                  = 11
| N                  = 1
| O                  = 2
| SMILES             = NCCc1cc(O)c(O)cc1
| StdInChI           = 1S/C8H11NO2/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,5,10-11H,3-4,9H2
| StdInChI_comment   = 
| StdInChIKey        = VYFYYTLLBUKUHU-UHFFFAOYSA-N
}}

'''Dopamine''' ('''DA''', a contraction of '''3,4-<u>d</u>ihydr<u>o</u>xy<u>p</u>henethyl<u>amine</u>''') is a [[neuromodulatory]] [[molecule]] that plays several important roles in cells. It is an [[organic compound|organic chemical]] of the [[catecholamine]] and [[phenethylamine]] families. It is an [[amine]] synthesized by removing a [[carboxyl group]] from a molecule of its [[precursor (chemistry)|precursor chemical]], [[L-DOPA]], which is [[biosynthesis|synthesized]] in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a [[neurotransmitter]]—a chemical released by [[neuron]]s (nerve cells) to send signals to other nerve cells. The brain includes several distinct [[dopaminergic pathway|dopamine pathways]], one of which plays a major role in the motivational component of [[reward system|reward-motivated behavior]]. The anticipation of most types of rewards increases the level of dopamine in the brain,<ref>{{cite journal |vauthors=Berridge KC |date=April 2007 |title=The debate over dopamine's role in reward: the case for incentive salience |journal=Psychopharmacology |language=en-US |volume=191 |issue=3 |pages=391–431 |doi=10.1007/s00213-006-0578-x |pmid=17072591 |s2cid=468204}}</ref> and many [[addiction|addictive]] [[Psychoactive drug|drugs]] increase dopamine release or block its [[reuptake]] into neurons following release.<ref name="Wise2020">{{cite journal |vauthors=Wise RA, Robble MA |date=January 2020 |title=Dopamine and Addiction |journal=Annual Review of Psychology |language=en-US |volume=71 |issue=1 |pages=79–106 |doi=10.1146/annurev-psych-010418-103337 |pmid=31905114 |s2cid=210043316 |doi-access=free}}</ref> Other brain dopamine pathways are involved in [[motor system|motor control]] and in controlling the release of various hormones. These pathways and [[dopaminergic cell groups|cell groups]] form a dopamine system which is [[neuromodulation|neuromodulatory]].<ref name="Wise2020"/>

In [[popular culture]] and media, dopamine is often portrayed as the main chemical of pleasure, but the current opinion in pharmacology is that dopamine instead confers [[motivational salience]];<ref name="NAcc function" /><ref name="pmid24107968">{{cite journal |vauthors=Baliki MN, Mansour A, Baria AT, Huang L, Berger SE, Fields HL, Apkarian AV |date=October 2013 |title=Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain |journal=The Journal of Neuroscience |language=en-US |volume=33 |issue=41 |pages=16383–93 |doi=10.1523/JNEUROSCI.1731-13.2013 |pmc=3792469 |pmid=24107968 |quote=<!--Recent evidence indicates that inactivation of D2 receptors, in the indirect striatopallidal pathway in rodents, is necessary for both acquisition and expression of aversive behavior, and direct pathway D1 receptor activation controls reward-based learning (Hikida et al., 2010; Hikida et al., 2013). It seems we can conclude that direct and indirect pathways of the NAc, via D1 and D2 receptors, subserve distinct anticipation and valuation roles in the shell and core of NAc, which is consistent with observations regarding spatial segregation and diversity of responses of midbrain dopaminergic neurons for rewarding and aversive conditions, some encoding motivational value, others motivational salience, each connected with distinct brain networks and having distinct roles in motivational control (Bromberg-Martin et al., 2010; Cohen et al., 2012; Lammel et al., 2013).&nbsp;... Thus, the previous results, coupled with the current observations, imply that the NAc pshell response reflects a prediction/anticipation or salience signal, and the NAc pcore response is a valuation response (reward predictive signal) that signals the negative reinforcement value of cessation of pain (i.e., anticipated analgesia). -->}}</ref><ref name="Aversion neurons">{{cite journal |vauthors=Wenzel JM, Rauscher NA, Cheer JF, Oleson EB |date=January 2015 |title=A role for phasic dopamine release within the nucleus accumbens in encoding aversion: a review of the neurochemical literature |journal=ACS Chemical Neuroscience |language=en-US |volume=6 |issue=1 |pages=16–26 |doi=10.1021/cn500255p |pmc=5820768 |pmid=25491156 |quote=Thus, fear-evoking stimuli are capable of differentially altering phasic dopamine transmission across NAcc subregions. The authors propose that the observed enhancement in NAcc shell dopamine likely reflects general motivational salience, perhaps due to relief from a CS-induced fear state when the US (foot shock) is not delivered. This reasoning is supported by a report from Budygin and colleagues<sup>112</sup> showing that, in anesthetized rats, the termination of tail pinch results in augmented dopamine release in the shell.}}</ref> in other words, dopamine signals the perceived motivational prominence (i.e., the desirability or aversiveness) of an outcome, which in turn propels the organism's behavior toward or away from achieving that outcome.<ref name="Aversion neurons" /><ref name="Motivational salience">{{cite journal | vauthors = Puglisi-Allegra S, Ventura R | title = Prefrontal/accumbal catecholamine system processes high motivational salience | journal = Front. Behav. Neurosci. | volume = 6 | page = 31 | date = June 2012 | pmid = 22754514 | pmc = 3384081 | doi = 10.3389/fnbeh.2012.00031 | quote = <!--Motivational salience regulates the strength of goal seeking, the amount of risk taken, and the energy invested from mild to extreme.&nbsp;... Motivation can be conceptually described as a continuum along which stimuli can either reinforce or punish responses to other stimuli. Behaviorally, stimuli that reinforce are called rewarding and those that punish aversive (Skinner, 1953). Reward and aversion describe the impact a stimulus has on behavior, and provided of motivational properties, thus able to induce attribution of motivational salience.&nbsp;... Attribution of motivational salience is related to the salience of an UCS (Dallman et al., 2003; Pecina et al., 2006). Thus, the more salient an UCS the more likely a neutral (to-be-conditioned) stimulus will be associated with it through motivational salience attribution. Prior experience is a major determinant of the motivational impact of any given stimulus (Borsook et al., 2007) and emotional arousal induced by motivational stimuli increases the attention given to stimuli influencing both the initial perceptual encoding and the consolidation process (Anderson et al., 2006; McGaugh, 2006).-->| doi-access = free }}</ref>

Outside the central nervous system, dopamine functions primarily as a local [[paracrine]] messenger. In 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 [[Gastrointestinal physiology#Motility|gastrointestinal motility]] 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 is synthesized locally and exerts its effects near the cells that release it.

Several important diseases of the nervous system are associated with dysfunctions of the dopamine system, and some of the key medications used to treat them work by altering the effects of dopamine. [[Parkinson's disease]], a degenerative condition causing [[tremor]] and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the [[midbrain]] called the [[substantia nigra]]. Its metabolic precursor L-DOPA can be manufactured; ''Levodopa'', a pure form of L-DOPA, is the most widely used treatment for Parkinson's. There is evidence that [[schizophrenia]] involves altered levels of dopamine activity, and most [[antipsychotic|antipsychotic drugs]] used to treat this are [[dopamine antagonist]]s which reduce dopamine activity.<ref>{{cite book | vauthors = Moncrieff J | title =The myth of the chemical cure. A critique of psychiatric drug treatment | year = 2008  | publisher = Palgrave MacMillan | location = Basingstoke, UK | isbn = 978-0-230-57432-8 }}</ref> Similar dopamine antagonist drugs are also some of the most effective [[antiemetic|anti-nausea agents]]. [[Restless legs syndrome]] and [[attention deficit hyperactivity disorder]] (ADHD) are associated with decreased dopamine activity.<ref>{{cite journal | vauthors = Volkow ND, Wang GJ, Kollins SH, Wigal TL, Newcorn JH, Telang F, Fowler JS, Zhu W, Logan J, Ma Y, Pradhan K, Wong C, Swanson JM | title = Evaluating dopamine reward pathway in ADHD: clinical implications | journal = JAMA | volume = 302 | issue = 10 | pages = 1084–91 | date = September 2009 | pmid = 19738093 | pmc = 2958516 | doi = 10.1001/jama.2009.1308 }}</ref> [[Dopaminergic]] [[sympathomimetic drug|stimulants]] can be addictive in high doses, but some are used at lower doses to treat ADHD. [[Dopamine (medication)|Dopamine]] itself is available as a manufactured medication for [[intravenous therapy|intravenous injection]]. It is useful in the treatment of [[heart failure|severe heart failure]] or [[cardiogenic shock]].<ref name="NHS2021">{{cite web |title=Dopamine infusion |url=https://www.bsuh.nhs.uk/library/wp-content/uploads/sites/8/2021/08/dopamine-infusion-August-2021-final.pdf |access-date=13 October 2023}}</ref> In newborn babies it may be used for [[hypotension]] and [[septic shock]].<ref name="medscape2021">{{cite web |title=Shock and Hypotension in the Newborn Medication: Alpha/Beta Adrenergic Agonists, Vasodilators, Inotropic agents, Volume Expanders, Antibiotics, Other |url=https://emedicine.medscape.com/article/979128-medication?form=fpf |access-date=13 October 2023 |website=emedicine.medscape.com |language=en-US}}</ref>
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==Structure==
A dopamine molecule consists of a [[catechol]] structure (a [[benzene]] ring with two [[hydroxyl]] side groups) with one [[amine]] group        attached via an [[ethyl group|ethyl]] chain.<ref name="PubChem">{{cite web |title=Dopamine |url=https://pubchem.ncbi.nlm.nih.gov/compound/dopamine |access-date=21 September 2015 |publisher=PubChem |language=en-US}}</ref> As such, dopamine is the simplest possible [[catecholamine]], a family that also includes the [[neurotransmitter]]s [[norepinephrine]] and [[epinephrine]].<ref name=Catecholamine>{{cite encyclopedia |url=https://www.britannica.com/science/catecholamine |title=Catecholamine |encyclopedia=Britannica |access-date=21 September 2015}}</ref> The presence of a benzene ring with this amine attachment makes it a [[substituted phenethylamine]], a family that includes numerous [[psychoactive drug]]s.<ref name="Phenethylamine">{{cite web |title=Phenylethylamine |url=http://www.chemicalland21.com/lifescience/phar/PHENYLETHYLAMINE.htm |access-date=21 September 2015 |publisher=ChemicalLand21.com |language=en-US}}</ref>

Like most [[amine]]s, dopamine is an [[organic base]].<ref name=Carter>{{cite journal |vauthors=Carter JE, Johnson JH, Baaske DM |year=1982 |title=Dopamine Hydrochloride |journal=Analytical Profiles of Drug Substances |volume=11 |pages=257–72|doi=10.1016/S0099-5428(08)60266-X |isbn=978-0122608117 }}</ref> As a [[base (chemistry)|base]], it is generally [[protonation|protonated]] in [[acid]]ic environments (in an [[acid-base reaction]]).<ref name=Carter/> The protonated form is highly water-soluble and relatively stable, but can become [[oxidation|oxidized]] if exposed to oxygen or other [[oxidising agent|oxidants]].<ref name=Carter/> In basic environments, dopamine is not protonated.<ref name=Carter/> In this [[free base]] form, it is less water-soluble and also more highly reactive.<ref name=Carter/> Because of the increased stability and water-solubility of the protonated form, dopamine is supplied for chemical or pharmaceutical use as dopamine [[hydrochloride]]—that is, the [[hydrochloride]] [[salt (chemistry)|salt]] that is created when dopamine is combined with [[hydrochloric acid]].<ref name=Carter/> In dry form, dopamine hydrochloride is a fine powder which is white to yellow in color.<ref>{{Cite web |title=Specification Sheet |url=https://www.sigmaaldrich.com/catalog/DataSheetPage.do?brandKey=SIGMA&symbol=H8502 |access-date=2019-09-13 |website=www.sigmaaldrich.com |language=en-US}}</ref>
<div class='skin-invert-image'>{{multiple image
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| image1=Dopamine2.svg
| caption1=Dopamine structure
| alt1=Chemical diagram of the structure of a dopamine molecule.
| width1=250
| image2=Fenyloetyloamina.svg
| caption2=[[Phenethylamine]] structure
| alt2=Chemical diagram of a phenethylamine structure.
| width2=256
| image3=Brenzcatechin.svg
| caption3=Catechol structure
| alt3=Chemical diagram of a catechol structure.
| width3=117
}}</div>

==Biochemistry==
{{Catecholamine and trace amine biosynthesis|align=right|caption=In humans, [[catecholamine]]s and phenethylaminergic [[trace amine]]s are derived from the amino acid [[phenylalanine]].  It is well established that dopamine is produced from <small>L</small>-tyrosine via <small>L</small>-DOPA; however, recent evidence has shown that CYP2D6 is expressed in the human brain and catalyzes the biosynthesis of dopamine from <small>L</small>-tyrosine via ''p''-tyramine.<ref name="CYP2D6 tyramine-dopamine metabolism" />}}

===Synthesis===
Dopamine is [[biosynthesis|synthesized]] in a restricted set of cell types, mainly neurons and cells in the [[adrenal medulla|medulla]] of the [[adrenal gland]]s.<ref name=Seeman/> The primary and minor [[metabolic pathway]]s respectively are:

:Primary: <small>L</small>-Phenylalanine → <small>L</small>-Tyrosine → <small>L</small>-DOPA → Dopamine<ref name="Trace amine template 1" /><ref name="Trace amine template 2" />
:Minor: <small>L</small>-Phenylalanine → <small>L</small>-Tyrosine → ''p''-Tyramine → Dopamine<ref name="Trace amine template 1" /><ref name="Trace amine template 2" /><ref name="CYP2D6 tyramine-dopamine metabolism" />
:Minor: <small>L</small>-Phenylalanine → [[L-m-tyrosine|''m''-Tyrosine]] → [[meta-tyramine|''m''-Tyramine]]  → Dopamine<ref name="CYP2D6 tyramine-dopamine metabolism" /><ref name="Tyrosine 3-hydroxylase m-tyrosine synthesis">{{cite encyclopedia|title=EC 1.14.16.2&nbsp;– Tyrosine 3-monooxygenase (Homo sapiens)|url=http://www.brenda-enzymes.org/enzyme.php?ecno=1.14.16.2&Suchword=&reference=&organism%5B%5D=Homo+sapiens&show_tm=0| encyclopedia =BRENDA|publisher=Technische Universität Braunschweig|access-date=7 October 2016|date=July 2016|quote = Substrate: L-phenylalanine + tetrahydrobiopterin + O2<br />Product: L-tyrosine + 3-hydroxyphenylalanine [(aka m-tyrosine)] + dihydropteridine + H2O<br />Organism: Homo sapiens}}<br />[http://www.brenda-enzymes.org/structure.php?show=reaction&id=428743&type=S&displayType=marvin Reaction diagram]</ref><ref name="AADC m-tyramine synthesis">{{cite encyclopedia|title=EC 4.1.1.28&nbsp;– Aromatic-L-amino-acid decarboxylase (Homo sapiens)|url=http://www.brenda-enzymes.org/enzyme.php?ecno=4.1.1.28&Suchword=&reference=&organism%5B%5D=Homo+sapiens&show_tm=0| encyclopedia =BRENDA|publisher=Technische Universität Braunschweig|access-date=7 October 2016|date=July 2016|quote = Substrate: m-tyrosine<br />Product: m-tyramine + CO2<br />Organism: Homo sapiens}}<br />[http://www.brenda-enzymes.org/structure.php?show=reaction&id=407269&type=S&displayType=marvin Reaction diagram]</ref>

The direct precursor of dopamine, [[L-DOPA|<small>L</small>-DOPA]], can be synthesized indirectly from the [[essential amino acid]] [[phenylalanine]] or directly from the non-essential amino acid [[tyrosine]].<ref name=Musacchio/> These [[amino acid]]s are found in nearly every protein and so are readily available in food, with tyrosine being the most common. Although dopamine is also found in many types of food, it is incapable of crossing the [[blood–brain barrier]] that surrounds and protects the brain.<ref name="Nice-pharma"/> It must therefore be synthesized inside the brain to perform its [[neurotransmission|neuronal activity]].<ref name="Nice-pharma"/>

<small>L</small>-Phenylalanine is converted into <small>L</small>-tyrosine by the [[enzyme]] [[phenylalanine hydroxylase]], with [[allotropes of oxygen#Dioxygen|molecular oxygen]] (O<sub>2</sub>) and [[tetrahydrobiopterin]] as [[cofactor (biochemistry)|cofactors]]. <small>L</small>-Tyrosine is converted into <small>L</small>-DOPA by the enzyme [[tyrosine hydroxylase]], with tetrahydrobiopterin, O<sub>2</sub>, and iron (Fe<sup>2+</sup>) as cofactors.<ref name=Musacchio>{{cite book |title=Biochemistry of Biogenic Amines |chapter=Chapter 1: Enzymes involved in the biosynthesis and degradation of catecholamines | vauthors= Musacchio JM | veditors = Iverson L |publisher=Springer | isbn = 978-1-4684-3171-1 |year=2013 |pages=1–35}}</ref> <small>L</small>-DOPA is converted into dopamine by the enzyme [[aromatic L-amino acid decarboxylase|aromatic <small>L</small>-amino acid decarboxylase]] (also known as DOPA decarboxylase), with [[pyridoxal phosphate]] as the cofactor.<ref name=Musacchio/>

Dopamine itself is used as precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine.<ref name=Musacchio/> Dopamine is converted into norepinephrine by the enzyme [[dopamine beta hydroxylase|dopamine β-hydroxylase]], with O<sub>2</sub> and [[ascorbic acid|<small>L</small>-ascorbic acid]] as cofactors.<ref name=Musacchio/> Norepinephrine is converted into epinephrine by the enzyme [[phenylethanolamine N-methyltransferase|phenylethanolamine ''N''-methyltransferase]] with [[S-Adenosyl methionine|''S''-adenosyl-<small>L</small>-methionine]] as the cofactor.<ref name=Musacchio/>

Some of the cofactors also require their own synthesis.<ref name=Musacchio/> Deficiency in any required amino acid or cofactor can impair the synthesis of dopamine, norepinephrine, and epinephrine.<ref name=Musacchio/>

===Degradation===
Dopamine is broken down into inactive [[metabolite]]s by a set of enzymes—[[monoamine oxidase]] (MAO), [[catechol-O-methyl transferase|catechol-''O''-methyl transferase]] (COMT), and [[aldehyde dehydrogenase]] (ALDH), acting in sequence.<ref name=Eisenhofer>{{cite journal | vauthors = Eisenhofer G, Kopin IJ, Goldstein DS | s2cid = 12825309 | title = Catecholamine metabolism: a contemporary view with implications for physiology and medicine | journal = Pharmacological Reviews | volume = 56 | issue = 3 | pages = 331–49 | date = September 2004 | pmid = 15317907 | doi = 10.1124/pr.56.3.1 }}</ref> Both [[protein isoform|isoforms]] of monoamine oxidase, [[Monoamine oxidase A|MAO-A]] and [[Monoamine oxidase B|MAO-B]], effectively metabolize dopamine.<ref name=Musacchio/> Different breakdown pathways exist but the main end-product is [[homovanillic acid]] (HVA), which has no known biological activity.<ref name=Eisenhofer/> From the bloodstream, homovanillic acid is filtered out by the kidneys and then excreted in the urine.<ref name=Eisenhofer/> The two primary metabolic routes that convert dopamine into HVA are:<ref>{{Cite book | vauthors = Zahoor I, Shafi A, Haq E | chapter = Pharmacological Treatment of Parkinson’s Disease: Figure 1: [Metabolic pathway of dopamine synthesis...] | veditors = Stoker TB, Greenland JC | title = Parkinson's Disease: Pathogenesis and Clinical Aspects [Internet]. | location = Brisbane (AU) | publisher = Codon Publications | date = December 2018 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK536726/figure/Ch7-f0001/ }}</ref>
* Dopamine → [[DOPAL]] → [[DOPAC]] → HVA&nbsp;– catalyzed by MAO, ALDH, and COMT respectively
* Dopamine → [[3-Methoxytyramine]] → HVA&nbsp;– catalyzed by COMT and MAO+ALDH respectively

In clinical research on schizophrenia, measurements of homovanillic acid in [[blood plasma|plasma]] have been used to estimate levels of dopamine activity in the brain. A difficulty in this approach however, is separating the high level of plasma homovanillic acid contributed by the metabolism of norepinephrine.<ref>{{cite journal | vauthors = Amin F, Davidson M, Davis KL | title = Homovanillic acid measurement in clinical research: a review of methodology | journal = Schizophrenia Bulletin | volume = 18 | issue = 1 | pages = 123–48 | year = 1992 | pmid = 1553492 | doi = 10.1093/schbul/18.1.123 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Amin F, Davidson M, Kahn RS, Schmeidler J, Stern R, Knott PJ, Apter S | title = Assessment of the central dopaminergic index of plasma HVA in schizophrenia | journal = Schizophrenia Bulletin | volume = 21 | issue = 1 | pages = 53–66 | date = 1995 | pmid = 7770741 | doi = 10.1093/schbul/21.1.53 | doi-access = free }}<!--|access-date=13 November 2015--></ref>

Although dopamine is normally broken down by an [[oxidoreductase]] enzyme, it is also susceptible to oxidation by direct reaction with oxygen, yielding [[quinone]]s plus various [[radical (chemistry)|free radicals]] as products.<ref name=Sulzer>{{cite journal | vauthors = Sulzer D, Zecca L | s2cid = 21892355 | title = Intraneuronal dopamine-quinone synthesis: a review | journal = Neurotoxicity Research | volume = 1 | issue = 3 | pages = 181–95 | date = February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289 }}</ref> The rate of oxidation can be increased by the presence of [[ferric]] iron or other factors. Quinones and free radicals produced by autoxidation of dopamine can [[neurotoxicity|poison cells]], and there is evidence that this mechanism may contribute to the cell loss that occurs in [[Parkinson's disease]] and other conditions.<ref>{{cite journal | vauthors = Miyazaki I, Asanuma M | title = Dopaminergic neuron-specific oxidative stress caused by dopamine itself | journal = Acta Medica Okayama | volume = 62 | issue = 3 | pages = 141–50 | date = June 2008 | pmid = 18596830 | doi = 10.18926/AMO/30942 | url = http://www.lib.okayama-u.ac.jp/www/acta/pdf/62_3_141.pdf }}</ref>

==Functions==
===Cellular effects===
{{Main|Dopamine receptor|TAAR1}}
{| class="wikitable" style="float:right; margin-left:10px; text-align:center;"
|+[[Biological target|Primary targets]] of dopamine in the human brain<ref name="DA IUPHAR">{{cite web |title=Dopamine: Biological activity |url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=940 |access-date=29 January 2016 |website=IUPHAR/BPS guide to pharmacology |publisher=International Union of Basic and Clinical Pharmacology |language=en-US}}</ref><ref name="Miller+Grandy 2016">{{cite journal | vauthors = Grandy DK, Miller GM, Li JX | title = "TAARgeting Addiction" – The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference | journal = Drug and Alcohol Dependence | volume = 159 | pages = 9–16 | date = February 2016 | pmid = 26644139 | pmc = 4724540 | doi = 10.1016/j.drugalcdep.2015.11.014 | quote = TAAR1 is a high-affinity receptor for METH/AMPH and DA }}</ref>
|-
! scope="col" | Family
! scope="col" | Receptor
! scope="col" | Gene
! scope="col" | Type
! scope="col" | Mechanism
|-
| rowspan=2 | [[D1-like receptor|D<sub>1</sub>-like]]
| [[Dopamine receptor D1|D<sub>1</sub>]]
| {{Gene|DRD1}}
| rowspan=2 | [[Gs alpha subunit|G<sub>s</sub>]]-coupled.
| rowspan=2 | Increase intracellular levels of [[cyclic adenosine monophosphate|cAMP]]<br /> by activating [[adenylate cyclase]].
|-
| [[Dopamine receptor D5|D<sub>5</sub>]]
| {{Gene|DRD5}}
|-
| rowspan=3 | [[D2-like receptor|D<sub>2</sub>-like]]
| [[Dopamine receptor D2|D<sub>2</sub>]]
| {{Gene|DRD2}}
| rowspan=3 | [[Gi alpha subunit|G<sub>i</sub>]]-coupled.
| rowspan=3 | Decrease intracellular levels of [[cyclic adenosine monophosphate|cAMP]]<br /> by inhibiting [[adenylate cyclase]].
|-
| [[Dopamine receptor D3|D<sub>3</sub>]]
| {{Gene|DRD3}}
|-
| [[Dopamine receptor D4|D<sub>4</sub>]]
| {{Gene|DRD4}}
|-
| [[Trace amine-associated receptor|TAAR]]
| [[TAAR1]]
| {{Gene|TAAR1}}
| [[Gs alpha subunit|G<sub>s</sub>]]-coupled.<br />[[Gq alpha subunit|G<sub>q</sub>]]-coupled.
| Increase intracellular levels of [[cyclic adenosine monophosphate|cAMP]]<br /> and intracellular calcium concentration.
|}

Dopamine exerts its effects by binding to and activating [[cell surface receptor]]s.<ref name=Seeman/> In humans, dopamine has a high [[binding affinity]] at [[dopamine receptor]]s and [[human trace amine-associated receptor 1]] (hTAAR1).<ref name="DA IUPHAR" /><ref name="Miller+Grandy 2016" /> In mammals, five subtypes of [[dopamine receptor]]s have been identified, labeled from D<sub>1</sub> to D<sub>5</sub>.<ref name=Seeman>{{cite book| title=The Dopamine Receptors |chapter=Chapter 1: Historical overview: Introduction to the dopamine receptors | vauthors = Seeman P | veditors = Neve K| publisher=Springer |year=2009 |isbn=978-1-60327-333-6 |pages=1–22}}</ref> All of them function as [[metabotropic receptor|metabotropic]], [[G protein-coupled receptor]]s, meaning that they exert their effects via a complex [[second messenger system]].<ref name=Romanelli>{{cite book| title=The Dopamine Receptors |chapter=Chapter 6: Dopamine receptor signalling: intracellular pathways to behavior | vauthors = Romanelli RJ, Williams JT, Neve KA | veditors = Neve KA| publisher = Springer | year = 2009 | isbn = 978-1-60327-333-6 | pages = 137–74}}</ref> These receptors can be divided into two families, known as [[D1-like receptor|D<sub>1</sub>-like]] and [[D2-like receptor|D<sub>2</sub>-like]].<ref name=Seeman/> For receptors located on neurons in the nervous system, the ultimate effect of D<sub>1</sub>-like activation (D<sub>1</sub> and D<sub>5</sub>) can be excitation (via opening of [[sodium channel]]s) or inhibition (via opening of [[potassium channel]]s); the ultimate effect of D<sub>2</sub>-like activation (D<sub>2</sub>, D<sub>3</sub>, and D<sub>4</sub>) is usually inhibition of the target neuron.<ref name=Romanelli/> 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 the second messenger [[Cyclic adenosine monophosphate|cAMP]].<ref name=Romanelli/> D<sub>1</sub> receptors are the most numerous dopamine receptors in the human nervous system; D<sub>2</sub> receptors are next; D<sub>3</sub>, D<sub>4</sub>, and D<sub>5</sub> receptors are present at significantly lower levels.<ref name=Romanelli/>

====Storage, release, and reuptake====
[[File:Dopaminergic synapse.svg|class=skin-invert-image|thumb|right|Dopamine processing in a synapse.  After release, dopamine can either be taken up again by the presynaptic terminal, or broken down by enzymes.<br />TH: [[tyrosine hydroxylase]]<br /> DOPA: [[L-DOPA]]<br /> DAT: [[dopamine transporter]]<br /> DDC: [[DOPA decarboxylase]]<br /> VMAT: [[vesicular monoamine transporter 2]]<br /> MAO: [[Monoamine oxidase]]<br /> COMT: [[Catechol-O-methyl transferase]]<br /> HVA: [[Homovanillic acid]]|alt=Cartoon diagram of a dopaminergic synapse, showing the synthetic and metabolic mechanisms as well as the things that can happen after release.]]
Inside the brain, dopamine functions as a neurotransmitter and [[neuromodulator]], and is controlled by a set of mechanisms common to all [[monoamine neurotransmitter]]s.<ref name=Seeman/> After synthesis, dopamine is transported from the [[cytosol]] into secretory vesicles, including [[synaptic vesicle]]s, small and [[large dense core vesicles]] by a [[solute carrier family|solute carrier]]—a [[vesicular monoamine transporter]], [[vesicular monoamine transporter 2|VMAT2]].<ref name=Eiden>{{cite journal | vauthors = Eiden LE, Schäfer MK, Weihe E, Schütz B | s2cid = 20764857 | title = The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine | journal = Pflügers Archiv | volume = 447 | issue = 5 | pages = 636–40 | date = February 2004 | pmid = 12827358 | doi = 10.1007/s00424-003-1100-5 }}</ref><ref>{{cite journal | vauthors = Westerink RH | title = Targeting exocytosis: ins and outs of the modulation of quantal dopamine release | journal = CNS & Neurological Disorders Drug Targets | volume = 5 | issue = 1 | pages = 57–77 | date = February 2006 | pmid = 16613554 | doi = 10.2174/187152706784111597 | hdl-access = free | hdl = 1874/11642 }}</ref> Dopamine is stored in these vesicles until it is ejected into the [[chemical synapse|synaptic cleft]]. In most cases, the release of dopamine occurs through a process called [[exocytosis]] which is caused by [[action potential]]s, but it can also be caused by the activity of an intracellular [[trace amine-associated receptor]], [[TAAR1]].<ref name="Miller+Grandy 2016" /> TAAR1 is a high-affinity receptor for dopamine, [[trace amine]]s, and certain [[substituted amphetamine]]s that is located along membranes in the intracellular milieu of the presynaptic cell;<ref name="Miller+Grandy 2016" /> activation of the receptor can regulate dopamine signaling by inducing dopamine [[reuptake inhibition]] and [[transporter reversal|efflux]] as well as by inhibiting neuronal firing through a diverse set of mechanisms.<ref name="Miller+Grandy 2016" /><ref name="Miller" />

Once in the synapse, dopamine binds to and activates dopamine receptors.<ref name="D2 Long and short" /> These can be [[chemical synapse|postsynaptic]] dopamine receptors, which are located on [[dendrite]]s (the postsynaptic neuron), or presynaptic [[autoreceptor]]s (e.g., the [[dopamine receptor D2#Isoforms|D<sub>2</sub>sh]] and presynaptic D<sub>3</sub> receptors), which are located on the membrane of an [[axon terminal]] (the presynaptic neuron).<ref name=Seeman/><ref name="D2 Long and short">{{cite journal | vauthors = Beaulieu JM, Gainetdinov RR | s2cid = 2545878 | title = The physiology, signaling, and pharmacology of dopamine receptors | journal = Pharmacological Reviews | volume = 63 | issue = 1 | pages = 182–217 | date = March 2011 | pmid = 21303898 | doi = 10.1124/pr.110.002642 }}</ref> After the postsynaptic neuron elicits an action potential, dopamine molecules quickly become unbound from their receptors. They are then absorbed back into the presynaptic cell, via [[reuptake]] mediated either by the [[dopamine transporter]] or by the [[plasma membrane monoamine transporter]].<ref name=Torres>{{cite journal | vauthors = Torres GE, Gainetdinov RR, Caron MG | s2cid = 21545649 | title = Plasma membrane monoamine transporters: structure, regulation and function | journal = Nature Reviews. Neuroscience | volume = 4 | issue = 1 | pages = 13–25 | date = January 2003 | pmid = 12511858 | doi = 10.1038/nrn1008 }}</ref> Once back in the cytosol, dopamine can either be broken down by a [[monoamine oxidase]] or repackaged into vesicles by VMAT2, making it available for future release.<ref name=Eiden/>

In the brain the level of extracellular dopamine is modulated by two mechanisms: [[Sensory receptor#Rate of adaptation|phasic and tonic transmission]].<ref name="Rice">{{cite journal | vauthors = Rice ME, Patel JC, Cragg SJ | title = Dopamine release in the basal ganglia | journal = Neuroscience | volume = 198 | pages = 112–37 | date = December 2011 | pmid = 21939738 | pmc = 3357127 | doi = 10.1016/j.neuroscience.2011.08.066 }}</ref> Phasic dopamine release, like most neurotransmitter release in the nervous system, is driven directly by action potentials in the dopamine-containing cells.<ref name=Rice/> Tonic dopamine transmission occurs when small amounts of dopamine are released without being preceded by presynaptic action potentials.<ref name=Rice/> Tonic transmission is regulated by a variety of factors, including the activity of other neurons and neurotransmitter reuptake.<ref name=Rice/>

==={{Anchor|Functions in the brain}} Central nervous system===
{{Main|Dopaminergic cell groups|Dopaminergic pathways}}
{{See also|Hypothalamic–pituitary–prolactin axis}}
[[File:Dopamine pathways.svg|thumb|Major dopamine pathways. As part of the reward pathway, dopamine is manufactured in nerve cell bodies located within the [[ventral tegmental area]] (VTA) and is released in the [[nucleus accumbens]] and the [[prefrontal cortex]]. The motor functions of dopamine are linked to a separate pathway, with cell bodies in the [[substantia nigra]] that manufacture and release dopamine into the [[dorsal striatum]].|alt=A labelled line drawing of dopamine pathways superimposed on a drawing of the human brain.]]

Inside the brain, dopamine plays important roles in [[executive function]]s, [[motor control]], [[motivation]], [[arousal]], [[reinforcement]], and [[reward system|reward]], as well as lower-level functions including [[prolactin#Function|lactation]], [[sexual gratification]], and [[nausea]]. The [[dopaminergic cell groups]] and [[dopaminergic pathways|pathways]] make up the dopamine system which is [[neuromodulation|neuromodulatory]].

[[Dopaminergic]] neurons (dopamine-producing nerve cells) are comparatively few in number—a total of around 400,000 in the human brain<ref name=SchultzAnnRev>{{cite journal | vauthors = Schultz W | s2cid = 13503219 | title = Multiple dopamine functions at different time courses | journal = Annual Review of Neuroscience | volume = 30 | pages = 259–88 | year = 2007 | pmid = 17600522 | doi = 10.1146/annurev.neuro.28.061604.135722 }}</ref>—and their [[soma (biology)|cell bodies]] are confined in groups to a few relatively small brain areas.<ref name=Bjorklund/> However their [[axon]]s project to many other brain areas, and they exert powerful effects on their targets.<ref name=Bjorklund/> These dopaminergic cell groups were first mapped in 1964 by [[Annica Dahlström]] and Kjell Fuxe, who assigned them labels starting with the letter "A" (for "aminergic").<ref name=DahlstromFuxe>{{cite journal | vauthors = Dahlstroem A, Fuxe K | 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 | volume = 232 | issue = Suppl | pages = 1–55 | year = 1964 | pmid = 14229500 }}</ref> In their scheme, areas A1 through A7 contain the neurotransmitter norepinephrine, whereas A8 through A14 contain dopamine. The dopaminergic areas they identified are the substantia nigra (groups 8 and 9); the [[ventral tegmental area]] (group 10); the posterior [[hypothalamus]] (group 11); the [[arcuate nucleus]] (group 12); the [[zona incerta]] (group 13) and the [[periventricular nucleus]] (group 14).<ref name=DahlstromFuxe/>

The substantia nigra is a small midbrain area that forms a component of the [[basal ganglia]]. This has two parts—an input area called the [[pars reticulata]] and an output area called the [[pars compacta]]. The dopaminergic neurons are found mainly in the pars compacta (cell group A8) and nearby (group A9).<ref name=Bjorklund>{{cite journal | vauthors = Björklund A, Dunnett SB | s2cid = 14239716 | title = Dopamine neuron systems in the brain: an update | journal = Trends in Neurosciences | volume = 30 | issue = 5 | pages = 194–202 | date = May 2007 | pmid = 17408759 | doi = 10.1016/j.tins.2007.03.006 }}</ref> In humans, the projection of dopaminergic neurons from the substantia nigra pars compacta to the dorsal striatum, termed the ''[[nigrostriatal pathway]]'', plays a significant role in the control of motor function and in learning new [[motor skill]]s.<ref name="Malenka pathways" /> These neurons are especially vulnerable to damage, and when a large number of them die, the result is a [[Parkinsonism|parkinsonian syndrome]].<ref>{{cite journal | vauthors = Christine CW, Aminoff MJ | title = Clinical differentiation of parkinsonian syndromes: prognostic and therapeutic relevance | journal = The American Journal of Medicine | volume = 117 | issue = 6 | pages = 412–19 | date = September 2004 | pmid = 15380498 | doi = 10.1016/j.amjmed.2004.03.032 }}</ref>

The [[ventral tegmental area]] (VTA) is another midbrain area. The most prominent group of VTA dopaminergic neurons projects to the prefrontal cortex via the [[mesocortical pathway]] and another smaller group projects to the nucleus accumbens via the [[mesolimbic pathway]]. Together, these two pathways are collectively termed the ''[[mesocorticolimbic projection]]''.<ref name=Bjorklund/><ref name="Malenka pathways" /> The VTA also sends dopaminergic projections to the [[amygdala]], [[cingulate gyrus]], [[hippocampus]], and [[olfactory bulb]].<ref name=Bjorklund/><ref name="Malenka pathways">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | veditors = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-148127-4 | pages = 147–48, 154–57 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin }}</ref> Mesocorticolimbic neurons play a central role in reward and other aspects of motivation.<ref name="Malenka pathways" /> Accumulating literature shows that dopamine also plays a crucial role in aversive learning through its effects on a number of brain regions.<ref>{{cite journal | vauthors = Fadok JP, Dickerson TM, Palmiter RD | title = Dopamine is necessary for cue-dependent fear conditioning | journal = The Journal of Neuroscience | volume = 29 | issue = 36 | pages = 11089–97 | date = September 2009 | pmid = 19741115 | pmc = 2759996 | doi = 10.1523/JNEUROSCI.1616-09.2009 }}</ref><ref>{{cite journal | vauthors = Tang W, Kochubey O, Kintscher M, Schneggenburger R | title = A VTA to basal amygdala dopamine projection contributes to signal salient somatosensory events during fear learning | journal = The Journal of Neuroscience | pages = JN–RM–1796-19 | date = April 2020 | volume = 40 | issue = 20 | pmid = 32277045 | doi = 10.1523/JNEUROSCI.1796-19.2020 | pmc = 7219297 }}</ref><ref>{{cite journal | vauthors = Jo YS, Heymann G, Zweifel LS | title = Dopamine Neurons Reflect the Uncertainty in Fear Generalization | language = en | journal = Neuron | volume = 100 | issue = 4 | pages = 916–925.e3 | date = November 2018 | pmid = 30318411 | pmc = 6226002 | doi = 10.1016/j.neuron.2018.09.028 }}</ref>

The posterior hypothalamus has dopamine neurons that project to the spinal cord, but their function is not well established.<ref name=Paulus/> There is some evidence that pathology in this area plays a role in restless legs syndrome, a condition in which people have difficulty sleeping due to an overwhelming compulsion to constantly move parts of the body, especially the legs.<ref name=Paulus>{{cite journal | vauthors = 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 Medicine Reviews | volume = 10 | issue = 3 | pages = 185–96 | date = June 2006 | pmid = 16762808 | doi = 10.1016/j.smrv.2006.01.004 }}</ref>

The arcuate nucleus and the periventricular nucleus of the hypothalamus have dopamine neurons that form an important projection—the ''[[tuberoinfundibular pathway]]'' which goes to the [[pituitary gland]], where it influences the secretion of the hormone [[prolactin]].<ref name=BenJonathan/> Dopamine is the primary [[neuroendocrine]] inhibitor of the secretion of [[prolactin]] from the [[anterior pituitary]] gland.<ref name=BenJonathan/> Dopamine produced by neurons in the arcuate nucleus is secreted into the [[hypophyseal portal system]] of the [[median eminence]], which supplies the [[pituitary gland]].<ref name=BenJonathan/> The [[prolactin cell]]s that produce prolactin, in the absence of dopamine, secrete prolactin continuously; dopamine inhibits this secretion.<ref name=BenJonathan>{{cite journal | vauthors = Ben-Jonathan N, Hnasko R | title = Dopamine as a prolactin (PRL) inhibitor | journal = Endocrine Reviews | volume = 22 | issue = 6 | pages = 724–63 | date = December 2001 | pmid = 11739329 | doi = 10.1210/er.22.6.724 | doi-access = free }}</ref>

The zona incerta, grouped between the arcuate and periventricular nuclei, projects to several areas of the hypothalamus, and participates in the control of [[gonadotropin-releasing hormone]], which is necessary to activate the development of the [[male reproductive system|male]] and [[female reproductive system]]s, following puberty.<ref name=BenJonathan/>

An additional group of dopamine-secreting neurons is found in the [[retina]] of the eye.<ref name=Witkovsky/> These neurons are [[retina amacrine cell|amacrine cells]], meaning that they have no axons.<ref name=Witkovsky/> They release dopamine into the extracellular medium, and are specifically active during daylight hours, becoming silent at night.<ref name=Witkovsky/> This retinal dopamine acts to enhance the activity of [[cone cell]]s in the retina while suppressing [[rod cell]]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 name=Witkovsky>{{cite journal | vauthors = Witkovsky P | s2cid = 10354133 | title = Dopamine and retinal function | journal = Documenta Ophthalmologica. Advances in Ophthalmology | volume = 108 | issue = 1 | pages = 17–40 | date = January 2004 | pmid = 15104164 | doi = 10.1023/B:DOOP.0000019487.88486.0a | url = https://zenodo.org/record/891239 }}</ref>

====Basal ganglia====
[[File:Basal ganglia circuits.svg|thumb|right|300px|Main circuits of the [[basal ganglia]]. The dopaminergic pathway from the [[substantia nigra pars compacta]] to the [[striatum]] is shown in light blue.|alt=At the top, a line drawing of a side view of the human brain, with a cross section pulled out showing the basal ganglia structures in color near the center.  At the bottom an expanded line drawing of the basal ganglia structures, showing outlines of each structure and broad arrows for their connection pathways.]]

The largest and most important sources of dopamine in the vertebrate brain are the substantia nigra and ventral tegmental area.<ref name=Bjorklund/> Both structures are components of the midbrain, closely related to each other and functionally similar in many respects.<ref name=Bjorklund/> The largest component of the basal ganglia is the striatum.<ref name=brs>{{cite book |vauthors=Fix JD| title = Neuroanatomy (Board Review Series) |edition=4th |location=Baltimore |publisher=Wulters Kluwer & Lippincott Williams & Wilkins |chapter=Basal Ganglia and the Striatal Motor System |year=2008 |pages=274–81 |isbn=978-0-7817-7245-7}}</ref> The substantia nigra sends a dopaminergic projection to the [[dorsal striatum]], while the ventral tegmental area sends a similar type of dopaminergic projection to the [[ventral striatum]].<ref name=Bjorklund/>

Progress in understanding the functions of the basal ganglia has been slow.<ref name="brs"/> The most popular hypotheses, broadly stated, propose that the basal ganglia play a central role in [[action selection]].<ref name=chakravarthy>{{cite journal | vauthors = Chakravarthy VS, Joseph D, Bapi RS | s2cid = 853119 | title = What do the basal ganglia do? A modeling perspective | journal = Biological Cybernetics | volume = 103 | issue = 3 | pages = 237–53 | date = September 2010 | pmid = 20644953 | doi = 10.1007/s00422-010-0401-y | url = https://www.researchgate.net/publication/45276082 }}</ref> The action selection theory in its simplest form 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 while continuing to inhibit other motor systems that if activated would generate competing behaviors.<ref name=Floresco>{{cite journal | vauthors = Floresco SB | title = The nucleus accumbens: an interface between cognition, emotion, and action | journal = Annual Review of Psychology | volume = 66 | pages = 25–52 | date = January 2015 | pmid = 25251489 | doi = 10.1146/annurev-psych-010213-115159 | s2cid = 28268183 | url = https://www.researchgate.net/publication/266085689 }}</ref> Thus the basal ganglia, in this concept, are responsible for initiating behaviors, but not for determining the details of how they are carried out. In other words, they essentially form a decision-making system.<ref name=Floresco/>

The basal ganglia can be divided into several sectors, and each is involved in controlling particular types of actions.<ref name=Balleine>{{cite journal |vauthors=Balleine BW, Dezfouli A, Ito M, Doya K |s2cid=53148662 |year=2015 |title=Hierarchical control of goal-directed action in the cortical–basal ganglia network |journal=Current Opinion in Behavioral Sciences |volume=5 |pages=1–7 |doi=10.1016/j.cobeha.2015.06.001}}</ref> The ventral sector of the basal ganglia (containing the ventral striatum and ventral tegmental area) operates at the highest level of the hierarchy, selecting actions at the whole-organism level.<ref name=Floresco/> The dorsal sectors (containing the dorsal striatum and substantia nigra) operate at lower levels, selecting the specific muscles and movements that are used to implement a given behavior pattern.<ref name=Balleine/>

Dopamine contributes to the action selection process in at least two important ways. First, it sets the "threshold" for initiating actions.<ref name=chakravarthy/> The higher the level of dopamine activity, the lower the impetus required to evoke a given behavior.<ref name=chakravarthy/> As a consequence, high levels of dopamine lead to high levels of motor activity and [[impulsivity|impulsive behavior]]; low levels of dopamine lead to [[torpor]] and slowed reactions.<ref name=chakravarthy/> Parkinson's disease, in which dopamine levels in the substantia nigra circuit are greatly reduced, is characterized by stiffness and difficulty initiating 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.<ref name=Jankovic/> In the opposite direction, drugs that increase dopamine release, such as cocaine or amphetamine, can produce heightened levels of activity, including, at the extreme, [[psychomotor agitation]] and [[stereotypy|stereotyped movements]].<ref name=Patti>{{cite journal | vauthors = Pattij T, Vanderschuren LJ | title = The neuropharmacology of impulsive behaviour | journal = Trends in Pharmacological Sciences | volume = 29 | issue = 4 | pages = 192–99 | date = April 2008 | pmid = 18304658 | doi = 10.1016/j.tips.2008.01.002 | url = https://www.researchgate.net/publication/5547125 }}</ref>

The second important effect of dopamine is as a "teaching" signal.<ref name=chakravarthy/> When an action 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.<ref name=chakravarthy/> This is a form of [[operant conditioning]], in which dopamine plays the role of a reward signal.<ref name=Floresco/>

====Reward====
[[File:Overview of reward structures in the human brain.jpg|thumb|Illustration of dopaminergic reward structures]]
In the language used to discuss the reward system, ''reward'' is the attractive and motivational property of a stimulus that induces [[appetitive behavior]] (also known as approach behavior) and [[consummatory behavior]].<ref name=Schultz /> A rewarding stimulus is one that can induce the organism to approach it and choose to consume it.<ref name=Schultz /> [[Pleasure]], [[learning]] (e.g., [[classical conditioning|classical]] and [[operant conditioning]]), and approach behavior are the three main functions of reward.<ref name=Schultz /> As an aspect of reward, ''pleasure'' provides a definition of reward;<ref name=Schultz /> however, while all pleasurable stimuli are rewarding, not all rewarding stimuli are pleasurable (e.g., extrinsic rewards like money).<ref name=Schultz /><ref name=Robinson>{{cite journal | vauthors = Robinson TE, Berridge KC | s2cid = 13471436 | title = The neural basis of drug craving: an incentive-sensitization theory of addiction | journal = Brain Research. Brain Research Reviews | volume = 18 | issue = 3 | pages = 247–91 | year = 1993 | pmid = 8401595 | doi = 10.1016/0165-0173(93)90013-p | hdl = 2027.42/30601 | hdl-access = free }}</ref> The motivational or desirable aspect of rewarding stimuli is reflected by the approach behavior that they induce, whereas the pleasure from intrinsic rewards results from consuming them after acquiring them.<ref name=Schultz /> A neuropsychological model which distinguishes these two components of an intrinsically rewarding stimulus is the [[incentive salience]] model, where "wanting" or desire (less commonly, "seeking"<ref name=Wright>{{cite journal | vauthors = Wright JS, Panksepp J | s2cid = 145747459 | year = 2012 | title = An evolutionary framework to understand foraging, wanting, and desire: the neuropsychology of the SEEKING system | journal = Neuropsychoanalysis | volume = 14 | issue = 1 | pages = 5–39 |  doi = 10.1080/15294145.2012.10773683 | url = https://www.researchgate.net/publication/233748400 |access-date=24 September 2015}}</ref>) corresponds to appetitive or approach behavior while "liking" or pleasure corresponds to consummatory behavior.<ref name=Schultz /><ref name="NAcc function" /><ref name="Berridge2">{{cite journal | vauthors = Berridge KC, Robinson TE, Aldridge JW | title = Dissecting components of reward: 'liking', 'wanting', and learning | journal = Current Opinion in Pharmacology | volume = 9 | issue = 1 | pages = 65–73 | date = February 2009 | pmid = 19162544 | pmc = 2756052 | doi = 10.1016/j.coph.2008.12.014 | quote = <!-- Conversely, amplification of 'wanting' without 'liking' has been produced by the activation of dopamine systems by amphetamine or similar catecholamine-activating drugs given systemically or microinjected directly into the nucleus accumbens, or by genetic mutation that raises extracellular levels of dopamine (via knockdown of dopamine transporters in the synapse) in mesocorticolimbic circuits, and by the near-permanent sensitization of mesocorticolimbic-dopamine-related systems by repeated administration of high-doses of addictive drugs (Figure 3–Figure 5) [39•,40•,61•,66]. We have proposed that in susceptible individuals the neural sensitization of incentive salience by drugs of abuse may generate compulsive 'wanting' to take more drugs, whether or not the same drugs are correspondingly 'liked', and thus contribute to addiction [39•,40•,42] (Figure 5).<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756052/figure/F5/ Incentive-sensitization model of addiction] --> }}</ref> In human [[addiction|drug addicts]], "wanting" becomes dissociated with "liking" as the desire to use an addictive drug increases, while the pleasure obtained from consuming it decreases due to [[drug tolerance]].<ref name="NAcc function" />

Within the brain, dopamine functions partly as a global reward signal. An initial dopamine response to a rewarding stimulus encodes information about the [[salience (neuroscience)|salience]], value, and context of a reward.<ref name=Schultz /> In the context of reward-related learning, dopamine also functions as a ''reward prediction error'' signal, that is, the degree to which the value of a reward is unexpected.<ref name=Schultz/> According to this hypothesis proposed by Montague, Dayan, and Sejnowski,<ref>{{cite journal | vauthors = Montague PR, Dayan P, Sejnowski TJ | title = A framework for mesencephalic dopamine systems based on predictive Hebbian learning | journal = The Journal of Neuroscience | volume = 16 | issue = 5 | pages = 1936–47 | date = March 1996 | pmid = 8774460 | pmc = 6578666 | doi = 10.1523/JNEUROSCI.16-05-01936.1996 | doi-access = free }}</ref> rewards that are expected do not produce a second phasic dopamine response in certain dopaminergic cells, but rewards that are unexpected, or greater than expected, produce a short-lasting increase in synaptic dopamine, whereas the omission of an expected reward actually causes dopamine release to drop below its background level.<ref name=Schultz/> The "prediction error" hypothesis has drawn particular interest from computational neuroscientists, because an influential computational-learning method known as [[temporal difference learning]] makes heavy use of a signal that encodes prediction error.<ref name=Schultz/> This confluence of theory and data has led to a fertile interaction between neuroscientists and computer scientists interested in [[machine learning]].<ref name=Schultz/>

Evidence from [[microelectrode]] recordings from the brains of animals shows that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra are strongly activated by a wide variety of rewarding events.<ref name="Schultz">{{cite journal | vauthors = Schultz W | title = Neuronal Reward and Decision Signals: From Theories to Data | journal = Physiological Reviews | volume = 95 | issue = 3 | pages = 853–951 | date = July 2015 | pmid = 26109341 | pmc = 4491543 | doi = 10.1152/physrev.00023.2014 | quote = <!-- Rewards are crucial objects that induce learning, approach behavior, choices, and emotions. Whereas emotions are difficult to investigate in animals, the learning function is mediated by neuronal reward prediction error signals which implement basic constructs of reinforcement learning theory. These signals are found in dopamine neurons, which emit a global reward signal to striatum and frontal cortex, and in specific neurons in striatum, amygdala, and frontal cortex projecting to select neuronal populations&nbsp;... Figure 12. Reward components inducing the two phasic dopamine response components. The initial component (blue) detects the event before having identified its value. It increases with sensory impact (physical salience), novelty (novelty/surprise salience), generalization to rewarded stimuli, and reward context. This component is coded as temporal event prediction error (389). The second component (red) codes reward value (as reward prediction error)&nbsp;... The salience of rewards derives from three principal factors, namely, their physical intensity and impact (physical salience), their novelty and surprise (novelty/surprise salience), and their general motivational impact shared with punishers (motivational salience). A separate form not included in this scheme, incentive salience, primarily addresses dopamine function in addiction and refers only to approach behavior (as opposed to learning) --> }}</ref> These reward-responsive dopamine neurons in the VTA and substantia nigra are crucial for reward-related cognition and serve as the central component of the reward system.<ref name="NAcc function">{{cite book |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |vauthors=Malenka RC, Nestler EJ, Hyman SE |publisher=McGraw-Hill Medical |year=2009 |isbn=978-0-07-148127-4 |veditors=Sydor A, Brown RY |edition=2nd |location=New York |pages=147–48, 366–67, 375–76 |language=en-US |quote=<!-- VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). In this example, dopamine modulates the processing of sensorimotor information in diverse neural circuits to maximize the ability of the organism to obtain future rewards.&nbsp;...<br />The brain reward circuitry that is targeted by addictive drugs normally mediates the pleasure and strengthening of behaviors associated with natural reinforcers, such as food, water, and sexual contact. Dopamine neurons in the VTA are activated by food and water, and dopamine release in the NAc is stimulated by the presence of natural reinforcers, such as food, water, or a sexual partner.&nbsp;...<br />The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement and the modulation of motoric responses to stimuli that satisfy internal homeostatic needs. The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc.&nbsp;... If motivational drive is described in terms of wanting, and hedonic evaluation in terms of liking, it appears that wanting can be dissociated from liking and that dopamine may influence these phenomena differently. Differences between wanting and liking are confirmed in reports by human addicts, who state that their desire for drugs (wanting) increases with continued use even when pleasure (liking) decreases because of tolerance. --><!--&nbsp;... Addictive drugs are rewarding and reinforcing because they act in brain reward pathways to enhance either dopamine release or the effects of dopamine in the NAc or related structures, or because they produce effects similar to dopamine. -->}}</ref><ref name="Hikosaka">{{cite journal | vauthors = Bromberg-Martin ES, Matsumoto M, Hikosaka O | title = Dopamine in motivational control: rewarding, aversive, and alerting | journal = Neuron | volume = 68 | issue = 5 | pages = 815–34 | date = December 2010 | pmid = 21144997 | pmc = 3032992 | doi = 10.1016/j.neuron.2010.11.022 }}</ref><ref name="Striatum">{{cite journal | vauthors = Yager LM, Garcia AF, Wunsch AM, Ferguson SM | title = The ins and outs of the striatum: Role in drug addiction | journal = Neuroscience | volume = 301 | pages = 529–41 | date = August 2015 | pmid = 26116518 | doi = 10.1016/j.neuroscience.2015.06.033 | pmc=4523218}}</ref> The function of dopamine varies in each [[axonal projection]] from the VTA and substantia nigra;<ref name="NAcc function" /> for example, the VTA–[[nucleus accumbens shell]] projection assigns incentive salience ("want") to rewarding stimuli and its associated [[cue reactivity|cues]], the VTA–[[prefrontal cortex]] projection updates the value of different goals in accordance with their incentive salience, the VTA–amygdala and VTA–hippocampus projections mediate the consolidation of reward-related memories, and both the VTA–[[nucleus accumbens core]] and substantia nigra–dorsal striatum pathways are involved in learning motor responses that facilitate the acquisition of rewarding stimuli.<ref name="NAcc function" /><ref name="NAcc core and shell">{{cite journal | vauthors = Saddoris MP, Cacciapaglia F, Wightman RM, Carelli RM | title = Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation | journal = The Journal of Neuroscience | volume = 35 | issue = 33 | pages = 11572–82 | date = August 2015 | pmid = 26290234 | pmc = 4540796 | doi = 10.1523/JNEUROSCI.2344-15.2015 | quote = <!-- Here, we have found that real-time dopamine release within the nucleus accumbens (a primary target of midbrain dopamine neurons) strikingly varies between core and shell subregions. In the core, dopamine dynamics are consistent with learning-based theories (such as reward prediction error) whereas in the shell, dopamine is consistent with motivation-based theories (e.g., incentive salience). --> }}</ref> Some activity within the VTA dopaminergic projections appears to be associated with reward prediction as well.<ref name="NAcc function" /><ref name="NAcc core and shell" />

====Pleasure====
While dopamine has a central role in causing "wanting," associated with the appetitive or approach behavioral responses to rewarding stimuli, detailed studies have shown that dopamine cannot simply be equated with hedonic "liking" or pleasure, as reflected in the consummatory behavioral response.<ref name=Robinson/> Dopamine neurotransmission is involved in some but not all aspects of pleasure-related cognition, since [[pleasure center]]s have been identified both within the dopamine system (i.e., nucleus accumbens shell) and outside the dopamine system (i.e., [[ventral pallidum]] and [[parabrachial nucleus]]).<ref name=Robinson/><ref name=Berridge2/><ref name="Pleasure system">{{cite journal | vauthors = Berridge KC, Kringelbach ML | title = Pleasure systems in the brain | journal = Neuron | volume = 86 | issue = 3 | pages = 646–64 | date = May 2015 | pmid = 25950633 | pmc = 4425246 | doi = 10.1016/j.neuron.2015.02.018 }}</ref> For example, [[Brain stimulation reward|direct electrical stimulation]] of dopamine pathways, using electrodes implanted in the brain, is experienced as pleasurable, and many types of animals are willing to work to obtain it.<ref name=Wise/> [[Antipsychotic drug]]s reduce dopamine levels and tend to cause [[anhedonia]], a diminished ability to experience pleasure.<ref name="Wise2">{{cite journal | vauthors = Wise RA | title = Dopamine and reward: the anhedonia hypothesis 30 years on | journal = Neurotoxicity Research | volume = 14 | issue = 2–3 | pages = 169–83 | date = October 2008 | pmid = 19073424 | pmc = 3155128 | doi = 10.1007/BF03033808 }}</ref> Many types of pleasurable experiences—such as sexual intercourse, eating, and playing video games—increase dopamine release.<ref name="fn5">{{cite journal |vauthors=Arias-Carrión O, Pöppel E |title=Dopamine, learning and reward-seeking behavior |journal=Acta Neurobiol Exp |volume=67 |issue=4 |pages=481–88 |year=2007|doi=10.55782/ane-2007-1664 |pmid=18320725 |doi-access=free }}</ref> All addictive drugs directly or indirectly affect dopamine neurotransmission in the nucleus accumbens;<ref name="NAcc function" /><ref name=Wise/> these drugs increase drug "wanting", leading to compulsive drug use, when repeatedly taken in high doses, presumably through the [[Addiction#Reward sensitization|sensitization of incentive-salience]].<ref name=Berridge2 /> Drugs that increase synaptic dopamine concentrations include [[psychostimulant]]s such as methamphetamine and cocaine. These produce increases in "wanting" behaviors, but do not greatly alter expressions of pleasure or change levels of satiation.<ref name=Berridge2/><ref name=Wise>{{cite journal | vauthors = Wise RA | title = Addictive drugs and brain stimulation reward | journal = Annual Review of Neuroscience | volume = 19 | pages = 319–40 | year = 1996 | pmid = 8833446 | doi = 10.1146/annurev.ne.19.030196.001535 }}</ref> However, [[opiate]] drugs such as heroin and morphine produce increases in expressions of "liking" and "wanting" behaviors.<ref name=Berridge2/> Moreover, animals in which the ventral tegmental 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 expressions indicative of pleasure.<ref>{{cite journal | vauthors = Ikemoto S | title = Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex | journal = Brain Research Reviews | volume = 56 | issue = 1 | pages = 27–78 | date = November 2007 | pmid = 17574681 | pmc = 2134972 | doi = 10.1016/j.brainresrev.2007.05.004 }}</ref>

A clinical study from January 2019 that assessed the effect of a dopamine precursor ([[levodopa]]), dopamine antagonist ([[risperidone]]), and a placebo on reward responses to music&nbsp;– including the degree of pleasure experienced during [[musical chill]]s, as measured by changes in [[electrodermal activity]] as well as subjective ratings&nbsp;– found that the manipulation of dopamine neurotransmission bidirectionally regulates pleasure cognition (specifically, the [[Euphoria#Music-induced|hedonic impact of music]]) in human subjects.<ref name="Dopaminergic control of hedonic impact" /><ref name="Secondary source for 'Dopaminergic control of hedonic impact'" /> This research demonstrated that increased dopamine neurotransmission acts as a ''[[sine qua non]]'' condition for pleasurable hedonic reactions to music in humans.<ref name="Dopaminergic control of hedonic impact">{{cite journal | vauthors = Ferreri L, Mas-Herrero E, Zatorre RJ, Ripollés P, Gomez-Andres A, Alicart H, Olivé G, Marco-Pallarés J, Antonijoan RM, Valle M, Riba J, Rodriguez-Fornells A | title = Dopamine modulates the reward experiences elicited by music | journal = Proceedings of the National Academy of Sciences of the United States of America | year = 2019 | volume = 116| issue = 9| pages = 3793–98 | pmid = 30670642 | pmc = 6397525 | doi = 10.1073/pnas.1811878116 | bibcode = 2019PNAS..116.3793F | quote = Listening to pleasurable music is often accompanied by measurable bodily reactions such as goose bumps or shivers down the spine, commonly called "chills" or "frissons."&nbsp;... Overall, our results straightforwardly revealed that pharmacological interventions bidirectionally modulated the reward responses elicited by music. In particular, we found that risperidone impaired participants' ability to experience musical pleasure, whereas levodopa enhanced it.&nbsp;... Here, in contrast, studying responses to abstract rewards in human subjects, we show that manipulation of dopaminergic transmission affects both the pleasure (i.e., amount of time reporting chills and emotional arousal measured by EDA) and the motivational components of musical reward (money willing to spend). These findings suggest that dopaminergic signaling is a sine qua non condition not only for motivational responses, as has been shown with primary and secondary rewards, but also for hedonic reactions to music. This result supports recent findings showing that dopamine also mediates the perceived pleasantness attained by other types of abstract rewards (37) and challenges previous findings in animal models on primary rewards, such as food (42, 43).|doi-access = free }}</ref><ref name="Secondary source for 'Dopaminergic control of hedonic impact'">{{cite journal | vauthors = Goupil L, Aucouturier JJ | title = Musical pleasure and musical emotions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 9 | pages = 3364–66 | date = February 2019 | pmid = 30770455 | pmc = 6397567 | doi = 10.1073/pnas.1900369116 | bibcode = 2019PNAS..116.3364G | quote = In a pharmacological study published in PNAS, Ferreri et al. (1) present evidence that enhancing or inhibiting dopamine signaling using levodopa or risperidone modulates the pleasure experienced while listening to music.&nbsp;... In a final salvo to establish not only the correlational but also the causal implication of dopamine in musical pleasure, the authors have turned to directly manipulating dopaminergic signaling in the striatum, first by applying excitatory and inhibitory transcranial magnetic stimulation over their participants' left dorsolateral prefrontal cortex, a region known to modulate striatal function (5), and finally, in the current study, by administrating pharmaceutical agents able to alter dopamine synaptic availability (1), both of which influenced perceived pleasure, physiological measures of arousal, and the monetary value assigned to music in the predicted direction.&nbsp;... While the question of the musical expression of emotion has a long history of investigation, including in PNAS (6), and the 1990s psychophysiological strand of research had already established that musical pleasure could activate the autonomic nervous system (7), the authors' demonstration of the implication of the reward system in musical emotions was taken as inaugural proof that these were veridical emotions whose study has full legitimacy to inform the neurobiology of our everyday cognitive, social, and affective functions (8). Incidentally, this line of work, culminating in the article by Ferreri et al. (1), has plausibly done more to attract research funding for the field of music sciences than any other in this community.<br />The evidence of Ferreri et al. (1) provides the latest support for a compelling neurobiological model in which musical pleasure arises from the interaction of ancient reward/valuation systems (striatal–limbic–paralimbic) with more phylogenetically advanced perception/predictions systems (temporofrontal).| doi-access = free }}</ref>

A study published in Nature in 1998 found evidence that playing video games releases dopamine in the human striatum. This dopamine is associated with learning, behavior reinforcement, attention, and [[Sensory-motor coupling|sensorimotor]] integration.<ref>{{cite journal | vauthors = Koepp MJ, Gunn RN, Lawrence AD, Cunningham VJ, Dagher A, Jones T, Brooks DJ, Bench CJ, Grasby PM | title = Evidence for striatal dopamine release during a video game | journal = Nature | volume = 393 | issue = 6682 | pages = 266–268 | date = May 1998 | pmid = 9607763 | doi = 10.1038/30498 | bibcode = 1998Natur.393..266K | s2cid = 205000565 }}</ref> Researchers used [[positron emission tomography]] scans and <sup>11</sup>C-labelled [[raclopride]] to track dopamine levels in the brain during goal-directed motor tasks and found that dopamine release was positively correlated with task performance and was greatest in the [[ventral striatum]]. This was the first study to demonstrate the behavioral conditions under which dopamine is released in humans. It highlights the ability of positron emission tomography to detect [[neurotransmitter]] fluxes during changes in behavior. According to research, potentially problematic video game use is related to personality traits such as low self-esteem and low self-efficacy, anxiety, aggression, and clinical symptoms of depression and anxiety disorders.<ref>{{cite journal | vauthors = von der Heiden JM, Braun B, Müller KW, Egloff B | title = The Association Between Video Gaming and Psychological Functioning | journal = Frontiers in Psychology | volume = 10 | article-number = 1731 | year = 2019 | pmid = 31402891 | pmc = 6676913 | doi = 10.3389/fpsyg.2019.01731 | doi-access = free }}</ref> Additionally, the reasons individuals play video games vary and may include [[coping]], [[socialization]], and personal satisfaction. The [[DSM-5]] defines Internet Gaming Disorder as a mental disorder closely related to Gambling Disorder. This has been supported by some researchers but has also caused controversy.

===Outside the central nervous system===

Dopamine does not cross the blood–brain barrier, so its synthesis and functions in peripheral areas are to a large degree independent of its synthesis and functions in the brain.<ref name="Nice-pharma"/> A substantial amount of dopamine circulates in the bloodstream, but its functions there are not entirely clear.<ref name=Eisenhofer/> Dopamine is found in blood plasma at levels comparable to those of epinephrine, but in humans, over 95% of the dopamine in the plasma is in the form of dopamine [[sulfate]], a conjugate produced by the enzyme [[SULT1A3|sulfotransferase 1A3/1A4]] acting on free dopamine.<ref name=Eisenhofer/> The bulk of this dopamine sulfate is produced in the mesenteric organs.<ref name=Eisenhofer/> The production of dopamine sulfate is thought to be a mechanism for detoxifying dopamine that is ingested as food or produced by the digestive process—levels in the plasma typically rise more than fifty-fold after a meal.<ref name=Eisenhofer/> Dopamine sulfate 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 [[sympathetic nervous system]], the digestive system, or possibly other organs.<ref name=Eisenhofer/> It may act on dopamine receptors in peripheral tissues, or be metabolized, or be converted to norepinephrine by the enzyme [[dopamine beta hydroxylase]], which is released into the bloodstream by the adrenal medulla.<ref name=Eisenhofer/> Some dopamine receptors are located in the walls of arteries, where they act as a [[vasodilation|vasodilator]] and an inhibitor of norepinephrine release from postganglionic sympathetic nerves terminals (dopamine can inhibit norepinephrine release by acting on presynaptic dopamine receptors, and also on presynaptic α-1 receptors, like norepinephrine itself).<ref name=Missale>{{cite journal | vauthors = Missale C, Nash SR, Robinson SW, Jaber M, Caron MG | s2cid = 223462 | title = Dopamine receptors: from structure to function | journal = Physiological Reviews | volume = 78 | issue = 1 | pages = 189–225 | date = January 1998 | pmid = 9457173 | doi = 10.1152/physrev.1998.78.1.189 | url = http://pdfs.semanticscholar.org/a34e/3fc62c3aed64ad85dbaf99a0986b6484225c.pdf | archive-url = https://web.archive.org/web/20190302122655/http://pdfs.semanticscholar.org/a34e/3fc62c3aed64ad85dbaf99a0986b6484225c.pdf | url-status = dead | archive-date = 2019-03-02 }}</ref> These responses might be activated by dopamine released from the [[carotid body]] under conditions of low oxygen, but whether arterial dopamine receptors perform other biologically useful functions is not known.<ref name=Missale/>

Beyond its role in modulating blood flow, there are several peripheral systems in which dopamine circulates within a limited area and performs an [[exocrine gland|exocrine]] or [[paracrine signalling|paracrine]] function.<ref name=Eisenhofer/> The peripheral systems in which dopamine plays an important role include the [[immune system]], the [[kidney]]s and the [[pancreas]].

====Immune system====

In the immune system dopamine acts upon receptors present on immune cells, especially [[lymphocyte]]s.<ref name="Buttarelli">{{cite journal | vauthors = 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 = Current Neuropharmacology | 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 [[spleen]], [[bone marrow]], and [[circulatory system]].<ref name="pmid19896530"/> 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 affords a possible route for interactions between the nervous system and immune system, and may be relevant to some autoimmune disorders.<ref name="pmid19896530">{{cite journal | vauthors = Sarkar C, Basu B, Chakroborty D, Dasgupta PS, Basu S | title = The immunoregulatory role of dopamine: an update | journal = Brain, Behavior, and Immunity | volume = 24 | issue = 4 | pages = 525–28 | date = May 2010 | pmid = 19896530 | pmc = 2856781 | doi = 10.1016/j.bbi.2009.10.015 }}</ref>

====Kidneys====

The renal dopaminergic system is located in the cells of the [[nephron]] in the kidney, where all subtypes of dopamine receptors are present.<ref>{{cite journal | vauthors = Hussain T, Lokhandwala MF | s2cid = 10896819 | title = Renal dopamine receptors and hypertension | journal = Experimental Biology and Medicine | volume = 228 | issue = 2 | pages = 134–42 | date = February 2003 | pmid = 12563019 | doi = 10.1177/153537020322800202 }}<!--|access-date=15 January 2016--></ref> Dopamine is also synthesized there, by [[renal tubule|tubule]] cells, and discharged into the [[tubular fluid]]. Its actions include increasing the blood supply to the kidneys, increasing the [[glomerular filtration rate]], and increasing the excretion of sodium in the urine. Hence, defects in renal dopamine function can lead to reduced sodium excretion and consequently result in the development of [[hypertension|high blood pressure]]. There is strong evidence that faults in the production of dopamine or in the receptors can result in a number of pathologies including [[oxidative stress]], [[edema]], and either genetic or essential hypertension. Oxidative stress can itself cause hypertension.<ref>{{cite journal | vauthors = Choi MR, Kouyoumdzian NM, Rukavina Mikusic NL, Kravetz MC, Rosón MI, Rodríguez Fermepin M, Fernández BE | title = Renal dopaminergic system: Pathophysiological implications and clinical perspectives | journal = World Journal of Nephrology | volume = 4 | issue = 2 | pages = 196–212 | date = May 2015 | pmid = 25949933 | pmc = 4419129 | doi = 10.5527/wjn.v4.i2.196 | doi-access = free }}</ref> Defects in the system can also be caused by genetic factors or high blood pressure.<ref name="pmid11566894">{{cite journal | vauthors = 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 | doi-access = free }}</ref>

====Pancreas====

In the pancreas the role of dopamine is somewhat complex. The pancreas consists of two parts, an [[exocrine component of pancreas|exocrine]] and an [[pancreatic islets|endocrine]] component. The exocrine part synthesizes and secretes [[digestive enzymes]] and other substances, including dopamine, into the small intestine.<ref name=Rubi/> 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 [[gastrointestinal motility]] (the rate at which content moves through the digestive system).<ref name=Rubi>{{cite journal | vauthors = 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 | doi-access = free }}</ref>

The pancreatic islets make up the endocrine part of the pancreas, and synthesize and secrete hormones including [[insulin]] into the bloodstream.<ref name=Rubi/> There is evidence that the [[beta cell]]s in the islets that synthesize insulin contain dopamine receptors, and that dopamine acts to reduce the amount of insulin they release.<ref name=Rubi/> 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/>

==Medical uses==
{{Main|Dopamine (medication)}}
[[File:Dopamine HCl.JPG|thumb|upright=0.75|Dopamine HCl preparation, single dose vial for intravenous administration|alt=Dopamine HCl preparation, single dose vial for intravenous administration.]]

Dopamine as a manufactured [[pharmaceutical drug|medication]] is sold under the trade names Intropin, Dopastat, and Revimine, among others. It is on the [[World Health Organization's List of Essential Medicines]].<ref>{{cite web|title=WHO Model List of Essential Medicines| url=http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf |archive-url=https://web.archive.org/web/20140210093816/http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf |archive-date=2014-02-10 |url-status=live| website=World Health Organization| access-date=24 September 2015| date=October 2013}}</ref> It is most commonly used as a stimulant drug in the treatment of severe [[hypotension|low blood pressure]], [[bradycardia|slow heart rate]], and [[cardiac arrest]]. It is especially important in treating these in [[neonates|newborn infants]].<ref name=Noori>{{cite journal |vauthors=Noori S, Friedlich P, Seri I |year=2003 |title=Pharmacology Review Developmentally Regulated Cardiovascular, Renal, and Neuroendocrine Effects of Dopamine |journal=NeoReviews |volume=4 |issue=10 |pages=e283–e288 |url=https://www.researchgate.net/publication/239322432 |access-date=24 September 2015 |doi=10.1542/neo.4-10-e283|s2cid=71902752 }}</ref><ref name="medscape2021"/> It is given intravenously. Since the half-life of dopamine in plasma is very short—approximately one minute in adults, two minutes in newborn infants and up to five minutes in preterm infants—it is usually given in a continuous intravenous drip 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 = 303–14 | year = 1989 | pmid = 2682552 | doi = 10.1002/j.1875-9114.1989.tb04142.x | s2cid = 25614283 }}</ref>

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]].<ref name=BhattMehta/> At low doses it acts through the sympathetic nervous system to increase [[stroke volume|heart muscle contraction force]] and heart rate, thereby increasing [[cardiac output]] and blood pressure.<ref name="BryantKnights2010"/> Higher doses also cause [[vasoconstriction]] 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 = 779–89 | date = March 2010 | pmid = 20200382 | doi = 10.1056/NEJMoa0907118 | url = http://pdfs.semanticscholar.org/9c4a/b0084f4be06a36c826a1e598ec6593827c9d.pdf | url-status = dead | s2cid = 2208904 | archive-url = https://web.archive.org/web/20190228043236/http://pdfs.semanticscholar.org/9c4a/b0084f4be06a36c826a1e598ec6593827c9d.pdf | archive-date = 2019-02-28 }}</ref> Older literature also describes very low doses thought to improve kidney function without other consequences, but recent 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 = 465–71 | year = 2006 | pmid = 17150046 | doi = 10.1111/j.1525-139X.2006.00208.x | s2cid = 22538344 }}</ref> While some effects result from stimulation of dopamine receptors, the prominent cardiovascular effects result from dopamine acting at [[Alpha-1 adrenergic receptor|α<sub>1</sub>]], [[Β1-adrenergic receptor|β<sub>1</sub>]], and [[Β2 receptor|β<sub>2</sub>]] [[adrenergic receptor]]s as a weak agonist.<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 --> }}</ref><ref>{{cite book | title = Clinical Cardiology: Current Practice Guidelines|url = https://books.google.com/books?id=YytoAgAAQBAJ|publisher = OUP Oxford|year= 2013|isbn = 978-0-19-150851-6 | vauthors = Katritsis DG, Gersh BJ, Camm AJ |quote = Dopamine binds to beta-1, beta-2, alpha-1 and dopaminergic receptors }}</ref><ref>{{cite journal | vauthors = Liapakis G, Chan WC, Papadokostaki M, Javitch JA | title = Synergistic contributions of the functional groups of epinephrine to its affinity and efficacy at the beta2 adrenergic receptor | language = English | journal = Molecular Pharmacology | volume = 65 | issue = 5 | pages = 1181–1190 | date = May 2004 | pmid = 15102946 | doi = 10.1124/mol.65.5.1181 }}</ref>

[[Side effects]] of dopamine include negative effects on kidney function and [[cardiac arrhythmias|irregular heartbeats]].<ref name="BryantKnights2010"/> The [[median lethal dose|LD<sub>50</sub>]], or lethal dose which is expected to prove fatal in 50% of the population, has been found to be: 59&nbsp;mg/kg (mouse; administered [[intravenously]]); 95&nbsp;mg/kg (mouse; administered [[intraperitoneally]]); 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 |edition=11th |page=1552 |publisher=Wiley & Sons |location=Hoboken, NJ |isbn=978-0-471-47662-7}}</ref>

==Disease, disorders, and pharmacology==
{{See also|List of dopaminergic drugs}}

The dopamine system plays a central role in several significant medical conditions, including [[Parkinson's disease]], [[attention deficit hyperactivity disorder]], [[Tourette syndrome]], [[schizophrenia]], [[bipolar disorder]], and [[addiction]]. Aside from dopamine itself, there are many other important drugs that act on dopamine systems in various parts of the brain or body. Some are used for medical or recreational purposes, but [[neurochemist]]s have also developed a variety of research drugs, some of which bind with high affinity to specific types of dopamine receptors and either [[agonist|agonize]] or [[receptor antagonist|antagonize]] their effects, and many that affect other aspects of dopamine physiology,<ref>{{cite book |title=Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy | vauthors = Standaert DG, Walsh RR |chapter=Pharmacology of dopaminergic neurotransmission |pages=186–206 | veditors = Tashjian AH, Armstrong EJ, Golan DE |isbn=978-1-4511-1805-6 |year=2011 |publisher=Lippincott Williams & Wilkins}}</ref> including [[dopamine transporter]] inhibitors, VMAT inhibitors, and [[enzyme inhibitors]].

=== Aging brain ===
{{Main|Aging brain}}
A number of studies have reported an age-related decline in dopamine synthesis and dopamine receptor density (i.e., the number of receptors) in the brain.<ref name="Hof 2009">{{cite book | vauthors = Mobbs CV, Hof PR |title=Handbook of the neuroscience of aging |publisher=Elsevier/Academic Press |location=Amsterdam |year=2009 |isbn=978-0-12-374898-0 |oclc= 299710911 }}</ref> This decline has been shown to occur in the striatum and [[extrastriate cortex|extrastriatal]] regions.<ref>{{cite journal | vauthors = Ota M, Yasuno F, Ito H, Seki C, Nozaki S, Asada T, Suhara T | title = Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with L-[beta-11C]DOPA | journal = Life Sciences | volume = 79 | issue = 8 | pages = 730–36 | date = July 2006 | pmid = 16580023 | doi = 10.1016/j.lfs.2006.02.017 }}</ref> Decreases in the [[Dopamine receptor D1|D<sub>1</sub>]], [[Dopamine receptor D2|D<sub>2</sub>]], and [[Dopamine receptor D3|D<sub>3</sub>]] receptors are well documented.<ref name="Kaasinen 2000">{{cite journal | vauthors = Kaasinen V, Vilkman H, Hietala J, Någren K, Helenius H, Olsson H, Farde L, Rinne J | s2cid = 40871554 | title = Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain | journal = Neurobiology of Aging | volume = 21 | issue = 5 | pages = 683–68 | year = 2000 | pmid = 11016537 | doi = 10.1016/S0197-4580(00)00149-4 }}</ref><ref name="Wang 1998">{{cite journal | vauthors = Wang Y, Chan GL, Holden JE, Dobko T, Mak E, Schulzer M, Huser JM, Snow BJ, Ruth TJ, Calne DB, Stoessl AJ | title = Age-dependent decline of dopamine D1 receptors in human brain: a PET study | journal = Synapse | volume = 30 | issue = 1 | pages = 56–61 | date = September 1998 | pmid = 9704881 | doi = 10.1002/(SICI)1098-2396(199809)30:1<56::AID-SYN7>3.0.CO;2-J | s2cid = 31445572 }}</ref><ref name="Wong 1984">{{cite journal | vauthors = Wong DF, Wagner HN, Dannals RF, Links JM, Frost JJ, Ravert HT, Wilson AA, Rosenbaum AE, Gjedde A, Douglass KH | s2cid = 24278577 | title = Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain | journal = Science | volume = 226 | issue = 4681 | pages = 1393–96 | date = December 1984 | pmid = 6334363 | doi = 10.1126/science.6334363 | bibcode = 1984Sci...226.1393W }}</ref> The reduction of dopamine with aging is thought to be responsible for many neurological symptoms that increase in frequency with age, such as decreased arm swing and increased [[Rigidity (neurology)|rigidity]].<ref name="Wang Snyder 1998">{{cite book | vauthors = Wang E, Snyder SD |year=1998 |title=Handbook of the aging brain |location=San Diego, California |publisher=Academic Press |isbn=978-0-12-734610-6 |oclc=636693117}}</ref> Changes in dopamine levels may also cause age-related changes in cognitive flexibility.<ref name="Wang Snyder 1998"/>

=== Multiple sclerosis ===
Studies reported that dopamine imbalance influences the fatigue in [[multiple sclerosis]].<ref name="Dopamine Imbalance">{{cite journal | vauthors = Dobryakova E, Genova HM, DeLuca J, Wylie GR | title = The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders | journal = Frontiers in Neurology | volume = 6 | pages = 52 | date = 12 March 2015 | pmid = 25814977 | pmc = 4357260 | doi = 10.3389/fneur.2015.00052 | doi-access = free }}</ref> In patients with multiple sclerosis, dopamine inhibits production of [[Interleukin 17|IL-17]] and [[IFN-γ]] by peripheral blood mononuclear cells.<ref>{{cite journal | vauthors = Marino F, Cosentino M | s2cid = 26319461 | title = Multiple sclerosis: Repurposing dopaminergic drugs for MS—the evidence mounts | journal = Nature Reviews. Neurology | volume = 12 | issue = 4 | pages = 191–92 | date = April 2016 | pmid = 27020558 | doi = 10.1038/nrneurol.2016.33 }}</ref>

===Parkinson's disease===

Parkinson's disease is an age-related disorder characterized by [[movement disorder]]s such as stiffness of the body, slowing of movement, and trembling of limbs when they are not in use.<ref name=Jankovic>{{cite journal | vauthors = Jankovic J | title = Parkinson's disease: clinical features and diagnosis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 79 | issue = 4 | pages = 368–76 | date = April 2008 | pmid = 18344392 | doi = 10.1136/jnnp.2007.131045 | url = http://jnnp.bmj.com/content/79/4/368.full | doi-access = free }}</ref> In advanced stages it progresses to [[dementia]] and eventually death.<ref name=Jankovic/> The main symptoms are caused by the loss of dopamine-secreting cells in the substantia nigra.<ref name=Dickson>{{cite book | vauthors = Dickson DV|chapter=Neuropathology of movement disorders | veditors = Tolosa E, Jankovic JJ| title=Parkinson's disease and movement disorders |publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2007 |pages= 271–83 |isbn=978-0-7817-7881-7}}</ref> These dopamine cells are especially vulnerable to damage, and a variety of insults, including [[encephalitis]] (as depicted in the book and movie ''[[Awakenings]]''), repeated sports-related [[concussion]]s, and some forms of chemical poisoning such as [[MPTP]], can lead to substantial cell loss, producing a [[Parkinsonism|parkinsonian syndrome]] that is similar in its main features to Parkinson's disease.<ref name=Tuite>{{cite journal | vauthors = Tuite PJ, Krawczewski K | title = Parkinsonism: a review-of-systems approach to diagnosis | journal = Seminars in Neurology | volume = 27 | issue = 2 | pages = 113–22 | date = April 2007 | pmid = 17390256 | doi = 10.1055/s-2007-971174 | s2cid = 260319916 }}</ref> Most cases of Parkinson's disease, however, are [[idiopathic]], meaning that the cause of cell death cannot be identified.<ref name=Tuite/>

The most widely used treatment for parkinsonism is administration of L-DOPA, the metabolic precursor for dopamine.<ref name="Nice-pharma"/> L-DOPA is converted to dopamine in the brain and various parts of the body by the enzyme DOPA decarboxylase.<ref name=Musacchio/> L-DOPA is used rather than dopamine itself because, unlike dopamine, it is capable of crossing the [[blood–brain barrier]].<ref name="Nice-pharma">{{cite book| chapter=Symptomatic pharmacological therapy in Parkinson's disease| editor=The National Collaborating Centre for Chronic Conditions| title=Parkinson's Disease| chapter-url=http://guidance.nice.org.uk/CG35/Guidance/pdf/English| access-date=24 September 2015| publisher=Royal College of Physicians| location=London| year=2006| isbn=978-1-86016-283-1| pages=59–100| archive-date=24 September 2010| archive-url=https://web.archive.org/web/20100924153546/http://guidance.nice.org.uk/CG35/Guidance/pdf/English| url-status=dead}}</ref> It is often co-administered with an [[enzyme inhibitor]] of peripheral [[decarboxylation]] such as [[carbidopa]] or [[benserazide]], to reduce the amount converted to dopamine in the periphery and thereby increase the amount of L-DOPA that enters the brain.<ref name="Nice-pharma"/> When L-DOPA is administered regularly over a long time period, a variety of unpleasant side effects such as [[dyskinesia]] often begin to appear; even so, it is considered the best available long-term treatment option for most cases of Parkinson's disease.<ref name="Nice-pharma"/>

L-DOPA 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.<ref name="Nice-pharma"/> 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.<ref name="Nice-pharma"/> Other drugs that enhance dopamine function, such as [[bromocriptine]] and [[pergolide]], are also sometimes used to treat Parkinsonism, but in most cases L-DOPA appears to give the best trade-off between positive effects and negative side-effects.<ref name="Nice-pharma"/>

Dopaminergic medications that are used to treat Parkinson's disease are sometimes associated with the development of a [[dopamine dysregulation syndrome]], which involves the overuse of dopaminergic medication and medication-induced compulsive engagement in [[natural reward]]s like gambling and sexual activity.<ref name="Natural and drug addictions">{{cite journal | vauthors = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–22 | date = December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = <!-- Notably, sensitization processes can also translate between drug and non-drug rewards (Fiorino and Phillips, 1999; Avena and Hoebel, 2003b; Robinson and Berridge, 2008). In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008). --> }}</ref><ref name="DDS in PD">{{cite journal | vauthors = Ceravolo R, Frosini D, Rossi C, Bonuccelli U | s2cid = 19277026 | title = Spectrum of addictions in Parkinson's disease: from dopamine dysregulation syndrome to impulse control disorders | journal = Journal of Neurology | volume = 257 | issue = Suppl 2 | pages = S276–83 | date = November 2010 | pmid = 21080189 | doi = 10.1007/s00415-010-5715-0 }}</ref> The latter behaviors are similar to those observed in individuals with a [[behavioral addiction]].<ref name="Natural and drug addictions" />

===Drug addiction and psychostimulants===
{{Main|Addiction}}
[[File:DAT1 regulation.svg|class=skin-invert-image|thumb|right|Cocaine increases dopamine levels by blocking [[dopamine transporter]]s (DAT), which transport dopamine back into a synaptic terminal after it has been emitted.|alt=Diagram describes the mechanisms by which cocaine and amphetamines reduce dopamine transporter activity.]]

[[Cocaine]], substituted amphetamines (including [[methamphetamine]]), [[Adderall]], [[methylphenidate]] (marketed as [[Ritalin]] or [[Concerta]]), and other [[stimulant|psychostimulants]] exert their effects primarily or partly by increasing dopamine levels in the brain by a variety of mechanisms.<ref name=Ghodse/> Cocaine and methylphenidate are dopamine transporter blockers or [[reuptake inhibitor]]s;<ref>{{cite journal | vauthors = Siciliano CA, Jones SR | title = Cocaine Potency at the Dopamine Transporter Tracks Discrete Motivational States During Cocaine Self-Administration | journal = Neuropsychopharmacology | volume = 42 | issue = 9 | pages = 1893–1904 | date = August 2017 | pmid = 28139678 | pmc = 5520781 | doi = 10.1038/npp.2017.24 }}</ref> they [[non-competitive inhibition|non-competitively inhibit]] dopamine reuptake, resulting in increased dopamine concentrations in the synaptic cleft.<ref name=Heal>{{cite journal | vauthors = Heal DJ, Pierce DM | title = Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system | journal = CNS Drugs | volume = 20 | issue = 9 | pages = 713–38 | year = 2006 | pmid = 16953648 | doi = 10.2165/00023210-200620090-00002 | s2cid = 39535277 }}</ref><ref name=Freye>{{cite book| vauthors = Freye E |title=Pharmacology and abuse of cocaine, amphetamines, ecstasy and related designer drugs a comprehensive review on their mode of action, treatment of abuse and intoxication |year=2009 |publisher=Springer |location=Dordrecht |isbn=978-90-481-2448-0}}</ref>{{rp|54–58}} Like cocaine, substituted amphetamines and amphetamine also increase the concentration of dopamine in the [[synaptic cleft]], but by different mechanisms.<ref name="Miller">{{cite journal | vauthors = Miller 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 | volume = 116 | issue = 2 | pages = 164–76 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}</ref><ref name=Freye/>{{rp|147–150}}

The effects of psychostimulants include increases in heart rate, body temperature, and sweating; improvements in alertness, attention, and endurance; increases in pleasure produced by rewarding events; but at higher doses agitation, anxiety, or even [[psychosis|loss of contact with reality]].<ref name=Ghodse>{{cite book | vauthors = Ghodse H|title=Ghodse's Drugs and Addictive Behaviour: A Guide to Treatment |date=2010 |publisher=Cambridge University Press |isbn=978-1-139-48567-8|pages=87–92|edition=4th}}</ref> Drugs in this group can have a high addiction potential, due to their activating effects on the dopamine-mediated reward system in the brain.<ref name=Ghodse/> However some can also be useful, at lower doses, for treating attention deficit hyperactivity disorder (ADHD) and [[narcolepsy]].<ref name=Kimko/><ref>{{cite journal | vauthors = Mignot EJ | title = A practical guide to the therapy of narcolepsy and hypersomnia syndromes | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 739–52 | date = October 2012 | pmid = 23065655 | pmc = 3480574 | doi = 10.1007/s13311-012-0150-9 }}</ref> An important differentiating factor is the onset and duration of action.<ref name=Ghodse/> Cocaine can take effect in seconds if it is injected or inhaled in free base form; the effects last from 5 to 90 minutes.<ref name=Zimmerman>{{cite journal | vauthors = Zimmerman JL | title = Cocaine intoxication | journal = Critical Care Clinics | volume = 28 | issue = 4 | pages = 517–26 | date = October 2012 | pmid = 22998988 | doi = 10.1016/j.ccc.2012.07.003 }}</ref> This rapid and brief action makes its effects easily perceived and consequently gives it high addiction potential.<ref name=Ghodse/> Methylphenidate taken in pill form, in contrast, can take two hours to reach peak levels in the bloodstream,<ref name=Kimko>{{cite journal | vauthors = Kimko HC, Cross JT, Abernethy DR | s2cid = 397390 | title = Pharmacokinetics and clinical effectiveness of methylphenidate | journal = Clinical Pharmacokinetics | volume = 37 | issue = 6 | pages = 457–70 | date = December 1999 | pmid = 10628897 | doi = 10.2165/00003088-199937060-00002 }}</ref> and depending on formulation the effects can last for up to 12&nbsp;hours.<ref>{{Cite web|title=Quillivant XR – methylphenidate hydrochloride suspension, extended release |url= https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e0157005-6e3e-4763-b910-9eb0937608c9 |access-date=2020-07-11|website=dailymed.nlm.nih.gov}}</ref> These longer acting formulations have the benefit of reducing the potential for abuse, and improving adherence for treatment by using more convenient dosage regimens.<ref>{{cite journal | vauthors = López FA, Leroux JR | title = Long-acting stimulants for treatment of attention-deficit/hyperactivity disorder: a focus on extended-release formulations and the prodrug lisdexamfetamine dimesylate to address continuing clinical challenges | journal = Attention Deficit and Hyperactivity Disorders | volume = 5 | issue = 3 | pages = 249–65 | date = September 2013 | pmid = 23564273 | pmc = 3751218 | doi = 10.1007/s12402-013-0106-x }}</ref>

[[File:Crystal Meth Rock.jpg|thumb|right|[[Methamphetamine#Physical properties|Methamphetamine hydrochloride]] also known as crystal meth|alt=A shiny translucent white crystal of methamphetamine, held between the ends of a finger and thumb]]
A variety of addictive drugs produce an increase in reward-related dopamine activity.<ref name=Ghodse/> Stimulants such as [[nicotine]], cocaine and methamphetamine promote increased levels of dopamine which appear to be the primary factor in causing addiction. For other addictive drugs such as the [[opioid]] heroin, the increased levels of dopamine in the reward system may play only a minor role in addiction.<ref name=Nutt>{{cite journal | vauthors = Nutt DJ, Lingford-Hughes A, Erritzoe D, Stokes PR | s2cid = 205511111 | title = The dopamine theory of addiction: 40 years of highs and lows | journal = Nature Reviews. Neuroscience | volume = 16 | issue = 5 | pages = 305–12 | date = May 2015 | pmid = 25873042 | doi = 10.1038/nrn3939 | url = https://kclpure.kcl.ac.uk/ws/files/44680387/Nutt_and_Stokes_Nature_Reviews_Neuroscience_2015_institutional_repository.pdf }}</ref> When people addicted to stimulants go through withdrawal, they do not experience the physical suffering associated with [[alcohol withdrawal syndrome|alcohol withdrawal]] or [[drug withdrawal|withdrawal]] from opiates; instead they experience craving, an intense desire for the drug characterized by irritability, restlessness, and other arousal symptoms,<ref name="Sinha">{{cite journal | vauthors = Sinha R | title = The clinical neurobiology of drug craving | journal = Current Opinion in Neurobiology | volume = 23 | issue = 4 | pages = 649–54 | date = August 2013 | pmid = 23764204 | pmc = 3735834 | doi = 10.1016/j.conb.2013.05.001 }}</ref> brought about by [[psychological dependence]].

The dopamine system plays a crucial role in several aspects of addiction. At the earliest stage, genetic differences that alter the expression of dopamine receptors in the brain can predict whether a person will find stimulants appealing or aversive.<ref name="Volkow">{{cite journal | vauthors = Volkow ND, Baler RD | title = Addiction science: Uncovering neurobiological complexity | journal = Neuropharmacology | volume = 76 | issue= Pt B | pages = 235–49 | date = January 2014 | pmid = 23688927 | pmc = 3818510 | doi = 10.1016/j.neuropharm.2013.05.007 }}</ref> Consumption of stimulants produces increases in brain dopamine levels that last from minutes to hours.<ref name=Ghodse/> Finally, the chronic elevation in dopamine that comes with repetitive high-dose stimulant consumption triggers a wide-ranging set of structural changes in the brain that are responsible for the behavioral abnormalities which characterize an addiction.<ref name="Nestler">{{cite journal | vauthors = Nestler EJ | title = Transcriptional mechanisms of drug addiction | journal = Clinical Psychopharmacology and Neuroscience | volume = 10 | issue = 3 | pages = 136–43 | date = December 2012 | pmid = 23430970 | pmc = 3569166 | doi = 10.9758/cpn.2012.10.3.136 }}</ref> Treatment of stimulant addiction is very difficult, because even if consumption ceases, the craving that comes with psychological withdrawal does not.<ref name=Sinha/> Even when the craving seems to be extinct, it may re-emerge when faced with stimuli that are associated with the drug, such as friends, locations and situations.<ref name=Sinha/> [[Cerebral cortex#Association areas|Association networks]] in the brain are greatly interlinked.<ref>{{cite journal | vauthors = Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, Roffman JL, Smoller JW, Zöllei L, Polimeni JR, Fischl B, Liu H, Buckner RL | title = The organization of the human cerebral cortex estimated by intrinsic functional connectivity | journal = Journal of Neurophysiology | volume = 106 | issue = 3 | pages = 1125–65 | date = September 2011 | pmid = 21653723 | pmc = 3174820 | doi = 10.1152/jn.00338.2011 }}</ref>

===Psychosis and antipsychotic drugs===
{{Main|Psychosis}}
Psychiatrists in the early 1950s discovered that a class of drugs known as [[typical antipsychotic]]s (also known as major [[tranquilizer]]s), were often effective at reducing the [[psychotic]] symptoms of schizophrenia.<ref name=Healy/> The introduction of the first widely used antipsychotic, [[chlorpromazine]] (Thorazine), in the 1950s, led to the release of many patients with schizophrenia from institutions in the years that followed.<ref name=Healy/> By the 1970s researchers understood that these typical antipsychotics worked as [[receptor antagonists|antagonists]] on the D<sub>2</sub> receptors.<ref name=Healy/><ref name=Brunton>{{cite book | vauthors = Brunton L | title = Goodman and Gilman's The Pharmacological Basis of Therapeutics|publisher=McGraw Hill|pages=417–55|edition=12th}}</ref> This realization led to the so-called [[dopamine hypothesis of schizophrenia]], which postulates that schizophrenia is largely caused by hyperactivity of brain dopamine systems.<ref name="Howes">{{cite journal | vauthors = Howes OD, Kapur S | title = The dopamine hypothesis of schizophrenia: version III—the final common pathway | journal = Schizophrenia Bulletin | volume = 35 | issue = 3 | pages = 549–62 | date = May 2009 | pmid = 19325164 | pmc = 2669582 | doi = 10.1093/schbul/sbp006 }}</ref> The dopamine hypothesis drew additional support from the observation that psychotic symptoms were often intensified by dopamine-enhancing stimulants such as methamphetamine, and that these drugs could also produce psychosis in healthy people if taken in large enough doses.<ref name=Howes/> In the following decades other [[atypical antipsychotics]] that had fewer serious side effects were developed.<ref name=Healy/> Many of these newer drugs do not act directly on dopamine receptors, but instead produce alterations in dopamine activity indirectly.<ref name=Horacek>{{cite journal | vauthors = Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, Höschl C | s2cid = 18226404 | title = Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia | journal = CNS Drugs | volume = 20 | issue = 5 | pages = 389–409 | year = 2006 | pmid = 16696579 | doi = 10.2165/00023210-200620050-00004 }}</ref> These drugs were also used to treat other psychoses.<ref name=Healy>{{Cite book |title=The Creation of Psychopharmacology | vauthors = Healy D |year=2004 |publisher=Harvard University Press |pages=37–73  |isbn=978-0-674-01599-9 }}</ref> [[Antipsychotic drugs]] have a broadly suppressive effect on most types of active behavior, and particularly reduce the delusional and agitated behavior characteristic of overt psychosis.<ref name=Brunton/>

Later observations, however, have caused the dopamine hypothesis to lose popularity, at least in its simple original form.<ref name=Howes/> For one thing, patients with schizophrenia do not typically show measurably increased levels of brain dopamine activity.<ref name=Howes/> Even so, many psychiatrists and neuroscientists continue to believe that schizophrenia involves some sort of dopamine system dysfunction.<ref name=Healy/> As the "dopamine hypothesis" has evolved over time, however, the sorts of dysfunctions it postulates have tended to become increasingly subtle and complex.<ref name=Healy/>

[[Psychopharmacology|Psychopharmacologist]] [[Stephen Stahl|Stephen M. Stahl]] suggested in a review of 2018 that in many cases of psychosis, including schizophrenia, three interconnected networks based on dopamine, serotonin, and glutamate – each on its own or in various combinations – contributed to an overexcitation of dopamine D<sub>2</sub> receptors in the [[ventral striatum]].<ref name="pmid29954475">{{cite journal| vauthors = Stahl SM| title=Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate. | journal=CNS Spectr | year= 2018 | volume= 23 | issue= 3 | pages= 187–91 | pmid=29954475 | doi=10.1017/S1092852918001013 | s2cid=49599226 | url=https://www.cambridge.org/core/services/aop-cambridge-core/content/view/3E9E50ED717219011DD1B570365010E8/S1092852918001013a.pdf/beyond_the_dopamine_hypothesis_of_schizophrenia_to_three_neural_networks_of_psychosis_dopamine_serotonin_and_glutamate.pdf |archive-url=https://web.archive.org/web/20200429212444/https://www.cambridge.org/core/services/aop-cambridge-core/content/view/3E9E50ED717219011DD1B570365010E8/S1092852918001013a.pdf/beyond_the_dopamine_hypothesis_of_schizophrenia_to_three_neural_networks_of_psychosis_dopamine_serotonin_and_glutamate.pdf |archive-date=2020-04-29 |url-status=live }}</ref>

===Attention deficit hyperactivity disorder===
{{Main|Attention deficit hyperactivity disorder}}
Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder (ADHD), a condition associated with impaired [[cognitive control]], in turn leading to problems with regulating attention ([[attentional control]]), inhibiting behaviors ([[inhibitory control]]), and forgetting things or missing details ([[working memory]]), among other problems.<ref name="Malenka ADHD neurosci">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | veditors = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-148127-4 | pages = 266, 318–23 | edition = 2nd | chapter = Chapters 10 and 13}}</ref> There are genetic links between dopamine receptors, the dopamine transporter, and ADHD, in addition to links to other neurotransmitter receptors and transporters.<ref name=Wu>{{cite journal | vauthors = Wu J, Xiao H, Sun H, Zou L, Zhu LQ | s2cid = 895006 | title = Role of dopamine receptors in ADHD: a systematic meta-analysis | journal = Molecular Neurobiology | volume = 45 | issue = 3 | pages = 605–20 | date = June 2012 | pmid = 22610946 | doi = 10.1007/s12035-012-8278-5 }}</ref> The most important relationship between dopamine and ADHD involves the drugs that are used to treat ADHD.<ref name=Berridge3/> Some of the most effective therapeutic agents for ADHD are psychostimulants such as methylphenidate (Ritalin, Concerta) and [[amphetamine]] (Evekeo, Adderall, Dexedrine), drugs that increase both dopamine and norepinephrine levels in the brain.<ref name="Berridge3">{{cite journal | vauthors = Berridge CW, Devilbiss DM | title = Psychostimulants as cognitive enhancers: the prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder | journal = Biological Psychiatry | volume = 69 | issue = 12 | pages = e101–11 | date = June 2011 | pmid = 20875636 | pmc = 3012746 | doi = 10.1016/j.biopsych.2010.06.023 }}</ref> The clinical effects of these psychostimulants in treating ADHD are mediated through the [[indirect agonist|indirect activation]] of dopamine and norepinephrine receptors, specifically [[Dopamine receptor D1|dopamine receptor D<sub>1</sub>]] and [[Alpha-2 adrenergic receptor|adrenoceptor α<sub>2</sub>]], in the prefrontal cortex.<ref name="Malenka ADHD neurosci" /><ref name="Unambiguous PFC D1 A2">{{cite journal | vauthors = Spencer RC, Devilbiss DM, Berridge CW | title = The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex | journal = Biological Psychiatry | volume = 77 | issue = 11 | pages = 940–50 | date = June 2015 | pmid = 25499957 | pmc = 4377121 | doi = 10.1016/j.biopsych.2014.09.013 }}</ref><ref name="Cognitive and motivational effects">{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | s2cid = 15788121 | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = Journal of Cognitive Neuroscience | volume = 27 | issue = 6 | pages = 1069–89 | date = June 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776 | url = https://repository.upenn.edu/neuroethics_pubs/130 | url-access = subscription }}</ref>

===Pain===
Dopamine plays a role in [[pain]] processing in multiple levels of the central nervous system including the spinal cord, [[periaqueductal gray]], [[thalamus]], basal ganglia, and [[cingulate cortex]].<ref name="Wood" /> Decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson's disease.<ref name="Wood" /> Abnormalities in dopaminergic neurotransmission also occur in several painful clinical conditions, including [[burning mouth syndrome]], [[fibromyalgia]], and restless legs syndrome.<ref name=Wood>{{cite journal | vauthors = Wood PB | s2cid = 24325199 | title = Role of central dopamine in pain and analgesia | journal = Expert Review of Neurotherapeutics | volume = 8 | issue = 5 | pages = 781–97 | date = May 2008 | pmid = 18457535 | doi = 10.1586/14737175.8.5.781 }}</ref>

===Nausea===
Nausea and [[vomiting]] are largely determined by activity in the [[area postrema]] in the [[medulla oblongata|medulla]] of the [[brainstem]], in a region known as the [[chemoreceptor trigger zone]].<ref name=Flake>{{cite journal | vauthors = Flake ZA, Scalley RD, Bailey AG | title = Practical selection of antiemetics | journal = American Family Physician | volume = 69 | issue = 5 | pages = 1169–74 | date = March 2004 | pmid = 15023018 | url = http://www.aafp.org/afp/2004/0301/p1169.html }}</ref> This area contains a large population of type D<sub>2</sub> dopamine receptors.<ref name=Flake/> Consequently, drugs that activate D<sub>2</sub> receptors have a high potential to cause nausea.<ref name=Flake/> This group includes some medications that are administered for Parkinson's disease, as well as other [[dopamine agonists]] such as [[apomorphine]].<ref name=Connolly>{{cite journal | vauthors = Connolly BS, Lang AE | title = Pharmacological treatment of Parkinson disease: a review | journal = JAMA | volume = 311 | issue = 16 | pages = 1670–83 | year = 2014 | pmid = 24756517 | doi = 10.1001/jama.2014.3654 }}</ref> In some cases, D<sub>2</sub>-receptor antagonists such as [[metoclopramide]] are useful as [[anti-emetics|anti-nausea drugs]].<ref name=Flake/>

'''Fear and anxiety'''

Simultaneous [[positron emission tomography]] (PET) and [[functional magnetic resonance imaging]] (fMRI), have shown that the amount of dopamine release is dependent on the strength of conditioned fear response and is linearly coupled to learning-induced activity in the amygdala.<ref>{{cite journal | vauthors = Frick A, Björkstrand J, Lubberink M, Eriksson A, Fredrikson M, Åhs F | title = Dopamine and fear memory formation in the human amygdala | journal = Molecular Psychiatry | volume = 27 | issue = 3 | pages = 1704–1711 | date = March 2022 | pmid = 34862441 | doi = 10.1038/s41380-021-01400-x | pmc = 9095491 }}</ref> Dopamine is generally linked to reward learning, but it also plays a key role in fear learning and extinction by helping to form, store and update fear memories through its interaction with other brain regions like amygdala, ventromedial prefrontal cortex and striatum.<ref>{{cite journal | vauthors = Hamati R, Ahrens J, Shvetz C, Holahan MR, Tuominen L | title = 65 years of research on dopamine's role in classical fear conditioning and extinction: A systematic review | journal = The European Journal of Neuroscience | volume = 59 | issue = 6 | pages = 1099–1140 | date = March 2024 | pmid = 37848184 | doi = 10.1111/ejn.16157 | doi-access = free }}</ref>

==Comparative biology and evolution==
===Microorganisms===
There are no reports of dopamine in [[archaea]], but it has been detected in some types of [[bacteria]] and in the [[protozoa]]n called ''[[Tetrahymena]]''.<ref>{{cite book | vauthors = Roshchina VV |year=2010 |chapter=Evolutionary considerations of neurotransmitters in microbial, plant, and animal cells |title=Microbial Endocrinology |pages=17–52 | veditors = Lyte M, Primrose PE |publisher=Springer |location=New York |isbn=978-1-4419-5576-0}}</ref> Perhaps more importantly, there are types of bacteria that contain [[homology (biology)|homologs]] of all the enzymes that animals use to synthesize dopamine.<ref name=Iyer/> It has been proposed that animals derived their dopamine-synthesizing machinery from bacteria, via [[horizontal gene transfer]] that may have occurred relatively late in evolutionary time, perhaps as a result of the [[symbiotic]] incorporation of bacteria into [[eukaryote|eukaryotic]] cells that gave rise to [[mitochondrion|mitochondria]].<ref name=Iyer>{{cite journal | vauthors = 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 in Genetics | volume = 20 | issue = 7 | pages = 292–99 | date = July 2004 | pmid = 15219393 | doi = 10.1016/j.tig.2004.05.007 }}</ref>

===Animals===
Dopamine is used as a neurotransmitter in most multicellular animals.<ref name=Barron/> In [[sponge]]s there is only a single report 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=154–63 |vauthors=Liu H, Mishima Y, Fujiwara T, Nagai H, Kitazawa A, Mine Y, etal |doi=10.3390/md204154|pmc=3783253 |doi-access=free }}</ref> however, dopamine has been reported in the nervous systems of many other [[symmetry in biology#radially symmetric|radially symmetric]] species, including the [[cnidarian]] [[jellyfish]], [[hydra (genus)|hydra]] and some [[coral]]s.<ref>{{cite journal | vauthors = Kass-Simon G, Pierobon P | title = Cnidarian chemical neurotransmission, an updated overview | journal = Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology | volume = 146 | issue = 1 | pages = 9–25 | date = January 2007 | pmid = 17101286 | doi = 10.1016/j.cbpa.2006.09.008 | url = https://digitalcommons.uri.edu/bio_facpubs/380 }}</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 [[Cambrian]] Period. Dopamine functions as a neurotransmitter in [[vertebrate]]s, [[echinoderm]]s, [[arthropod]]s, [[mollusca|molluscs]], and several types of [[worm]].<ref name="Cottrell">{{cite journal | vauthors = Cottrell GA | title = Occurrence of dopamine and noradrenaline in the nervous tissue of some invertebrate species | journal = British Journal of Pharmacology and Chemotherapy | volume = 29 | issue = 1 | pages = 63–69 | date = January 1967 | pmid = 19108240 | pmc = 1557178 | doi = 10.1111/j.1476-5381.1967.tb01939.x }}</ref><ref>{{cite journal | vauthors = Kindt KS, Quast KB, Giles AC, De S, Hendrey D, Nicastro I, Rankin CH, Schafer WR | s2cid = 2092645 | 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 | doi-access = free }}</ref>

In every type of animal that has been examined, dopamine has been seen to modify motor behavior.<ref name="Barron">{{cite journal | vauthors = Barron AB, Søvik E, Cornish JL | title = The roles of dopamine and related compounds in reward-seeking behavior across animal phyla | journal = Frontiers in Behavioral Neuroscience | volume = 4 | pages = 163 | year = 2010 | pmid = 21048897 | pmc = 2967375 | doi = 10.3389/fnbeh.2010.00163 | doi-access = free }}</ref> In the [[model organism]], [[nematode]] ''[[Caenorhabditis elegans]]'', it reduces [[animal locomotion|locomotion]] and increases food-exploratory movements; in [[flatworm]]s it produces "screw-like" movements; in [[leech]]es it inhibits swimming and promotes crawling. 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/><ref>{{cite journal | vauthors = Kalivas PW, Stewart J | s2cid = 10775295 | title = Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity | journal = Brain Research. Brain Research Reviews | volume = 16 | issue = 3 | pages = 223–44 | date = 1 September 1991 | pmid = 1665095 | doi = 10.1016/0165-0173(91)90007-U }}</ref>

Dopamine has also consistently been shown to play a role in reward learning, in all animal groups.<ref name=Barron/> As in all vertebrates – [[invertebrate]]s such as [[Nematodes|roundworms]], [[flatworm]]s, [[mollusc]]s and [[Drosophila melanogaster|common fruit flies]] can all be trained to repeat an action if it is consistently followed by an increase in dopamine levels.<ref name="Barron"/> In [[Drosophila melanogaster|fruit flies]], distinct elements for reward learning suggest a modular structure to the insect reward processing system that broadly parallels that in the mammalian one.<ref>{{cite journal | vauthors = Perry CJ, Barron AB | s2cid = 19678766 | title = Neural mechanisms of reward in insects | journal = Annual Review of Entomology | volume = 58 | issue = 1 | pages = 543–62 | date = 2013 | pmid = 23020615 | doi = 10.1146/annurev-ento-120811-153631 | url = http://pdfs.semanticscholar.org/5526/26c5fe0572b4d6419555a1976877c757b0da.pdf | archive-url = https://web.archive.org/web/20200605184440/http://pdfs.semanticscholar.org/5526/26c5fe0572b4d6419555a1976877c757b0da.pdf | url-status = dead | archive-date = 2020-06-05 }}</ref> For example, dopamine regulates short- and long-term learning in monkeys;<ref>{{cite journal | vauthors = Takikawa Y, Kawagoe R, Hikosaka O | title = A possible role of midbrain dopamine neurons in short- and long-term adaptation of saccades to position-reward mapping | journal = Journal of Neurophysiology | volume = 92 | issue = 4 | pages = 2520–29 | date = October 2004 | pmid = 15163669 | doi = 10.1152/jn.00238.2004 | s2cid = 12534057 | url = http://pdfs.semanticscholar.org/b8a6/84a6d815d43db0b2491e4d3db5c664970e6e.pdf | archive-url = https://web.archive.org/web/20190302163535/http://pdfs.semanticscholar.org/b8a6/84a6d815d43db0b2491e4d3db5c664970e6e.pdf | url-status = dead | archive-date = 2019-03-02 }}</ref> in fruit flies, different groups of dopamine neurons mediate reward signals for short- and long-term memories.<ref>{{cite journal | vauthors = Yamagata N, Ichinose T, Aso Y, Plaçais PY, Friedrich AB, Sima RJ, Preat T, Rubin GM, Tanimoto H | title = Distinct dopamine neurons mediate reward signals for short- and long-term memories | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 2 | pages = 578–83 | date = January 2015 | pmid = 25548178 | doi = 10.1073/pnas.1421930112 | pmc = 4299218 | bibcode = 2015PNAS..112..578Y | doi-access = free }}</ref>

It had long been believed that arthropods were an exception to this with dopamine being seen as having an adverse effect. Reward was seen to be mediated instead by [[octopamine]], a neurotransmitter closely related to [[norepinephrine]].<ref name=Waddell/> More recent studies, however, have shown that dopamine does play a part in reward learning in fruit flies. It has also been found that the rewarding effect of octopamine is due to its activating a set of dopaminergic neurons not previously accessed in the research.<ref name="Waddell">{{cite journal | vauthors = Waddell S | title = Reinforcement signalling in Drosophila; dopamine does it all after all | journal = Current Opinion in Neurobiology | volume = 23 | issue = 3 | pages = 324–329 | date = June 2013 | pmid = 23391527 | pmc = 3887340 | doi = 10.1016/j.conb.2013.01.005 }}</ref> Dopamine can also be found in [[cephalopod ink]].<ref>{{cite journal | vauthors = Lucero MT, Farrington H, Gilly WF | title = Quantification of L-Dopa and Dopamine in Squid Ink: Implications for Chemoreception | journal = The Biological Bulletin | volume = 187 | issue = 1 | pages = 55–63 | date = August 1994 | pmid = 29281314 | doi = 10.2307/1542165 | jstor = 1542165 }}</ref>

===Plants===

[[File:Bananas white background DS.jpg|thumb|right|Dopamine can be found in the [[Banana peel|peel]] and fruit pulp of [[bananas]].|alt=Photo of a bunch of bananas.]]

Many plants, including a variety of food plants, synthesize dopamine to varying degrees.<ref name=Kulma/> The highest concentrations have been observed in bananas—the fruit pulp of [[red banana|red]] and [[Cavendish banana|yellow bananas]] contains dopamine at levels of 40 to 50 parts per million by weight.<ref name=Kulma/> Potatoes, avocados, broccoli, and Brussels sprouts 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 |vauthors=Kulma A, Szopa J |title=Catecholamines are active compounds in plants |journal=Plant Science |year=2007 |volume=172 |pages=433–40 |doi=10.1016/j.plantsci.2006.10.013 |issue=3|bibcode=2007PlnSc.172..433K }}</ref> The dopamine in plants is synthesized from the amino acid [[tyrosine]], by biochemical mechanisms similar to those that animals use.<ref name=Kulma/> It can be metabolized in a variety of ways, producing [[melanin]] and a variety of [[alkaloid]]s as byproducts.<ref name=Kulma/> The functions of plant [[catecholamine]]s 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 blood–brain barrier.<ref name="Nice-pharma"/> However, there are also a variety of plants that contain L-DOPA, the metabolic precursor of dopamine.<ref name=Ingle>{{cite journal | vauthors = Ingle PK |year=2003 |title=L-DOPA bearing plants |journal=Natural Product Radiance |volume=2 |pages=126–33 |url=http://nopr.niscair.res.in/bitstream/123456789/12261/1/NPR%202%283%29%20126-133.pdf |archive-url=https://web.archive.org/web/20140302114720/http://nopr.niscair.res.in/bitstream/123456789/12261/1/NPR%202%283%29%20126-133.pdf |archive-date=2014-03-02 |url-status=live |access-date=24 September 2015}}</ref> The highest concentrations are found in the leaves and bean pods of plants of the genus ''[[Mucuna]]'', especially in ''[[Mucuna pruriens]]'' (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=259–64 |doi=10.1007/BF02319010 | vauthors = Wichers HJ, Visser JF, Huizing HJ, Pras N|bibcode=1993PCTOC..33..259W |s2cid=44814336 }}</ref> Another plant containing substantial amounts of L-DOPA is ''[[Vicia faba]]'', 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 | vauthors = Longo R, Castellani A, Sberze P, Tibolla M | title = Distribution of l-dopa and related amino acids in Vicia | journal = Phytochemistry | year = 1974 | volume = 13 | issue = 1 | pages = 167–71 | doi = 10.1016/S0031-9422(00)91287-1| bibcode = 1974PChem..13..167L }}</ref> The seeds of ''[[Cassia (genus)|Cassia]]'' and ''[[Bauhinia]]'' trees also contain substantial amounts of L-DOPA.<ref name=Ingle/>

In a species of [[seawater|marine]] [[green algae]] ''[[Ulvaria obscura]]'', a major component of some [[algal bloom]]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-[[herbivore]] defense, reducing consumption by snails and [[isopoda|isopods]].<ref name="pmid16489461">{{cite journal | vauthors = Van Alstyne KL, Nelson AV, Vyvyan JR, Cancilla DA | s2cid = 5029574 | title = Dopamine functions as an antiherbivore defense in the temperate green alga Ulvaria obscura | journal = Oecologia | volume = 148 | issue = 2 | pages = 304–11 | date = June 2006 | pmid = 16489461 | doi = 10.1007/s00442-006-0378-3 | bibcode = 2006Oecol.148..304V }}</ref>

===As a precursor for melanin===
{{anchor|dopamine-melanin}}

Melanins are a family of dark-pigmented substances found in a wide range of organisms.<ref name=Simon/> 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 [[tyrosinase]].<ref name=Simon>{{cite journal | vauthors = 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 Research | volume = 22 | issue = 5 | pages = 563–79 | date = October 2009 | pmid = 19627559 | doi = 10.1111/j.1755-148X.2009.00610.x | doi-access = free }}</ref> The melanin that darkens human skin is not of this type: it is synthesized by a pathway that uses L-DOPA as a precursor but not dopamine.<ref name=Simon/> However, there is substantial evidence that the [[neuromelanin]] that gives a dark color to the brain's substantia nigra is at least in part dopamine-melanin.<ref>{{cite journal | vauthors = Fedorow H, Tribl F, Halliday G, Gerlach M, Riederer P, Double KL | s2cid = 503902 | title = Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson's disease | journal = Progress in Neurobiology | 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 | vauthors = Andrews RS, Pridham JB|bibcode=1967PChem...6...13A }}</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 | vauthors = Beldade P, Brakefield PM | s2cid = 17417235 | 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>

==History and development==
{{Main|History of catecholamine research}}
Dopamine was first synthesized in 1910 by [[George Barger]] and James Ewens at [[Wellcome Trust|Wellcome]] Laboratories in London, 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 = S497–508 | year = 2008 | pmid = 18781671 | doi = 10.1002/mds.22028 | s2cid = 45572523 }}</ref> and first identified in the human brain by [[Katharine Montagu]] in 1957. It was named dopamine because it is a [[monoamine]] whose precursor in the Barger-Ewens synthesis is 3,4-'''d'''ihydr'''o'''xy'''p'''henyl'''a'''lanine (levodopa or L-DOPA). Dopamine's function as a neurotransmitter was first recognized in 1958 by [[Arvid Carlsson]] and [[Nils-Åke Hillarp]] at the Laboratory for Chemical Pharmacology of the National Heart Institute of [[Sweden]].<ref name="pmid11165672">{{cite journal | vauthors = Benes FM | title = Carlsson and the discovery of dopamine | journal = Trends in Pharmacological Sciences | volume = 22 | issue = 1 | pages = 46–47 | date = January 2001 | pmid = 11165672 | doi = 10.1016/S0165-6147(00)01607-2 }}</ref> Carlsson was awarded the 2000 [[Nobel Prize in Physiology or Medicine]] for showing that dopamine is not only a precursor of norepinephrine (noradrenaline) and epinephrine (adrenaline), but is also itself a neurotransmitter.<ref name=Barondes>{{cite book| vauthors = Barondes SH | year=2003| title=Better Than Prozac| pages=[https://archive.org/details/betterthanprozac00baro/page/21 21–22, 39–40]| location=New York| publisher=Oxford University Press| isbn=978-0-19-515130-5| url-access=registration| url=https://archive.org/details/betterthanprozac00baro/page/21}}</ref>

===Polydopamine===
Research motivated by [[bioadhesive|adhesive]] [[polyphenolic protein]]s in [[mussel]]s 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>{{cite journal | vauthors = Lee H, Dellatore SM, Miller WM, Messersmith PB | title = Mussel-inspired surface chemistry for multifunctional coatings | journal = Science | volume = 318 | issue = 5849 | pages = 426–30 | date = October 2007 | pmid = 17947576 | pmc = 2601629 | doi = 10.1126/science.1147241 | bibcode = 2007Sci...318..426L }}</ref><ref name=Dreyer>{{cite journal | title = Perspectives on poly(dopamine) | vauthors = Dreyer DR, Miller DJ, Freeman BD, Paul DR, Bielawski CW | journal = Chemical Science | year = 2013 | doi = 10.1039/C3SC51501J | volume=4 | issue = 10 | page=3796}}</ref> This polymerized dopamine forms by a spontaneous oxidation reaction, and is formally a type of melanin.<ref name=Lynge>{{cite journal | vauthors = 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 = https://www.researchgate.net/publication/51742922 | archive-url = https://web.archive.org/web/20140307205318/http://www.researchgate.net/profile/Almar_Postma/publication/51742922_Polydopamine--a_nature-inspired_polymer_coating_for_biomedical_science/file/d912f50318c9e0c7bb.pdf | bibcode = 2011Nanos...3.4916L | archive-date = 7 March 2014 }}</ref> Furthermore, dopamine self-polymerization can be used to modulate the mechanical properties of peptide-based gels.<ref>{{cite journal | vauthors = Fichman G, Schneider JP | title = Dopamine Self-Polymerization as a Simple and Powerful Tool to Modulate the Viscoelastic Mechanical Properties of Peptide-Based Gels | journal = Molecules | volume = 26 | issue = 5 | pages = 1363 | date = March 2021 | pmid = 33806346 | pmc = 7961423 | doi = 10.3390/molecules26051363 | doi-access = free }}</ref> Synthesis of polydopamine usually involves reaction of dopamine hydrochloride with [[Tris]] as a base in water. The structure of polydopamine is unknown.<ref name=Dreyer />

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

== See also ==
* [[Dopamine fasting]]
* [[Breastfeeding and fertility]]
* [[Endorphin]]
* [[Serotonin]]
* [[Oxytocin]]
* [[Enkephalin]]

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

==Further reading==
*{{cite news
| vauthors = Szalavitz M
|title=A 'Dopamine Fast' Will Not Save You From Addiction
|date=September 13, 2024
|newspaper=[[The New York Times]]
|url=https://www.nytimes.com/2024/09/13/opinion/addiction-dopamine-brain-chemistry.html}}

* {{cite news
|title=We Have a Dopamine Problem
| vauthors = Smith DG 
|date=June 30, 2023
|newspaper=[[The New York Times]]
|url=https://www.nytimes.com/2023/06/30/well/mind/dopamine-brain-behavior.html?pgtype=Article&action=click&module=RelatedLinks}}

* {{cite book
|title=One Man's Endless Hunt for a Dopamine Rush in Virtual Reality
| vauthors = Metz C
| work = The New York Times
|date=September 29, 2021
|url=https://www.nytimes.com/2021/09/29/technology/virtual-reality-fascination.html}}

* {{cite book
|title=Dopamine Nation
| vauthors = Lembke A
|year=2021
|publisher=Headline
|isbn=9781472294128}}

==External links==
* {{Wiktionary-inline|Dopamine}}
* {{Commons category-inline}}

{{Neurotransmitters}}
{{Cardiac stimulants}}
{{Dopamine receptor modulators}}
{{TAAR ligands}}
{{Monoamine neurotoxins}}
{{Phenethylamines}}
{{Emergency medicine}}
{{Authority control}}

[[Category:Dopamine| ]]
[[Category:Aminoethyl compounds]]