Editing Dopamine (section)

==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 | pages = 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/>