Dopamine - Wikipedia, The Free Encyclopedia

Dopamine

4-(2-aminoethyl)benzene-1,2-diol

2-(3,4-dihydroxyphenyl)ethylamine;3,4-dihydroxyphenethylamine;

3-hydroxytyramine; DA; Intropin; Revivan; Oxytyramine

Identifiers

CAS

number

51-61-6 , 62-31-7 (hydrochloride)

PubChem 681

ChemSpider661

UNII VTD58H1Z2X

DrugBank DB00988

KEGG D07870

ChEBI CHEBI:18243

ChEMBL CHEMBL59

ATC code C01CA04 (http://www.whocc.no/atc_ddd_index

/?code=C01CA04)

Jmol-3D

images

Image 1 (http://chemapps.stolaf.edu

/jmol/jmol.php?model=c1cc%28c%28cc1CCN%29O%29O)

Properties

Molecular

formula

C8H11NO2

Molar mass 153.18 g/mol

Appearance colorless solid

Density 1.26 g/cm3

DopamineFrom Wikipedia, the free encyclopedia

Dopamine is a simple organic chemicalin the catecholamine andphenethylamine families that plays anumber of important roles in the brainsand bodies of animals. Its name derivesfrom its chemical structure: it is an aminethat is formed by removing a carboxylgroup from a molecule of L-DOPA.

In the brain, dopamine functions as aneurotransmitter—a chemical releasedby nerve cells to send signals to othernerve cells. The brain includes severaldistinct dopamine systems, one of whichplays a major role in reward-motivatedbehavior. Every type of reward that hasbeen studied increases the level ofdopamine in the brain, and a variety ofaddictive drugs, including stimulantssuch as cocaine, amphetamine, andmethamphetamine, act by amplifying theeffects of dopamine. Other braindopamine systems are involved in motorcontrol and in controlling the release ofseveral important hormones.

Several important diseases of thenervous system are associated withdysfunctions of the dopamine system.Parkinson's disease, a degenerativecondition causing tremor and motorimpairment, is caused by loss ofdopamine-secreting neurons in themidbrain area called the substantia nigra.There is evidence that schizophreniainvolves altered levels of dopamineactivity, and the antipsychotic drugs thatare frequently used to treat it have aprimary effect of attenuating dopamineactivity. Attention deficit hyperactivitydisorder (ADHD) and restless legssyndrome (RLS) are also believed to beassociated with decreased dopamineactivity.

Outside the nervous system, dopaminefunctions in several parts of the body asa local chemical messenger. In the bloodvessels it inhibits norepinephrine releaseand acts as a vasodilator; in the kidneys

IUPAC name

Other names

SMILES

InChI

Dopamine - Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Dopamine

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Melting

point128 °C, 401 K, 262 °F

Boiling

pointdecomposes

Solubility

in water

60.0 g/100 ml

(verify) (what is: / ?)

Except where noted otherwise, data are given for materials in their

standard state (at 25 °C, 100 kPa)

Infobox references

it increases sodium excretion and urineoutput; in the pancreas it reduces insulinproduction; in the digestive system itreduces gastrointestinal motility andprotects intestinal mucosa; and in theimmune system it reduces the activity oflymphocytes. With the exception of theblood vessels, dopamine in each of theseperipheral systems has a "paracrine"function: it is synthesized locally andexerts its effects on cells that are locatednear the cells that release it.

A variety of important drugs work by altering the way the body makes or uses dopamine. Dopamine itself isavailable for intravenous injection: although it cannot reach the brain from the bloodstream, its peripheraleffects make it useful in the treatment of heart failure or shock, especially in newborn babies. L-DOPA, themetabolic precursor of dopamine, does reach the brain and is the most widely used treatment for Parkinson'sdisease. Dopamine-activating stimulants such as cocaine, amphetamine, and Ritalin are addictive in highdoses, but are used at lower doses to treat ADHD. Conversely, many antipsychotic drugs act by suppressingthe effects of dopamine. Drugs that act against dopamine by a different mechanism are also some of themost effective anti-nausea agents.

Contents

1 Dopaminergic systems of the body1.1 In the brain1.2 Outside the nervous system

2 Cellular effects3 The substantia nigra dopamine system and motor control

3.1 Anatomy and physiology4 The ventral tegmental area, reward, and cognition

4.1 Reinforcement and reward-seeking behavior4.1.1 Animal studies

5 Diseases and disorders5.1 Parkinson's disease5.2 Attention deficit hyperactivity disorder5.3 Drug addiction5.4 Pain5.5 Nausea5.6 Psychosis

6 Comparative biology and evolution6.1 Microorganisms6.2 Animals6.3 Plants6.4 As a precursor for melanin

7 Pharmacology7.1 Dopamine as an injectable drug7.2 L-DOPA7.3 Psychomotor stimulants7.4 Antipsychotic drugs7.5 Toxicity

8 Biochemical mechanisms


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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 striatum.

8.1 Biosynthesis8.2 Storage, release, and reuptake8.3 Degradation

9 Chemistry9.1 Oxidation9.2 Polydopamine

10 History11 See also12 References13 External links

Dopaminergic systems of the body

In the brain

Main article: Dopaminergic pathways

Inside the brain, dopamine plays important roles in motor control,motivation, arousal, cognition, and reward, as well as a number oflower-level functions including lactation, sexual gratification, andnausea.

Dopaminergic neurons (i.e., neurons whose primary neurotransmitteris dopamine) are comparatively few in number — a total of around

400,000 in the human brain[1] — and their cell bodies are confined toa few relatively small brain areas, but they send projections to manyother brain areas and exert powerful effects on their targets. Thesedopaminergic cell groups were first mapped in 1964 by AnnicaDahlström and Kjell Fuxe, who assigned them labels starting with the

letter "A" (for "aminergic").[2] In their scheme, areas A1 through A7contain the neurotransmitter norepinephrine, whereas A8 throughA14 contain dopamine. Here is a list of the dopaminergic areas theyidentified:

The substantia nigra, a small midbrain area that forms acomponent of the basal ganglia. The dopamine neurons arefound mainly in a part of this structure called the pars

compacta (cell group A8) and nearby (group A9).[3] In rodents, their most important projections go tothe striatum, globus pallidus, and subthalamic nucleus, all of which also belong to the basal ganglia,and play important roles in motor control. The name substantia nigra is Latin for "dark substance",and refers to the fact that the dopaminergic neurons there are darkly pigmented. These neurons areespecially vulnerable to damage. When a large fraction of them die, the result is a Parkinsoniansyndrome.[4]

The ventral tegmental area (VTA), another midbrain area. This cell group (A10) is the largest group ofdopaminergic cells in the human brain, though still quite small in absolute terms. Projections fromthese dopaminergic neurons go to the nucleus accumbens and the prefrontal cortex as well as severalother areas.[3] These neurons play a central role in reward and other aspects of motivation. Thenucleus accumbens is often considered to be the "limbic" part of the striatum. As such, it is the part ofthe striatum involved in the highest level aspects of motor control, which include motivation anddecision-making. Thus, the role of the VTA in motivation and decision-making is structurally


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analogous to the role of the substantia nigra in low-level motor control.[5] In primates (i.e. monkeysand humans), the dopamine neurons from the regions of the substantia nigra and VTA projectthroughout most of the cortical mantle, with particularly dense innervation of the motor and premotorcortices. Thus, there are major species differences in cortical dopamine projections.[6]

The posterior hypothalamus. These dopaminergic cells (group A11) project to the spinal cord, andtheir function is not well established. There is some evidence that pathology in this area plays a role inrestless legs syndrome, a condition in which people have difficulty sleeping due to an overwhelmingcompulsion to constantly move parts of the body, especially the legs.[7]

The arcuate nucleus (cell group A12) and periventricular nucleus (cell group A14) of thehypothalamus. An important projection from these dopaminergic neurons goes to the pituitary gland,where it influences the section of the hormone prolactin. Dopamine is the primary neuroendocrineinhibitor of the secretion of prolactin from the anterior pituitary gland. Dopamine produced byneurons in the arcuate nucleus is secreted into the hypothalamo-hypophysial blood vessels of themedian eminence, which supply the pituitary gland. The lactotrope cells that produce prolactin, in theabsence of dopamine, secrete prolactin continuously; dopamine inhibits this secretion. Thus, in thecontext of regulating prolactin secretion, dopamine is occasionally called prolactin-inhibiting factor(PIF), prolactin-inhibiting hormone (PIH), or prolactostatin.[8]

The zona incerta. These cells (group A13) project to several areas of the hypothalamus, andparticipate in the control of gonadotropin-releasing hormone, which is necessary to activate thedevelopment of reproductive systems that occurs following puberty, both in males and females.[8]

An additional group of dopamine-secreting neurons are located in the retina of the eye. These neurons areamacrine cells, meaning that they have no axons. They release dopamine into the extracellular medium, andare specifically active during daylight hours, becoming silent at night. This retinal dopamine acts to enhancethe activity of cone cells in the retina while suppressing rod cells — 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.[9]

Outside the nervous system

Dopamine does not cross the blood–brain barrier, so its synthesis and functions in peripheral areas are to alarge degree independent of its synthesis and functions in the brain. A substantial amount of dopaminecirculates in the bloodstream, but its functions there are not entirely clear. Dopamine is found in bloodplasma at levels comparable to those of epinephrine, but in humans, over 95% of the dopamine in the plasmais in the form of dopamine sulphate, a conjugate produced by the enzyme Sulfotransferase 1A3/1A4 actingon free dopamine. The bulk of this dopamine sulphate is produced in the mesentric organs that surroundparts of the digestive system. The production of dopamine sulphate is thought to be a mechanism fordetoxifying dopamine that is ingested as food or produced by the digestive process — plasma levels typicallyrise more than fifty-fold after a meal. Dopamine sulphate has no known biological functions and is excreted

in urine.[10]

The relatively small quantity of unconjugated dopamine in the bloodstream may be produced by thesympathetic nervous system, the digestive system, or possibly other organs. It may act on dopaminereceptors 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.[10] Somedopamine receptors are located in the walls of arteries, where they act as a vasodilator and an inhibitor of

norepinephrine release.[11] These responses might be activated by dopamine released from the carotid bodyunder conditions of low oxygen, but whether arterial dopamine receptors perform other biologically usefulfunctions is not known.

Beyond its role in modulating blood flow, there are several peripheral systems in which dopamine circulates


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Family Receptor Gene Type Mechanism

D1-like

D1DRD1 (http://www.genenames.org

/data/hgnc_data.php?match=DRD1)Gs-coupled.

Increase intracellularlevels of cAMPby activating

adenylate cyclase.D5DRD5 (http://www.genenames.org

/data/hgnc_data.php?match=DRD5)

D2-like



Gi/Go-coupled.

Decrease intracellularlevels of cAMP

by inhibitingadenylate cyclase.





Dopamine receptors in the mammal brain

within a limited area and performs an exocrine or paracrine function.[10] The peripheral systems in whichdopamine plays an important role include:

The immune system. Dopamine acts upon receptors present on immune cells, especiallylymphocytes.[12] Dopamine can also affect immune cells in the spleen, bone marrow, and circulatorysystem.[13] In addition, dopamine can be synthesized and released by immune cells themselves.[12]

The main effect of dopamine on lymphocytes is to reduce their activation level. The functionalsignificance of this system is unclear, but it afford a possible route for interactions between thenervous system and immune system, and may be relevant to some autoimmune disorders.[14]

The kidneys. Multiple types of dopamine receptors are present in cells of the kidneys. Dopamine isalso synthesized there, by tubule cells, and discharged into the tubular fluid. Its actions includeincreasing the blood supply to the kidneys, increasing filtration by the glomeruli, and increasingexcretion of sodium in the urine. Defects in renal dopamine function can be produced by high bloodpressure or by genetic problems, and can lead to reduced sodium excretion as well as hypertension.[15]

The pancreas. The role of dopamine here is somewhat complex. The pancreas consists of two parts,known as exocrine and endocrine. The exocrine part synthesizes enzymes and other substances, andsecretes them into the small intestine, where food is digested. One of the substances synthesized andsecreted by the exocrine pancreas is dopamine. The function of this secreted dopamine after it entersthe small intestine is not clearly established — the possibilities include protecting the intestinal mucosafrom damage and reducing gastrointestinal mobility (the rate at which food moves through theintestines).[16]

The endocrine part of the pancreas, also known as the islets of Langerhans, synthesizes a number ofhormones, including insulin, and secretes them into the bloodstream. There is evidence that the betacells that synthesize insulin contain dopamine receptors, and that dopamine acts to reduce the amountof insulin they release. The source of their dopamine input is not clearly established — it may comefrom dopamine that circulates in the bloodstream and derives from the sympathetic nervous system, orit may be synthesized locally by other types of pancreatic cells.[16]

Cellular effects

Main article: Dopamine receptor

Like many other biologically active substances, dopamine exerts its effects by binding to and activatingreceptors located on the surface of cells. In mammals, five subtypes of dopamine receptors have been


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Main circuits of the basal ganglia. The dopaminergic

pathway from the substantia nigra pars compacta to

the striatum is shown in light blue.

identified, labeled D1 through D5. All of them function as G protein-coupled receptors, meaning that theyexert their effects via a complex second messenger system. Glossing over the details, dopamine receptors inmammals can be divided into two families, known as D1-like and D2-like. The ultimate effect of D1-likereceptors (D1 and D5) can be excitation (via opening of sodium channels) or inhibition (via opening ofpotassium channels); the ultimate effect of D2-like receptors (D2, D3, and D4) is usually inhibition of thetarget neuron. Consequently, it is incorrect to describe dopamine itself as either excitatory or inhibitory. Itseffect on a target neuron depends on which types of receptors are present on the membrane of that neuronand on the internal responses of that neuron to cyclic AMP. D1 receptors are the most numerous dopaminereceptors in the central nervous system; D2 receptors are next; D3, D4, and D5 receptors are present atsignificantly lower levels.

The level of extracellular dopamine is modulated by two mechanisms: tonic and phasic dopaminetransmission. Tonic dopamine transmission occurs when small amounts of dopamine are releasedindependently of neuronal activity, and is regulated by the activity of other neurons and neurotransmitter

reuptake.[17] Phasic dopamine release results from the activity of the dopamine-containing cells themselves.This activity is characterized by irregular pacemaking activity of single spikes, and rapid bursts of typically

2-6 spikes in quick succession.[18][19]

The substantia nigra dopamine system and motor control

The substantia nigra is a component of the basal ganglia,a group of interconnected structures in the forebrain andmidbrain that play a central role in motor control. Theprecise nature of that role has been difficult to work out,but one popular line of thought describes it as "responseselection". The response selection theory proposes thatwhen a person or animal is in a situation where severalbehaviors are possible, activity in the basal gangliadetermines which of them is executed, by releasing thatresponse from inhibition. Thus the basal ganglia areresponsible for initiating behaviors but not fordetermining the details of how they are carried out.

Dopamine is thought to modulate the response selectionprocess in at least two important ways. First, dopaminesets the "effort threshold" for initiating behaviors. Thehigher the level of dopamine activity, the lower theimpetus required to evoke a given behavior. As aconsequence, high levels of dopamine lead to high levelsof motor activity and "impulsive" behavior; low levels ofdopamine lead to torpor and slowed reactions.Parkinson's disease, in which dopamine levels in thesubstantia nigra circuit are greatly reduced, ischaracterized by stiffness and greatly reduced movement—however, when people with the disease are confrontedwith strong stimuli such as a serious threat, theirreactions can be as vigorous as those of a healthyperson. In the opposite direction, drugs that increase theeffects of dopamine, such as cocaine or amphetamine, produce heightened levels of activity, including at thehighest levels psychomotor agitation and stereotyped movements.

The second important effect of dopamine is as a "teaching" signal. When a motor response is followed by anincrease in dopamine activity, the basal ganglia circuit is altered in a way that makes the same response


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easier to evoke when similar situations arise in the future. This is a form of operant conditioning, in whichdopamine plays the role of a reward signal.

Anatomy and physiology

The anatomy of the basal ganglia is extraordinarily complex, and the role of dopamine there iscorrespondingly complex. On a macroscopic scale there is only one major dopamine projection, from thesubstantia nigra pars compacta to the striatum, but the dopamine inputs contact multiple types of neuronsand have several distinct effects on their targets, activating some via D1 receptors while inhibiting others viaD2 receptors. A substantial number of dopamine inputs are delivered to the necks of dendritic spines, wherethey are well-placed to exert a gating effect on specific synaptic connections, often arising from the cerebralcortex. There are two distinct pathways of signal flow arising from the striatum, known as the direct pathwayand indirect pathway. Dopamine is thought to promote action by upregulating the direct pathway whilesuppressing the indirect pathway.

Many theoreticians believe that the mechanism underlying motor learning in the basal ganglia involves aform of long-term potentiation that occurs in the striatum and is strongly modulated by dopamine—in otherwords, a mechanism by which dopamine activity induces strengthening or weakening of synaptic

connections inside the striatum.[20]

The ventral tegmental area, reward, and cognition

The ventral tegmental area (VTA) contains the largest group of dopamine neurons in the human brain. Theyproject to numerous brain areas, but the two largest projections are the mesolimbic pathway, which targetsthe nucleus accumbens and other limbic structures, and the mesocortical pathway, which targets theprefrontal and insular parts of the cerebral cortex.

There is a strong functional analogy between the VTA dopamine system and the substantia nigra dopaminesystem. The basal ganglia consist of a set of parallel circuits, which all have similar architecture but controldifferent aspects of behavior. Most of these circuits run through the striatum, which receives dopamine fromthe substantia nigra. The striatal circuits control low-level forms of response selection, that is, behaviors thatuse particular muscle groups or specific action patterns. The "limbic" circuit, however, runs through thenucleus accumbens (also known as the "limbic striatum"), which receives dopamine from the VTA. Thelimbic circuit controls the highest-level aspects of response selection, such as planning and decision-making.The low-level striatal circuits are connected to the primary motor and premotor parts of the cerebral cortex;the limbic circuit is connected to the prefrontal cortex. Thus, the effect of VTA dopamine on high-leveldecision-making is functionally analogous to the effect of substantia nigra dopamine on the execution ofsimple movements.

Reinforcement and reward-seeking behavior

Dopamine is strongly associated with the reward system of the brain. Dopamine is released in areas such asthe nucleus accumbens and prefrontal cortex as a result of rewarding experiences such as food, sex, and

neutral stimuli that become associated with them.[21] The source of this dopamine is primarily the VTA,although the substantia nigra may also contribute. Electrical stimulation of the VTA or its output pathwayscan itself serve as a potent reward: animals will quickly learn to press a lever if it results in stimulation of

dopamine release, and often will continue pressing the lever for a long time, at steadily increasing rates.[22]

A variety of drugs that increase dopamine levels are intrinsically rewarding and increase the effects of other

types of reward.[22]

In spite of the overwhelming evidence showing a strong association between dopamine and reward, therehas been a great deal of dispute about whether the function of dopamine should be described as reward per


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se, or as some more complex construct that relates strongly to reward. The difficulty arises mainly from twoobservations: (1) in addition to being rewarding, dopamine is also arousing — it produces a general increasein movement of all sorts; (2) dopamine release can be caused by events that do not seem to have anything todo with reward, most notably pain. One of the most popular alternatives to the reward theory is the"incentive salience" theory, which argues that the function of dopamine is to increase the effects of

motivators of all sorts, both positive and negative.[23]

A substantial body of evidence suggests that dopamine encodes not reward itself, but rather rewardprediction error, that is, the degree to which reward is surprising. According to this hypothesis, whichderives initially from recordings made by Wolfram Schultz, rewards that are expected do not produce anyactivation of dopamine cells, but rewards that are greater than expected produce a short-lasting increase indopamine, whereas the omission of an expected reward actually causes dopamine release to drop below itsordinary background level. The "prediction error" hypothesis has drawn particular interest fromcomputational neuroscientists, because an influential computational-learning method known as temporaldifference learning makes heavy use of a signal that encodes prediction error. This confluence of theory and

data has led to a fertile interaction between theoretical and empirical neuroscientists.[23]

Recent research finds that while some dopaminergic neurons react in the way expected of reward neurons,

others do not and seem to respond in regard to salience, including aversive stimuli.[24] This research findsthe reward neurons predominate in the ventromedial region in the substantia nigra pars compacta as well asthe ventral tegmental area. Neurons in these areas project mainly to the ventral striatum and thus might

transmit value-related information in regard to reward values.[24] The salience neurons are predominate inthe dorsolateral area of the substantia nigra pars compacta which projects to the dorsal striatum and may

relate to orienting behaviour.[24] It has been suggested that the difference between these two types ofdopaminergic neurons arises from their input: reward-linked ones have input from the basal forebrain, while

the salience-related ones from the lateral habenula.[24] In primates, neurons from the regions of both the

substantia nigra and VTA project to the prefrontal cortex;[25] the origins of the dopamine innervation ofother cortical areas in primate have not been studied. It has been appreciated for many years that exposureto even mild, uncontrollable stress increases dopamine release in the rodent prefrontal cortex, e.g. reviewed

in,[26] suggesting that dopamine salience cells have a large influence on this cortical region.

Animal studies

Clues to dopamine's role in motivation, desire, and pleasure, as well as in higher cognition, have come fromstudies performed on animals. In one such study, rats were depleted of dopamine by up to 99 percent in the

nucleus accumbens and neostriatum using 6-hydroxydopamine.[21] With this large reduction in dopamine,the rats would no longer eat of their own volition. The researchers then force-fed the rats food and notedwhether they had the proper facial expressions indicating whether they liked or disliked it. The researchersof this study concluded that the reduction in dopamine did not reduce the rat's consummatory pleasure, onlythe desire to eat. In another study, mutant hyperdopaminergic (increased dopamine) mice show higher

"wanting" but not "liking" of sweet rewards.[27] Mice who cannot synthesize dopamine are unable to feedsufficiently to survive more than a few weeks after birth, but will feed normally and survive if administered

L-DOPA.[28]

Dopamine modulates foraging behavior in animals, by activating brain systems registering reward when food

sources are found.[29] When monkeys are given a highly palatable food, dopamine levels rise, but levels then

decline when the palatable food is available for prolonged periods of time and is no longer novel.[30]

Dopamine's effects on higher cognitive function have been studied in monkeys and rodents. This work beganwith the landmark study of Brozoski et al., 1979 showing that depletion of catecholamines from thedorsolateral prefrontal cortex in monkeys impaired spatial working memory to the same degree as removing


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the cortex itself.[31] It is now known that both dopamine and norepinephrine have essential actions on

prefrontal cortical function, and help coordinate cognitive state with arousal state.[32] Dopamine has an"inverted U" influence on prefrontal function through its actions on D1 receptors, where either too little or

too much impairs working memory function.[33] In the primate prefrontal cortex, dopamine D1 receptorstimulation selectively influences the firing of "Delay" cells (also called "Memory" cells), while dopamine

D2 receptors selectively alter the firing of "Response cells".[34] The role of dopamine in primate cortexbeyond the frontal lobe has not been

Diseases and disorders

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

Parkinson's disease

Parkinson's disease is a disorder characterized by stiffness of the body, slowing of movement, and tremblingof limbs when they are not in use. In advanced stages it progresses to dementia and eventually death. Themain symptoms are caused by massive loss of dopamine-secreting cells in the substantia nigra. Thesedopamine cells are especially vulnerable to damage, and a variety of insults, including encephalitis (asdepicted in the book and movie "Awakenings"), repeated sports-related concussions, and some forms ofchemical poisoning, can lead to substantial cell loss, producing a Parkinsonian syndrome that is similar in itsmain features to Parkinson's disease. Most cases of Parkinson's disease, however, are "idiopathic", meaningthat the cause of cell death cannot be identified.

The most widely used treatment for Parkinsonism is administration of L-DOPA, the metabolic precursor fordopamine. This treatment cannot restore the dopamine cells that have been lost, but it causes the remainingcells to produce more dopamine, thereby compensating for the loss to at least some degree. In advancedstages the treatment begins to fail because the cell loss is so severe that the remaining ones cannot produceenough dopamine regardless of L-DOPA levels. As this stage is approached, the metabolic regulatorymechanisms in the dopamine cells, operating far above their normal level, become erratic, producingdopamine dysregulation syndrome, in which patients fluctuate unpredictably between states of hyperactivity

and paralysis.[35]

Attention deficit hyperactivity disorder

Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder (ADHD), acondition associated with impaired ability to regulate attention, behavior, and/or impulses. There are some

genetic links between dopamine receptors, the dopamine transporter and ADHD,[36], in addition to links toother neurotransmitter receptors and transporters. The most important relationship between dopamine andADHD involves the drugs that are used to treat ADHD. Some of the most effective therapeutic agents forADHD are psychostimulants such as Ritalin and amphetamine, drugs that increase both dopamine and

norepinephrine levels in brain.[37]

Drug addiction

A variety of addictive drugs produce an increase in reward-related dopamine activity. For some addictivedrugs such as alcohol or heroin, activation of the reward system may play only a minor role in addiction,with suppression of suffering being the dominant mechanism, but for other drugs, including nicotine andpsychomotor stimulants such as cocaine and methamphetamine, enhancement of dopamine activity appearsto be the primary factor. When people addicted to stimulants go through withdrawal, they do not experiencethe physical suffering associated with withdrawal from alcohol or opiates; instead they experience apathy,


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boredom, restlessness, and most importantly an overwhelming urge to consume more of the drug. Whendopamine levels are increased for a period of time, the sensitivity of the receptors is down-regulated — theconsequence is that steadily increasing doses of a drug are required to produce the same effect, and that thebrain's reward system becomes less active than usual in the absence of the drug. This mechanism causespeople who abuse stimulants to feel an urge to steadily escalate their consumption. If consumption levelsbecome very high, the ability of the body to regulate dopamine may be compromised, producing erraticbehavior as well as cardiac side-effects that in some cases can be fatal.

The addiction potential for stimulants is strongly dependent on the level of dopamine increase they produce,and particularly on the speed with which they act. The most addictive drugs, such as cocaine in the form of"crack", raise dopamine levels in the brain within seconds of consumption. For drugs such as these, even afew exposures can be enough to produce symptoms of addiction in some people.

Treatment of stimulant addiction is very difficult, because even if consumption ceases, the urge to consumetakes a long time to decrease, and even when apparently gone can reappear unexpectedly if a person isplaced in a situation that is mentally associated with drug use. The brain mechanisms underlying thesecravings have been a topic of extensive research. There is evidence that they are associated with long-lastingchanges in the density of dopamine receptors in parts of the brain.

Pain

Dopamine has been demonstrated to play a role in pain processing in multiple levels of the central nervoussystem including the spinal cord, periaqueductal gray (PAG), thalamus, basal ganglia, and cingulate cortex.Accordingly, decreased levels of dopamine have been associated with painful symptoms that frequentlyoccur in Parkinson's disease. Abnormalities in dopaminergic neurotransmission have also been demonstrated

in painful clinical conditions, including burning mouth syndrome,[38] fibromyalgia, and restless legssyndrome. In general, the analgesic capacity of dopamine occurs as a result of dopamine D2 receptoractivation; however, exceptions to this exist in the PAG, in which dopamine D1 receptor activation

attenuates pain presumably via activation of neurons involved in descending inhibition.[39] In addition, D1receptor activation in the insular cortex appears to attenuate subsequent pain-related behavior.

Nausea

Nausea and vomiting are largely determined by activity in a brainstem area known as the chemoreceptortrigger zone. This area contains a large population of type D2 dopamine receptors. Consequently, drugs thatactivate D2 receptors have a high potential to cause nausea. This group includes some medications that areadministered for Parkinson's disease, as well as other dopamine agonists such as apomorphine. In manycases, D2-receptor antagonists such as metoclopramide are useful as anti-nausea drugs.

Psychosis

Main article: Dopamine hypothesis of schizophrenia

Abnormally high dopaminergic transmission has been linked to psychosis and schizophrenia.[40] However,clinical studies relating schizophrenia to brain dopamine metabolism have ranged from controversial to

negative, with HVA levels in the CSF the same for schizophrenics and controls.[41] Increased dopaminergicfunctional activity, specifically in the mesolimbic pathway, is found in schizophrenic individuals. However,decreased activity in another dopaminergic pathway, the mesocortical pathway, may also be involved. Thetwo pathways are thought to be responsible for differing sets of symptoms seen in schizophrenia.[citation needed]

Antipsychotic medications act largely as dopamine antagonists, inhibiting dopamine at the receptor level,and thereby blocking the effects of the neurochemical in a dose-dependent manner. The older, so-called


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typical antipsychotics most commonly act on D2 receptors,[42] while the atypical drugs also act on D1, D3

and D4 receptors, though they have a lower affinity for dopamine receptors in general.[43][44] The findingthat drugs such as amphetamines, methamphetamine and cocaine, which can increase dopamine levels by

more than tenfold,[45] can temporarily cause psychosis, provides further evidence for this link.[46] However,

many non-dopaminergic drugs can induce acute and chronic psychosis.[47] The NMDA antagonistsKetamine and PCP both are used in research to reproduce the positive and negative symptoms commonly

associated with schizophrenia.[48][49]

Dopaminergic dysregulation has also been linked to depressive disorders.[50] Early research in humans usedvarious methods of analyzing dopamine levels and function in depressed patients. Studies have reported thatthere is decreased concentration of tyrosine, a precursor to dopamine, in the blood plasma, ventricular spinal

fluid, and lumbar spinal fluid of depressed patients compared to control subjects.[51][52] One study measuredthe amount of homovanillic acid, the major metabolite of dopamine in the CSF, as a marker for the dopaminepathway turnover rate, and found decreased concentrations of homovanillic acid in the CSF of depressed

patients.[53] Postmordem real time reverse transcriptase-polymerase chain reaction (RT-PCR) has also beenused to find that gene expression of a specific subtype of dopamine receptor was elevated in the amygdale of

people suffering from depression as compared to control subjects.[54]

The action of commonly used antidepressant drugs also has yielded information about possible alterations ofthe dopaminergic pathway in treating depression. It has been reported that many antidepressant drugs

increase extracellular dopamine concentrations in the rat prefrontal cortex,[55] but vary greatly in their

affects on the striatum and nucleus accumbens.[56][57] This can be compared to electro convulsive shocktreatment (ECT), which has been shown to have a multiple fold increase in striatal dopamine levels in

rats.[58]

More recent research studies with rodents have found that depression-related behaviors are associated with

dopaminergic system dysregulation.[59] In rodents exposed to chronic mild stress, decreased escape behavior

and decreased forced swimming is reversed with activation of the dopaminergic mesolimbic pathway.[59]

Also, rodents that are susceptible to depression-related behavior after social defeat can have their behavior

reversed with dopamine pathway activation.[60] Depletion of dopamine in the caudate nucleus and nucleusaccumbens has also been reported in cases of learned helplessness in animals. These symptoms can bereversed with dopamine agonists and antidepressant administration prior to the learned helplessness

protocol.[61]

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 a type

of protozoan called Tetrahymena.[62] Perhaps more importantly, there are types of bacteria that containhomologs of all the enzymes that animals use to synthesize dopamine. It has even been proposed thatanimals derived their dopamine-synthesizing machinery from horizontal gene transfer that may haveoccurred relatively late in evolutionary time, perhaps as a result of the symbiotic incorporation of bacteria

into eukaryotic cells that gave rise to mitochondria.[63]

Animals

Dopamine is used as an intercellular messenger in virtually all multicellular animals. In sponges only a single

report exists of the presence of dopamine, with no indication of its function;[64] however, dopamine has


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Dopamine can be found in the peel and

fruit pulp of bananas

been reported in the nervous systems of numerous radially symmetric species, including cnidaria (jellyfish,

hydra, corals, etc.).[65] This dates the emergence of dopamine as a neurotransmitter back to the earliestappearance of the nervous system, over 500 million years ago in the Cambrian era. Among existing species,dopamine functions as a neurotransmitter in vertebrates, echinoderms, arthropods, molluscs, and several

types of worms.[66][67]

In every type of animal that has been examined, dopamine acts to modify motor behavior.[68] In themuch-studied nematode worm Caenorhabditis elegans, it reduces locomotion and increasesfood-exploratory movements; in planarian worms it produces "screw-like" movements; in leeches it inhibitsswimming and promotes crawling; etc. Across a wide range of vertebrates, dopamine has an "activating"

effect on behavior-switching and response selection, comparable to its effect in mammals.[68]

Dopamine also consistently plays a role in reward learning, in all animal groups that have been examinedexcept arthropods. In nematodes, planarians, molluscs, and vertebrates, animals can be trained to repeat an

action if it is consistently followed by an increase in dopamine levels.[68] Arthropods are an exception,though. In these species — insects, crustaceans, etc. — dopamine has an aversive effect, and reward isinstead mediated by octopamine, a neurotransmitter that is not found in vertebrates but is thought to beclosely related to norepinephrine. In insects, dopamine increases aversion learning for olfactory stimuli aswell as visual stimuli, and reduces approach learning for stimuli that are followed by rewards. It also

improves recall for aversive memories and reduces recall for positive memories.[68] The origin of the strikingreversal between dopamine's effects in arthropods versus all other types of animals has not been explained.

Plants

Many plants synthesize dopamine to varying degrees, including avariety of food plants. The highest concentrations have beenobserved in bananas — the fruit pulp of red and yellow bananascontains dopamine at levels of 40 to 50 parts per million by weight.Potatoes, avocados, broccoli, and Brussels sprouts may also containdopamine 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.[69] The dopamine in plants is synthesizedfrom the amino acid tyrosine, by biochemical mechanisms similar tothose that animals use. It can be metabolized in a number of ways,

producing melanin and a variety of alkaloids as byproducts.[69] Thefunctions of plant catecholamines have not been clearly established,but there is evidence that they play a role in the response to stressors such as bacterial infection, act asgrowth-promoting factors in some situations, and modify the way that sugars are metabolized. The receptorsthat mediate these actions have not yet been identified, nor have the intracellular mechanisms that they

activate.[69]

Dopamine consumed in food cannot act on the brain, because it cannot cross the blood–brain barrier.

However, there are also a variety of plants that contain L-DOPA, the metabolic precursor of dopamine.[70]

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.[71] Anotherplant containing substantial amounts of L-DOPA is Vicia faba, the plant that produces fava beans (alsoknown 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.[72] The seeds of Cassia and Bauhinia trees also contain substantial amounts of

L-DOPA.[70]

In the marine green alga Ulvaria obscura, which is a major component of some algal blooms, dopamine is


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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 isopods.[73]

As a precursor for melanin

Melanins are a family of dark-pigmented substances that are found in a wide range of organisms. Theirphysical properties make them difficult to work with experimentally, and consequently a number of aspectsof their biochemistry are not well understood. Chemically they are closely related to dopamine, and there isa type of melanin, known as "dopamine-melanin", that can be synthesized by oxidation of dopamine via the

enzyme tyrosinase.[74] The melanin that darkens human skin is not of this type: it is synthesized by apathway that uses L-DOPA as a precursor but not dopamine. 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.[75]

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.[76] The complex patterns thatappear 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.[77]

Pharmacology

Dopamine as an injectable drug

Under the trade names Intropin , Dopastat, Revimine, or other names, dopamine can be used as a drug ininjectable form. It is most commonly used in the treatment of severe hypotension, bradycardia (slow heartrate), circulatory shock, or cardiac arrest, especially in newborn infants. Its effects, depending on dosage,include an increase in sodium excretion by the kidneys, an increase in urine output, an increase in heart rate,and an increase in blood pressure. At a "cardiac dose" of 5 to 10 µg/kg/min, dopamine acts through thesympathetic nervous system to increase heart muscle contraction force and heart rate, thereby increasingcardiac output and blood pressure. At a "pressor dose" of 10 to 20 µg/kg/min, dopamine also causesvasoconstriction that further increases blood pressure, but can produce negative side effects such as an

impairment of kidney function.[78] Older literature also describes a so-called "renal dose" of 2 to 5µg/kg/min thought to improve kidney function without other consequences, but recent reviews have

concluded that doses at this low level are not clinically effective and may sometimes be harmful.[79]

L-DOPA

Levodopa is a dopamine precursor used in various forms to treat Parkinson's disease and dopa-responsivedystonia. It is typically co-administered with an inhibitor of peripheral decarboxylation (DDC, dopadecarboxylase), such as carbidopa or benserazide. Inhibitors of alternative metabolic route for dopamine bycatechol-O-methyl transferase are also used. These include entacapone and tolcapone.

Psychomotor stimulants

Cocaine and amphetamines inhibit the re-uptake of dopamine; however, they influence separate mechanismsof action. Cocaine is a dopamine transporter and norepinephrine transporter blocker that competitivelyinhibits dopamine uptake to increase the lifetime of dopamine and augments an overabundance of dopamine(an increase of up to 150 percent) within the parameters of the dopamine neurotransmitters. Like cocaine,amphetamines increase the concentration of dopamine in the synaptic gap, but by a different mechanism.Amphetamines and methamphetamine are similar in structure to dopamine, and so can enter the terminalbouton of the presynaptic neuron via its dopamine transporters as well as by diffusing through the neural

membrane directly.[citation needed] By entering the presynaptic neuron, amphetamines force dopamine


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molecules out of their storage vesicles and expel them into the synaptic gap by making the dopaminetransporters work in reverse.

Antipsychotic drugs

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

Even so, the widespread use of antipsychotic drugs has long been controversial. There are several reasonsfor this. First, these drugs are perceived as very aversive by people who have to take them, because they

produce a general dullness of thought and suppress the ability to experience pleasure.[80] Second, it isdifficult to show that they act specifically against psychotic behaviors rather than merely suppressing alltypes of active behavior. Third, they can produce a range of serious side effects, including weight gain,diabetes, fatigue, sexual dysfunction, hormonal changes, and a type of movement disorder known as tardivedyskinesia. Some of these side effects may continue long after the cessation of drug use, or evenpermanently.

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

Toxicity

The LD50, or dose which is expected to be lethal in 50% of the population, has been found to be: 59 mg/kg(mouse; administered i.v.); 950 mg/kg (mouse; administered i.p.); 163 mg/kg (rat; administered i.p.);

79 mg/kg (dog; administered i.v.)[81]

Biochemical mechanisms

Structurally, dopamine belongs to the catecholamine and phenethylamine classes. In biological systems,dopamine is synthesized in brain cells and adrenal cells from the precursor L-DOPA. In brain cells, it istransported to synaptic sites and packaged into vesicles for release, which occurs during synaptictransmission. After release, free dopamine is either reabsorbed into the presynaptic terminal for reuse, orbroken down by the enzymes monoamine oxidase or COMT, producing a variety of degradation metabolites.

Biosynthesis

Dopamine is synthesized in a restricted set of cell types, mainly neurons and cells in the medulla of theadrenal glands. This is the metabolic pathway:

L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine

Thus the direct precursor of dopamine is L-DOPA, but this itself can be synthesized from the essential amino


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Catecholamine biosynthesis

acid phenylalanine or the non-essential amino acid tyrosine. Theseamino acids are found in nearly every protein and as such are providedfrom ingestion of protein-containing food, with tyrosine being the mostcommon. Although dopamine itself is also found in many types of food,it is incapable of crossing the blood–brain barrier that surrounds andprotects the brain. It must therefore be synthesized inside the brain inorder to perform its neural actions.

L-Phenylalanine is converted into L-tyrosine by the enzymephenylalanine hydroxylase (PAH), with molecular oxygen (O2) andtetrahydrobiopterin (THB) as cofactors. L-Tyrosine is converted intoL-DOPA by the enzyme tyrosine hydroxylase (TH), with

tetrahydrobiopterin (THB), O2, and ferrous iron (Fe2+) as cofactors.L-DOPA is converted into dopamine by the enzyme aromatic L-aminoacid decarboxylase (AAAD; also known as DOPA decarboxylase(DDC)), with pyridoxal phosphate (PLP) as the cofactor.

Dopamine itself is also used as precursor in the synthesis of theneurotransmitters norepinephrine and epinephrine. Dopamine isconverted into norepinephrine by the enzyme dopamine β-hydroxylase(DBH), with O2 and L-ascorbic acid as cofactors. Norepinephrine isconverted into epinephrine by the enzyme phenylethanolamineN-methyltransferase (PNMT) with S-adenosyl-L-methionine (SAMe) asthe cofactor.

It should be noted that some of the cofactors also require their ownsynthesis. Deficiency in any required amino acid or cofactor will resultin subsequent dopamine, norepinephrine, and epinephrine biosynthesis impairment and deficiency.

Storage, release, and reuptake

Inside the brain dopamine functions as a neurotransmitter, and is controlled by a set of mechanisms that arecommon to all neurotransmitters. After synthesis, dopamine is transported from the cytosol into synapticvesicles by the vesicular monoamine transporter 2 (VMAT2). Dopamine is stored in and remains in thesevesicles until an action potential occurs and causes the contents of the vesicles to be ejected into thesynaptic cleft.

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

After an action potential, the dopamine molecules quickly become unbound from their receptors. They arethen absorbed back into the presynaptic cell, via reuptake mediated either by the high-affinity dopaminetransporter (DAT) or by the low-affinity plasma membrane monoamine transporter (PMAT). Once back inthe cytosol, dopamine is subsequently repackaged into vesicles by VMAT2, making it available for futurerelease.

Degradation

Dopamine is broken down into inactive metabolites by a set of enzymes, monoamine oxidase (MAO),aldehyde dehydrogenase (ALDH), and catechol-O-methyl transferase (COMT), acting in sequence. Bothisoforms of MAO, MAO-A and MAO-B, are equally effective.

The metabolites produced by these processes are:


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Dopamine degradation

DOPAL

(3,4-Dihydroxyphenylacetaldehyde)DOPAC (3,4-Dihydroxyphenylacetic acid)DOPET (3,4-dihydroxyphenylethanol, also known as Hydroxytyrosol)MOPET (3-methoxy-4-hydroxyphenylethanol, also known as Homovanillyl alcohol)3-MT (3-Methoxytyramine)HVA (Homovanillic acid)

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

The specific reactions that make up these pathways are:

Dopamine → DOPAL, mediated by MAODOPAL → DOPAC, mediated by ALDHDOPAL → DOPET, mediated by aldose reductase (minor pathway)DOPAC → HVA, mediated by COMTDOPET → MOPET, mediated by COMTDopamine → 3-MT, mediated by COMT3-MT → HVA, mediated by MAO

In most areas of the brain, including the striatum and basal ganglia, dopamine is inactivated by reuptake viathe DAT, then enzymatic breakdown by MAO into DOPAC. In the prefrontal cortex, however, there are veryfew DAT proteins, and dopamine is inactivated instead by reuptake via the norepinephrine transporter(NET), presumably on neighboring norepinephrine neurons, then enzymatic breakdown by COMT into

3-MT.[82] The DAT pathway is roughly an order of magnitude faster than the NET pathway: in mice,dopamine concentrations decay with a half-life of 200 milliseconds in the caudate nucleus (which uses the

DAT pathway) versus 2,000 milliseconds in the prefrontal cortex.[83] Dopamine that is not broken down byenzymes is repackaged into vesicles for future release.

Chemistry


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Dopamine Catechol

structurePhenethylamine structure

Chemically, a dopamine molecule consists of a catechol structure (a benzene ring with two hydroxyl sidegroups) with one amine group attached. As such, dopamine is the simplest possible catecholamine, a familythat also includes the neurotransmitters norepinephrine and epinephrine. The presence of a benzene ringwith an attached amine group makes it a phenethylamine, a family that includes numerous psychoactivedrugs.

Dopamine, like most amines, is an organic base. At neutral or acidic pH levels it is generally protonated. Theprotonated form is highly water-soluble and relatively stable, though it is capable of oxidizing if exposed tooxygen or other oxidants. At basic pH levels, dopamine becomes deprotonated. In this free base form it isless soluble and also highly reactive and easily oxidized. Because of this pH-dependence, dopamine issupplied for chemical or pharmaceutical use in the form of dopamine hydochloride, that is, the hydrochloridesalt that is created when dopamine is combined with hydrochloric acid. In dry form, dopamine hydrochlorideis a fine colorless powder. When dissolved in distilled water it gives a solution that is mildly acidic andtherefore relatively stable. It cannot, however, be combined with alkaline solutions such as a bicarbonatebuffer without being rendered inactive.

Oxidation

Dopamine in the body is normally broken down by oxidation catalyzed by the enzyme monoamine oxidase.However, dopamine is also capable of autoxidation, that is, direct reaction with oxygen, yielding quinones

plus various free radicals as products.[84] The rate of autoxidation can be increased by the presence offerrous iron or other factors. The ability of dopamine autoxidation to produce quinones and free radicalsmakes it a potent cell toxin, and there is evidence that this mechanism may contribute to cell loss that occurs

in Parkinson's disease or other conditions.[85]

Polydopamine

Research motivated by mussel adhesive proteins led to the discovery in 2007 that a wide variety ofmaterials, if placed in a solution of dopamine at slightly basic pH, will become coated with a layer ofpolymerized dopamine, often referred to as "polydopamine". This polymerized dopamine forms by a

spontaneous oxidation reaction, and is formally a type of melanin.[86] Polydopamine coatings can form onobjects ranging in size from nanoparticles to large surfaces. Polydopamine layers have chemical propertiesthat have the potential to be extremely useful, and numerous studies have examined their possibleapplications. At the simplest level, they can be used for protection against damage by light, or to formcapsules for drug delivery. At a more sophisticated level, their adhesive properties may make them useful as

substrates for biosensors or other biologically active macromolecules.[86]

History

Main article: History of catecholamine research

Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in


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London, England.[87] It was named dopamine because it is a monoamine whose precursor in theBarger-Ewens synthesis is 3,4-dihydroxyphenylalanine (levodopamine or L-DOPA). Dopamine's function asa 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.[88] Carlsson was awarded the 2000Nobel Prize in Physiology or Medicine for showing that dopamine is not only a precursor of norepinephrine(noradrenaline) and epinephrine (adrenaline), but also a neurotransmitter.

See also

AddictionAmphetamineAntipsychoticCatecholamineCatechol-O-methyltransferaseClassical conditioningCocaine

DepressionDopamine hypothesis ofschizophreniaDopamine reuptakeinhibitorEpinine(N-methyldopamine)Limbic systemMethylphenidate

N,N-DimethyldopamineNeurotransmitterOperant conditioningParkinson's diseaseProlactinomaSchizophreniaSelegilineSerotonin

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External links

DrugBank APRD00085 (http://www.drugbank.ca/drugs/APRD00085)U.S. National Library of Medicine: Drug Information Portal - Dopamine (http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Dopamine)

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Dopamine - Wikipedia, The Free Encyclopedia

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