Acetylcholine

From Wikipedia, the free encyclopedia

Acetylcholine

IUPAC name[hide]
2-Acetoxy-N,N,N-trimethylethanaminium
Identifiers
Abbreviations
ACh
CAS number
51-84-3
PubChem
187
ChemSpider
182
UNII
N9YNS0M02X
EC number
200-128-9
DrugBank
EXPT00412
KEGG
C01996
MeSH
Acetylcholine
ChEBI
CHEBI:15355
ChEMBL
CHEMBL667
IUPHAR ligand
294
ATC code
S01EB09
Beilstein Reference 1764436
Gmelin Reference
326108
3DMet
B00379
Jmol-3D images
Image 1
SMILES
[show]
InChI
[show]
Properties
C
Molecular formula 7H
16NO+
2

Molar mass
Elimination
half-life

146.2074 g mol-1
Pharmacology
2 min

Except where noted otherwise, data are given for

materials in their standard state (at 25 C (77 F),
100 kPa)
(verify) (what is: / ?)
Infobox references

Acetylcholine (ACh, pron. ah-Seh-til-KO-leen) is an organic molecule that acts as a

neurotransmitter in many organisms, including humans. It is an ester of acetic acid and
choline, with chemical formula CH
3COO(CH
2)2N+
(CH
3)3 and systematic name 2-acetoxy-N,N,N-trimethylethanaminium.
Acetylcholine is one of many neurotransmitters in the autonomic nervous system (ANS). It
acts on both the peripheral nervous system (PNS) and central nervous system (CNS) and is
the only neurotransmitter used in the motor division of the somatic nervous system.
Acetylcholine is also the principal neurotransmitter in all autonomic ganglia.[citation needed]
In cardiac tissue acetylcholine neurotransmission has an inhibitory effect, which lowers heart
rate. However, acetylcholine also behaves as an excitatory neurotransmitter at neuromuscular
junctions in skeletal muscle.[1]

Contents
History
Acetylcholine (ACh) was first identified in 1915 by Henry Hallett Dale for its actions on heart
tissue. It was confirmed as a neurotransmitter by Otto Loewi, who initially gave it the name
Vagusstoff because it was released from the vagus nerve. Both received the 1936 Nobel Prize
in Physiology or Medicine for their work. Acetylcholine was also the first neurotransmitter to
be identified.

Function
Acetylcholine
Abbreviation
Sources
Targets
Receptors
Agonists
Antagonists
Precursor
Synthesizing
enzyme

ACh
many
many
nicotinic; muscarinic
nicotine, muscarine,
succinylcholine
curare, atropine
choline
Choline acetyltransferase
(ChAT)

Metabolizing
enzyme

Acetylcholinesterase (AChE)

Acetylcholine has functions both in the peripheral nervous system (PNS) and in the central
nervous system (CNS) as a neuromodulator. Its receptors have very high binding constants.
In the peripheral nervous system, acetylcholine activates muscles, and is a major
neurotransmitter in the autonomic nervous system.
In the central nervous system, acetylcholine and the associated neurons form a
neurotransmitter system, the cholinergic system, which tends to cause inhibitory actions.

In the peripheral nervous system

In the peripheral nervous system, acetylcholine activates skeletal muscles, and is a major
neurotransmitter in the autonomic nervous system. Acetylcholine binds to acetylcholine
receptors on skeletal muscle fibers, it opens ligand-gated sodium channels in the cell
membrane. Sodium ions then enter the muscle cell, initiating a sequence of steps that finally
produce muscle contraction. Although acetylcholine induces contraction of skeletal muscle, it
acts via a different type of receptor (muscarinic) to inhibit contraction of cardiac muscle
fibers..

In the autonomic nervous system

In the autonomic nervous system, acetylcholine is released in the following sites:

all pre- and post-ganglionic parasympathetic neurons

all preganglionic sympathetic neurons
o

The suprarenal medullae are modified sympathetic ganglia. On stimulation by

acetylcholine, the suprarenal medulla releases epinephrine and norepinephrine

some postganglionic sympathetic fibers

o

sudomotor neurons to sweat glands.

In the central nervous system

Micrograph of the nucleus basalis (of Meynert), which produces acetylcholine in the CNS.
LFB-HE stain.

In the central nervous system, ACh has a variety of effects as a neuromodulator upon
plasticity, arousal and reward. ACh has an important role in the enhancement of sensory
perceptions when we wake up[2] and in sustaining attention.[3]
Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to
be plausibly associated with the memory deficits associated with Alzheimer's disease.[4] ACh
has also been shown to promote REM sleep.[5] Recently, it has been suggested that
acetylcholine disruption may be a primary cause of depression.[6]
Pathways
There are three ACh pathways in the CNS.[citation needed]

Pons to thalamus and cortex

Magnocellular forebrain nucleus to cortex

Septohippocampal

Structure
Acetylcholine is a polyatomic cation. It and the associated neurons form a neurotransmitter
system, the cholinergic system from the brainstem and basal forebrain that projects axons to
many areas of the brain. In the brainstem it originates from the Pedunculopontine nucleus and
laterodorsal tegmental nucleus collectively known as the mesopontine tegmentum area or
pontomesencephalotegmental complex.[7][8] In the basal forebrain, it originates from the basal
optic nucleus of Meynert and medial septal nucleus:

The pontomesencephalotegmental complex acts mainly on M1 receptors in the

brainstem, deep cerebellar nuclei, pontine nuclei, locus caeruleus, raphe nucleus,
lateral reticular nucleus and inferior olive.[8] It also projects to the thalamus, tectum,
basal ganglia and basal forebrain.[7]
Basal optic nucleus of Meynert acts mainly on M1 receptors in the neocortex.

Medial septal nucleus acts mainly on M1 receptors in the hippocampus and neocortex.

In addition, ACh acts as an important "internal" transmitter in the striatum, which is part of
the basal ganglia. It is released by cholinergic interneurons. In humans, non-human primates
and rodents, these interneurons respond to salient environmental stimuli with stereotyped
responses that are temporally aligned with the responses of dopaminergic neurons of the
substantia nigra.[9][10]
Plasticity
Excitability and inhibition
Acetylcholine also has other effects on neurons. One effect is to cause a slow
depolarization[citation needed] by blocking a tonically active K+
current, which increases neuronal excitability. In alternative fashion, acetylcholine can
activate non-specific cation conductances to directly excite neurons.[11] An effect upon
postsynaptic M4-muscarinic ACh receptors is to open inward-rectifier potassium ion channel

(Kir) and cause inhibition.[12] The influence of acetylcholine on specific neuron types can be
dependent upon the duration of cholinergic stimulation. For instance, transient exposure to
acetylcholine (up to several seconds) can inhibit cortical pyramidal neurons via M1 type
muscarinic receptors that are linked to Gq-type G-protein alpha subunits. M1 receptor
activation can induce calcium-release from intracellular stores, which then activate a calciumactivated potassium conductance, which inhibits pyramidal neuron firing.[13] On the other
hand, tonic M1 receptor activation is strongly excitatory. Thus, ACh acting at one type of
receptor can have multiple effects on the same postsynaptic neuron, depending on the
duration of receptor activation.[14] Recent experiments in behaving animals have demonstrated
that cortical neurons indeed experience both transient and persistent changes in local
acetylcholine levels during cue-detection behaviors.[15]
In the cerebral cortex, tonic ACh inhibits layer 4 medium spiny neurons, the main targets of
thalamocortical inputs while exciting pyramidal cells in layers 2/3 and layer 5.[12] This filters
out weak sensory inputs in layer 4 and amplifies inputs that reach the layers 2/3 and layer L5
excitatory microcircuits. As a result, these layer-specific effects of ACh might function to
improve the signal noise ratio of cortical processing.[12] At the same time, acetylcholine acts
through nicotinic receptors to excite certain groups of inhibitory interneurons in the cortex,
which further dampen down cortical activity.[16]

Decision making

One well-supported function of acetylcholine (ACh) in cortex is increased responsiveness to

sensory stimuli, a form of attention. Phasic increases of ACh during visual,[17] auditory[18] and
somatosensory[19] stimulus presentations have been found to increase the firing rate of neurons
in the corresponding primary sensory cortices. When cholinergic neurons in the basal
forebrain are lesioned, animals' ability to detect visual signals was robustly and persistently
impaired.[20] In that same study, animals' ability to correctly reject non-target trials was not
impaired, further supporting the interpretation that phasic ACh facilitates responsiveness to
stimuli. Looking at ACh's effect on thalamocortical connections, a known pathway of sensory
information, in vitro application of cholinergic agonist carbachol to mouse auditory cortex
enhanced thalamocortical activity.[21] In addition, Gil et al. (1997) applied a different
cholinergic agonist, nicotine, and found that activity was enhanced at thalamocortical
synapses.[22] This finding provides further evidence for a facilitative role of ACh in
transmission of sensory information from the thalamus to selective regions of cortex.

An additional suggested function of ACh in cortex is suppression of intracortical information

transmission. Gil et al. (1997) applied the cholinergic agonist muscarine to neocortical layers
and found that excitatory post-synaptic potentials between intracortical synapses were
depressed.[22] In vitro application of cholinergic agonist carbachol to mouse auditory cortex
suppressed intracortical activity as well.[21] Optical recording with a voltage-sensitive dye in
rat visual cortical slices demonstrated significant suppression in intracortical spread of
excitement in the presence of ACh.[23]
Some forms of learning and plasticity in cortex appear dependent on the presence of
acetylcholine. Bear et al. (1986) found that the typical synaptic remapping in striate cortex
that occurs during monocular deprivation is reduced when there is a depletion of cholinergic
projections to that region of cortex.[24] Kilgard et al. (1998) found that repeated stimulation of
the basal forebrain, a primary source of ACh neurons, paired with presentation of a tone at a
specific frequency, resulted in remapping of the auditory cortex to better suit processing of
that tone.[25] Baskerville et al. (1996) investigated the role of ACh in experience-dependent
plasticity by depleting cholinergic inputs to the barrel cortex of rats.[26] The cholinergicdepleted animals had a significantly reduced amount of whisker-pairing plasticity. Apart from
the cortical areas, Crespo et al. (2006) found that the activation of nicotinic and muscarinic
receptors in the nucleus accumbens is necessary for the acquisition of an appetitive task.[27]
ACh has been implicated in the reporting of expected uncertainty in the environment[28] based
both on the suggested functions listed above and results recorded while subjects perform a
behavioral cuing task. Reaction time difference between correctly cued trials and incorrectly
cued trials, called the cue validity, was found to vary inversely with ACh levels in primates
with pharmacologically (e.g. Witte et al., 1997) and surgically (e.g. Voytko et al., 1994)
altered levels of ACh.[29][30] The result was also found in Alzheimer's disease patients
(Parasuraman et al., 1992) and smokers after nicotine (an ACh agonist) consumption.[31][32]
The inverse covariance is consistent with the interpretation of ACh as representing expected
uncertainty in the environment, further supporting this claim.

Synthesis and degradation

Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from
the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing ACh.
An example of a central cholinergic area is the nucleus basalis of Meynert in the basal
forebrain.[citation needed]
The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline
and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free
acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins
work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at the
neuromuscular junction, causing paralysis of the muscles needed for breathing and stopping
the beating of the heart.

Receptors
Main article: Acetylcholine receptor

There are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine
receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). They are named for the
ligands used to activate the receptors.

Nicotinic
Nicotinic AChRs are ionotropic receptors permeable to sodium, potassium, and calcium ions.
They are stimulated by nicotine and acetylcholine. They are of two main types, muscle-type
and neuronal-type. The former can be selectively blocked by curare and the latter by
hexamethonium. The main location of nicotinic AChRs is on muscle end plates, on autonomic
ganglia (both sympathetic and parasympathetic), and in the CNS.[33]
Myasthenia gravis
The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when
the body inappropriately produces antibodies against acetylcholine nicotinic receptors, and
thus inhibits proper acetylcholine signal transmission. Over time, the motor end plate is
destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine,
physostigmine, or primarily pyridostigmine) are effective in treating this disorder. They allow
endogenously released acetylcholine more time to interact with its respective receptor before
being inactivated by acetylcholinesterase in the synaptic cleft (the space between nerve and
muscle).

Muscarinic
Muscarinic receptors are metabotropic, and affect neurons over a longer time frame. They are
stimulated by muscarine and acetylcholine. Muscarinic receptors are found in both the central
nervous system and in the peripheral nervous system of the heart, lungs, upper GI tract, and
sweat glands. ACh is sometimes used during cataract surgery to produce rapid constriction of
the pupil. Atropine, occurring in the plant Deadly nightshade produces the opposite effect
(anticholinergic) by blocking of the muscarinic AChRs and thereby increasing pupil size
(dilation). This gives the plant both its common name (for atropine-caused heart attacks make
it deadly) and its scientific name, Atropa belladonna (for women used to dilate their pupils
with this plant for cosmetic purposes, "bella donna" is Italian for "beautiful lady"). It must be
administered intraocularly because corneal cholinesterase metabolizes topically administered
ACh before it can diffuse into the eye. Similar drugs are used to induce mydriasis (dilation of
the pupil), in cardiopulmonary resuscitation and many other situations.[citation needed].

Drugs acting on the cholinergic system

Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine.
Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the
system, or antagonists, inhibiting it.
ACh and its receptors
Drug
ACh, Carbachol, AChEi (Physostigmine, Galantamine, Neostigmine,
Pyridostigmine)
Nicotine, Varenicline, Cotinine

Nm Nn M1 M2 M3
+

+ +

Succinylcholine
Tubocurarine, Atracurium, Cisatracurium, Rocuronium, Vecuronium,
Pancuronium
Epibatidine, DMPP, Decamethonium
Trimethaphan, Mecamylamine, Bupropion, Dextromethorphan,
Hexamethonium
Muscarine, Methacholine, Oxotremorine, Bethanechol, Pilocarpine
Atropine, Tolterodine, Oxybutynin
Vedaclidine, Talsaclidine, Xanomeline, Ipratropium
Pirenzepine, Telenzepine
Methoctramin
Darifenacin, 4-DAMP, Darifenacin, Solifenacin

+/+
+
-

+
-

+
-

ACh receptor agonists/antagonists

Acetylcholine receptor agonists and antagonists can either have an effect directly on the
receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase,
which degrades the receptor ligand. Agonists increase the level of receptor activation,
antagonists reduce it.
Associated disorders
ACh Receptor Agonists are used to treat myasthenia gravis and Alzheimer's disease.
Alzheimer's disease

Since 42 AchRs are reduced in Alzheimer's disease, drugs that inhibit acetylcholinesterase,
e.g. galantamine hydrobromide (a competitive and reversible cholinesterase inhibitor), are
commonly used in its treatment.
Direct acting
These are drugs that mimic acetylcholine on the receptor. In low doses[citation needed], they
stimulate the receptors, in high doses they numb them due to depolarisation block.

Acetyl l-carnitine[34]

Acetylcholine itself

Bethanechol

Carbachol

Cevimeline

Pilocarpine

Muscarine

Suberylcholine

Nicotine

Suxamethonium

Cholinesterase inhibitors
Main article: Cholinesterase inhibitors

Most indirect acting ACh receptor agonists work by inhibiting the enzyme
acetylcholinesterase. The resulting accumulation of acetylcholine causes continuous
stimulation of the muscles, glands, and central nervous system.
They are examples of enzyme inhibitors, and increase the action of acetylcholine by delaying
its degradation; some have been used as nerve agents (Sarin and VX nerve gas) or pesticides
(organophosphates and the carbamates). In clinical use, they are administered to reverse the
action of muscle relaxants, to treat myasthenia gravis, and to treat symptoms of Alzheimer's
disease (rivastigmine, which increases cholinergic activity in the brain).
Reversible

The following substances reversibly inhibit the enzyme acetylcholinesterase (which breaks
down acetylcholine), thereby increasing acetylcholine levels.[citation needed]

Many medications in Alzheimer's disease

o Donepezil
o

Galantamine

Rivastigmine

Tacrine

Edrophonium (differs myasthenic and cholinergic crisis)

Neostigmine (commonly used to reverse the effect of neuromuscular blockers used in

anaesthesia, or less often in myasthenia gravis)

Physostigmine (in glaucoma and anticholinergic drug overdoses)

Pyridostigmine (in myasthenia gravis)

Carbamate insecticides (e.g., Aldicarb)

Huperzine A

Irreversible

Semi-permanently inhibit the enzyme acetylcholinesterase.

Echothiophate
Isofluorophate

Organophosphate Insecticides (Malathion, Parathion, Azinphos methyl, Chlorpyrifos,

among others)

Organophosphate-containing nerve agents (e.g., Sarin, VX)

Victims of organophosphate-containing nerve agents commonly die of suffocation, as they

cannot relax their diaphragm.
Reactivation of acetylcholine esterase

Pralidoxime

ACh receptor antagonists

Antimuscarinic agents

Atropine
Ipratropium

Scopolamine

Tiotropium

Diphenhydramine

Ganglionic blockers

Mecamylamine
Hexamethonium

Trimethaphan

Neuromuscular blockers

Atracurium

Mivacurium

Cisatracurium

Pancuronium

Tubocurarine

Doxacurium

Rocuronium

Vecuronium

Metocurine

Succinylcholine

Synthesis inhibitors

Organic mercurial compounds, such as methylmercury, have a high affinity for

sulfhydryl groups, which causes dysfunction of the enzyme choline acetyltransferase.
This inhibition may lead to acetylcholine deficiency, and can have consequences on
motor function.

Choline Reuptake Inhibitors

Hemicholine

Release inhibitors

Botulin acts by suppressing the release of acetylcholine, whereas the venom from a
black widow spider (alpha-latrotoxin) has the reverse effect. ACh inhibition causes
paralysis. When bitten by a black widow spider, one experiences the wastage of ACh
supplies and the muscles begin to contract. If and when the supply is depleted,
paralysis occurs.

Other/uncategorized/unknown

Surugatoxin

Chemical syntheses
Acetylcholine, 2-acetoxy-N,N,N-trimethylethyl ammonium chloride, is easily synthesized in a
number of different ways. For example, 2-chloroethanol is reacted with trimethylamine, and
the resulting N,N,N-trimethylethyl-2-ethanolamine hydrochloride, also called choline, is
acetylated by acetic acid anhydride or acetylchloride, giving acetylcholine. A second method
consists of reacting trimethylamine with ethylene oxide, giving N,N,N-trimethylethyl-2ethanolamine hydroxide, which upon reaction with hydrogen chloride changes into the
hydrochloride, which is further acetylated in the manner described above. Finally,
acetylcholine is also formed by reacting 2-chloroethanol acetate with trimethylamine.

Acetylcholine chemical syntheses

A. Bayer, Ann. Chem., 142, 235 (1867).
G. Nothnagel, Arch. Pharm., 232, 265 (1894).

E. Fourneau, H. G. Page, Bull. Soc. Chim. France [4], 15, 544 (1914).

H. Hopff, K. Vierling, Ger. Pat., DE 801210 (1948).

J.K. Cline, U.S. Patent 1,957,443 (1934).

J.K. Cline, U.S. Patent 2,012,268 (1935).

J.K. Cline, U.S. Patent 2,013,536 (1935).

Acetylcholine is a choline molecule that has been acetylated at the oxygen atom. Because of
the presence of a highly polar, charged ammonium group, acetylcholine does not penetrate
lipid membranes. Because of this, when the drug is introduced externally, it remains in the
extracellular space and does not pass through the bloodbrain barrier. Acetylcholine does not
have therapeutic value as a drug for intravenous administration because of its multi-faceted
action and rapid inactivation by cholinesterase. Likewise, it is possible for a collaptoid state to
develop, and arterial pressure can rapidly fall and the heart can stop. However, it is used in the
form of eye drops to cause miosis during cataract surgery, which makes it advantageous
because it facilitates quick post-operational recovery. A synonym of this drug is miochol.

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doi:10.1093/brain/115.3.711. PMID 1628198.

32.

Witte EA, Davidson MC, Marrocco RT (August 1997). "Effects of altering

brain cholinergic activity on covert orienting of attention: comparison of monkey and
human performance". Psychopharmacology (Berl.) 132 (4): 32434.
doi:10.1007/s002130050352. PMID 9298509.

33.

Katzung, B.G. (2003). Basic and Clinical Pharmacology (9th ed.). McGrawHill Medical. ISBN 0-07-141092-9.

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transport and physiological functions in the brain". Molecular aspects of medicine 25
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References

Brenner, G.M.; Stevens, C.W. (2006). Pharmacology (2nd ed.). Philadelphia PA: W.B.
Saunders. ISBN 1-4160-2984-2.
Canadian Pharmacists Association (2000). Compendium of Pharmaceuticals and
Specialties (25th ed.). Toronto ON: Webcom. ISBN 0-919115-76-4.

Carlson, NR (2001). Physiology of Behavior (7th ed.). Needham Heights MA: Allyn
and Bacon. ISBN 0-205-30840-6.

Gershon, Michael D. (1998). The Second Brain. New York NY: HarperCollins.
ISBN 0-06-018252-0.

Siegal, A.; Sapru, H.N. (2006). "Ch. 15". Essential Neuroscience (Revised 1st ed.).
Philadelphia: Lippincott, Williams & Wilkins. pp. 255267.

Hasselmo ME (February 1995). "Neuromodulation and cortical function: modeling the

physiological basis of behavior". Behav. Brain Res. 67 (1): 127. doi:10.1016/01664328(94)00113-T. PMID 7748496. as PDF

Yu, AJ; Dayan, P (May 2005). "Uncertainty, neuromodulation, and attention". Neuron
46 (4): 68192. doi:10.1016/j.neuron.2005.04.026. PMID 15944135. as PDF

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Neurotransmitters
Categories:
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Neurotransmitator

Posted by neurostuff on noiembrie 14, 2011

Sentimentele, emotiile chiar si deciziile noastre cele mai importante sunt controlate de
fapt de niste substante chimice. De multe ori principiul cauzalitatii se inverseaza
(emotiile produc substantele dar si substantele produc emotiile). Ce sunt de fapt aceste
substante? Ele se numesc neurotransmitatori.

Neurotransmitatorii sunt niste substante care trec dintr-un neuron in altul ca in desen,
transmitand in felul asta impulsul nervos. Sunt de fapt niste substante chimice similare
cu hormonii sa zicem (unii neurotransmitatori sunt si hormoni de ex. dopamina) care
transmit un mesaj.

Neurotransmitatorii sunt de fapt mesageri chimici . Procesul este ceva de genul:

1. In neuronul presinaptic vine un impuls electric
2. Neuronul elibereaza un neurotransmitator
3. Acesta trece prin sinapsa si se cupleaza cu un neuroreceptor al neuronului post
sinaptic. Pt. fiecare tip de neurotransmitator (sa zicem culoare) exista un tip de

receptor. Prespunand ca dopamina ar fi galbena, neurotransmitatorul galben se aseaza

pe receptori galbeni, dopaminergici. Neuronii dopaminergici (ex. cei din centrul
placerii) fabrica dopamina dar pot avea si alt tip de receptori decat cei dopaminergici
(ex. nicotinici da, nicotina este un neurotransmitator si exista receptorii specifici
pentru nicotina). Probabil fiecare neuron din creier are receptori inhibitori GABA A
(cei afectati de alcool si diazepam) si/sau pentru glicina. Multe celule (nu toate) fac
GABA.
4. Neuronul postsinaptic poate trimite si el mai departe prin axonul lui un semnal
electric. Procesul in sine e putin mai complicat, implica si notiunea de potential de
actiune action potential si notiunea de canal de ioni. Vom explica pe parcurs
aceste notiuni.
Daca semnalul trece mai departe se spune ca neuronul a declansat fire.
In general, eliberarea neurotransmitatorului urmeaza dupa un potential de
actiune. Acesta este un eveniment de scurta durata la nivelul unei celule (cum ar fi
neuronul dar si celulele de la nivelul inimii) in care potentialul membranei celulare
(diferenta de potential electric intre interiorul si exteriorul celulei) creste si scade
rapid urmand o traiectorie consistenta. Acest eveniment genereaza impulsul nervos
care duce la eliberarea transmitatorului.
Deci, inca odata, ce este un neurotransmitator? Un neurotransmitator este un mesager
chimic (am spus asta deja). Este o substanta care isi face simtita prezenta in sinapsa
(zona de contact dintre doi neuroni) in momentul in care un neuron trebuie sa
transmita un mesaj altui neuron.

Dopamine
From Wikipedia, the free encyclopedia
For other uses, see Dopamine (disambiguation).
Dopamine

Systematic (IUPAC) name

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

Clinical data
Licence data US FDA:link
Prescription only
Legal status
Dependence
Low
liability
Routes
Intravenous Injection

Pharmacokinetic data
ALDH, DBH, MAO-A, MAO-B,
Metabolism
COMT
Excretion
Renal
Identifiers
CAS number 51-61-6 62-31-7 (hydrochloride)
ATC code
C01CA04
PubChem
CID 681
IUPHAR
940
ligand
DrugBank DB00988
ChemSpider 661
UNII
VTD58H1Z2X
KEGG
D07870
ChEBI
CHEBI:18243
ChEMBL
CHEMBL59
2-(3,4-Dihydroxyphenyl)ethylamine;
3,4-Dihydroxyphenethylamine; 3Synonyms
hydroxytyramine; DA; Intropin;
Revivan; Oxytyramine
Chemical data
Formula
C8H11NO2
Mol. mass
153.18 g/mol
InChI[show]
Physical data
Density
1.26 g/cm
Melt. point 128 C (262 F)
(what is this?) (verify)
Dopamine (contracted from 3,4-dihydroxyphenethylamine) is a hormone and
neurotransmitter of the catecholamine and phenethylamine families that plays a number of
important roles in the human brain and body. Its name derives from its chemical structure: it is
an amine that is formed by removing a carboxyl group from a molecule of L-DOPA.
In the brain, dopamine functions as a neurotransmittera chemical released by nerve cells to
send signals to other nerve cells. The brain includes several distinct dopamine systems, one of
which plays a major role in reward-motivated behavior. Most types of reward increase the
level of dopamine in the brain, and a variety of addictive drugs increase dopamine neuronal
activity. Other brain dopamine systems are involved in motor control and in controlling the
release of several other important hormones. Dopamina (contractat de la 3,4dihydroxyphenethylamine) este un hormon i neurotransmitor a catecolaminelor i
fenetilamin familiile care joaca mai multe roluri importante n creierul i corpul uman.
Numele su deriv din structura sa chimic: este o amin care este format prin eliminarea unei
grupri carboxil dintr-o molecul de L-DOPA.
In creier, funciile dopaminei ca un neurotransmitor-un produs chimic eliberate de celulele
nervoase pentru a trimite semnale de la alte celule nervoase. Creierul include mai multe

sisteme de dopamina distincte, dintre care unul joac un rol important n comportamentul
motivat-recompens. Cele mai multe tipuri de recompensa creste nivelul de dopamina din
creier, i o varietate de dependenta de droguri crete dopamina activitii neuronale. Alte
sisteme de dopamina creierului sunt implicate in controlul motor i n controlul eliberarea mai
multor altor hormoni importante.

Several important diseases of the nervous system are associated with dysfunctions of the
dopamine system. Parkinson's disease, a degenerative condition causing tremor and motor
impairment, has been related to the loss of dopamine-secreting neurons in the midbrain area
called the substantia nigra. There is evidence that schizophrenia involves highly altered levels
of dopamine activity, and the antipsychotic drugs that are frequently used to treat it have a
primary effect of attenuating dopamine activity. Attention deficit hyperactivity disorder
(ADHD) and restless legs syndrome (RLS) are also believed to be associated with decreased
dopamine activity.
Outside the nervous system, dopamine functions in several parts of the body as a local
chemical messenger. In the blood vessels, it inhibits norepinephrine release and acts as a
vasodilator; in the kidneys, it increases sodium excretion and urine output; in the pancreas, it
reduces insulin production; in the digestive system, it reduces gastrointestinal motility and
protects intestinal mucosa; and in the immune system, it reduces the activity of lymphocytes.
With the exception of the blood vessels, dopamine in each of these peripheral systems has a
"paracrine" function: it is synthesized locally and exerts its effects on cells that are located
near the cells that release it.
Mai multe boli importante ale sistemului nervos sunt asociate cu disfuncii ale sistemului
dopaminei. Boala Parkinson, o afeciune degenerativ care provoac tremor i insuficien
motorie, a fost legat de pierderea de neuroni secretoare de dopamin n zona de midbrain
numita substantia nigra. Exist dovezi c schizofrenia implica un nivel extrem de alterate de
activitate dopaminei, i medicamentele antipsihotice care sunt frecvent folosite pentru a trata
aceasta avea un efect primar de atenuare activitate dopaminei. Tulburare cu deficit de atenie
(ADHD) i sindromul picioarelor nelinitite (RLS), sunt, de asemenea, considerate a fi
asociate cu scaderea activitatii dopaminei.
n afara sistemului nervos, functiile de dopamin n mai multe pri ale corpului ca un
mesager chimic local. In vasele de sange, aceasta inhib eliberarea noradrenalina si actioneaza
ca un vasodilatator; n rinichi, creste excretia de sodiu i de urin; n pancreas, se reduce
producia de insulin; n sistemul digestiv, reduce motilitii gastro-intestinale si protejeaza
mucoasa intestinal; i n sistemul imunitar, reduce activitatea limfocitelor. Cu excepia
vaselor de snge, dopamin n fiecare dintre aceste sisteme periferice are o funcie de
"paracrin": acesta este sintetizat la nivel local i i exercit efectele sale asupra celulelor care
sunt situate n apropiere de celulele care se elibereaza.

A variety of important drugs work by altering the way the body makes or uses dopamine.
Dopamine itself is available for intravenous injection: although it cannot reach the brain from
the bloodstream, its peripheral effects make it useful in the treatment of heart failure or shock,
especially in newborn babies. L-DOPA, the metabolic precursor of dopamine, does reach the

brain and is the most widely used treatment for Parkinson's disease. Dopaminergic stimulants
can be addictive in high doses, but some are used at lower doses to treat ADHD. Conversely,
many antipsychotic drugs act by suppressing the effects of dopamine. Drugs that act against
dopamine by a different mechanism are also some of the most effective anti-nausea agents.
O varietate de medicamente importante de lucru prin modificarea modului n
care organismul face sau utilizeaz dopamina. Dopamina n sine este disponibil
pentru injecie intravenoas: dei nu se poate ajunge la creier din sange, efectele
sale periferice fac util n tratamentul insuficienei cardiace sau oc, n special la
nou-nscui. L-dopa, precursorul metabolic al dopaminei, nu ajunge la creier i
este cel mai utilizat pe scar larg tratamentul pentru boala Parkinson.
Stimulente dopaminergice pot da dependen n doze mari, dar unele sunt
folosite la doze mai mici pentru a trata ADHD. Invers, multe medicamente
antipsihotice acioneaz prin suprimarea efectelor dopaminei. Medicamentele
care acioneaz mpotriva dopamina printr-un mecanism diferit de asemenea,
unele dintre cele mai eficiente ageni anti-grea.

Contents
Dopaminergic systems of the body
In the brain

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.
Main article: Dopaminergic pathways
Inside the brain, dopamine plays important roles in motor control, motivation, arousal,
cognition, and reward, as well as a number of basic lower-level functions including lactation,
sexual gratification, and nausea.
Cai de dopamin majore. Ca parte a cii recompensa, dopamina este fabricat n
organismele de celule nervoase situate n zona ventral tegmental (TVA) i este
eliberat n nucleul accumbens si cortexul prefrontal. Funciile motorii de
dopamina sunt legate de o cale separat, cu organismele de celule din substantia
nigra c fabricarea i eliberarea de dopamin n striatum.
Articol principal: ci dopaminergice
In interiorul creierului, dopamina joaca un rol important in controlul motor,

motivaie, excitare, cunoatere, i rsplata, precum i o serie de funcii de nivel

inferior de baz, inclusiv lactaie, satisfacie sexual, i grea.

Dopaminergic neurons (i.e., neurons whose primary neurotransmitter is dopamine) are

comparatively few in number a total of around 400,000 in the human brain[1] and their
cell bodies are confined to a few relatively small brain areas, but they send projections to
many other brain areas and exert powerful effects on their targets. These dopaminergic cell
groups were first mapped in 1964 by Annica Dahlstrm and Kjell Fuxe, who assigned them
labels starting with the letter "A" (for "aminergic").[2] In their scheme, areas A1 through A7
contain the neurotransmitter norepinephrine, whereas A8 through A14 contain dopamine.
Here is a list of the dopaminergic areas they identified: Neuronilor dopaminergici (de
exemplu, neuronii cror principal neurotransmitator este dopamina) sunt relativ
puine la numr - un total de aproximativ 400.000 n creierul uman [1] - i a
organismelor de celule lor sunt limitate la cteva zone ale creierului relativ mici,
dar ele trimite proieciile de multe alte zone ale creierului i exercita efecte
puternice asupra obiectivelor lor. Aceste grupuri de celule dopaminergic au fost
cartografiate pentru prima dat n 1964 de ctre Annica Dahlstrm i Kjell Fuxe,
care a atribuit-le etichete incepand cu litera "A" (pentru "aminergic"). [2] In
schema lor, zonele A1 prin intermediul A7 conine noradrenalina
neurotransmitator, ntruct A8 prin A14 conine dopamin. Aici este o list a
zonelor dopaminergici au identificat:

The substantia nigra, a small midbrain area that forms a component of the basal
ganglia. The dopamine neurons are found 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 to the 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 are especially
vulnerable to damage. When a large fraction of them die, the result is a Parkinsonian
syndrome.[4] substantia nigra, o zon mic mezencefal care formeaz o
component a ganglionilor bazali. Neuronilor dopaminergici se gsesc n
principal ntr-o parte din aceast structur numit (grupul de celule A8)
pars compacta si imprejurimi (grup A9). [3] La roztoare, proieciile lor cele
mai importante du-te la striatum, globus pallidus, i nucleul subthalamic,
toate acestea fiind, de asemenea, fac parte din ganglionii bazali, i joac
roluri importante n controlul motor.Numele substantia nigra este latin
pentru "substan ntuneric", i se refer la faptul c neuronilor
dopaminergici sunt misterios pigmentate. Aceti neuroni sunt deosebit de
vulnerabile la daune. Atunci cnd o mare parte dintre ei mor, rezultatul
este un sindrom parkinsoniene. [4]

The ventral tegmental area (VTA), another midbrain area. This cell group (A10) is the largest
group of dopaminergic cells in the human brain, though still quite small in absolute terms.
Projections from these dopaminergic neurons go to the nucleus accumbens and the prefrontal
cortex as well as several other areas.[3] These neurons play a central role in reward and other
aspects of motivation. The nucleus accumbens is often considered to be the "limbic" part of
the striatum. As such, it is the part of the striatum involved in the highest level aspects of
motor control, which include motivation and decision-making. Thus, the role of the VTA in
motivation and decision-making is structurally analogous to the role of the substantia nigra in
low-level motor control.[5] In primates (i.e. monkeys and humans), the dopamine neurons

zona ventral tegmental (TVA), un alt domeniu mezencefal. Acest grup de celule
(A10) este cel mai mare grup de celule dopaminergice n creierul uman, dei nc
destul de mic n termeni absolui. Proieciile din aceste neuronilor dopaminergici
Mergi la nucleul accumbens i cortexul prefrontal, precum i mai multe alte
domenii. [3] Aceste neuroni juca un rol central n rsplat i alte aspecte ale
motivaiei. Nucleul accumbens este adesea considerat a fi "limbic" o parte din
nucleul striat. Ca atare, aceasta este o parte din corpul striat implicat n cele mai
nalte aspecte la nivel de control al motorului, care includ motivaia i de luare a
deciziilor. Astfel, rolul VTA n motivaie i de luare a deciziilor este structural
analog cu rolul de substantia nigra n control al motorului de nivel sczut. [5] n
primate (de exemplu, maimue i oameni), neuronilor dopaminergici

from the regions of the substantia nigra and VTA project throughout most of the cortical
mantle, with particularly dense innervation of the motor and premotor cortices. Thus,
there are major species differences in cortical dopamine projections.[6] din regiunile
substantia nigra i proiectul de TVA n ntreaga de cele mai multe mantalei
corticale, cu inervaie n special densa de motor i premotor corticale. Astfel,
exist diferene de specii majore n proiecii dopaminei corticale. [6]

The posterior hypothalamus. These dopaminergic cells (group A11) project to the
spinal cord, and their function is not well established. There is some evidence that
pathology in this area plays a role in 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.[7]

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

The zona incerta. These cells (group A13) project to several areas of the
hypothalamus, and participate in the control of gonadotropin-releasing hormone,
which is necessary to activate the development 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 are amacrine cells, meaning that they have no axons. They release dopamine into the
extracellular medium, and are specifically active during daylight hours, becoming silent at
night. This retinal dopamine acts to enhance the activity of 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 bloodbrain barrier, so its synthesis and functions in peripheral
areas are to a large degree independent of its synthesis and functions in the brain. A
substantial amount of dopamine circulates in the bloodstream, but its functions there are not
entirely clear. Dopamine is found in blood plasma at levels comparable to those of
epinephrine, but in humans, over 95% of the dopamine in the plasma is in the form of
dopamine sulphate, a conjugate produced by the enzyme Sulfotransferase 1A3/1A4 acting on
free dopamine. The bulk of this dopamine sulphate is produced in the mesenteric organs that
surround parts of the digestive system. The production of dopamine sulphate is thought to be
a mechanism for detoxifying dopamine that is ingested as food or produced by the digestive
process plasma levels typically rise more than fifty-fold after a meal. Dopamine sulphate
has no known biological functions and is excreted in urine.[10]
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. 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.[10] Some dopamine 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 body under conditions of
low oxygen, but whether arterial dopamine receptors perform other biologically useful
functions is not known.
Beyond its role in modulating blood flow, there are several peripheral systems in which
dopamine circulates within a limited area and performs an exocrine or paracrine function.[10]
The peripheral systems in which dopamine plays an important role include:

The immune system. Dopamine acts upon receptors present on immune cells,
especially lymphocytes.[12] Dopamine can also affect immune cells in the spleen, bone
marrow, and circulatory system.[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 functional significance of this system is unclear,
but it afford a possible route for interactions between the nervous system and immune
system, and may be relevant to some autoimmune disorders.[14]

The kidneys. Multiple types of dopamine receptors are present in cells of the kidneys.
Dopamine is also synthesized there, by tubule cells, and discharged into the tubular
fluid. Its actions include increasing the blood supply to the kidneys, increasing
filtration by the glomeruli, and increasing excretion of sodium in the urine. Defects in
renal dopamine function can be produced by high blood pressure or by genetic
problems, and can lead to reduced sodium excretion as well as hypertension.[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, and secretes them into the small intestine, where food
is digested. One of the substances synthesized and secreted by the exocrine pancreas is
dopamine. The function of this secreted dopamine after it enters the small intestine is
not clearly established the possibilities include protecting the intestinal mucosa

from damage and reducing gastrointestinal motility (the rate at which food moves
through the intestines).[16]
The endocrine part of the pancreas, also known as the islets of Langerhans,
synthesizes a number of hormones, including insulin, and secretes them into the
bloodstream. There is evidence that the beta cells that synthesize insulin contain
dopamine receptors, and that dopamine acts to reduce the amount of insulin they
release. The source of their dopamine input is not clearly established it may come
from dopamine that circulates in the bloodstream and derives from the sympathetic
nervous system, or it may be synthesized locally by other types of pancreatic cells.[16]

Cellular effects
Main article: Dopamine receptor
Dopamine receptors in the mammal brain
Family Receptor Gene
D1-like

D2-like

Type

Mechanism

Gs-coupled.

Increase intracellular levels of cAMP

by activating adenylate cyclase.

D1

DRD1

D5

DRD5

D2

DRD2

D3

DRD3 Gi/Go-coupled.

D4

DRD4

Decrease intracellular levels of cAMP

by inhibiting adenylate cyclase.

Like many other biologically active substances, dopamine exerts its effects by binding to and
activating receptors located on the surface of cells. In mammals, five subtypes of dopamine
receptors have been identified, labeled D1 through D5. All of them function as G proteincoupled receptors, meaning that they exert their effects via a complex second messenger
system. Glossing over the details, dopamine receptors in mammals can be divided into two
families, known as D1-like and D2-like. The ultimate effect of D1-like receptors (D1 and D5)
can be excitation (via opening of sodium channels) or inhibition (via opening of potassium
channels); the ultimate effect of D2-like receptors (D2, D3, and D4) is usually inhibition of
the target neuron. Consequently, it is incorrect to describe dopamine itself as either excitatory
or inhibitory. Its effect on a target neuron depends on which types of receptors are present on
the membrane of that neuron and on the internal responses of that neuron to cyclic AMP. D1
receptors are the most numerous dopamine receptors in the central nervous system; D2
receptors are next; D3, D4, and D5 receptors are present at significantly lower levels.
The level of extracellular dopamine is modulated by two mechanisms: tonic and phasic
dopamine transmission. Tonic dopamine transmission occurs when small amounts of
dopamine are released independently of neuronal activity, and is regulated by the activity of
other neurons and neurotransmitter reuptake.[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 26 spikes in
quick succession.[18][19]

The substantia nigra dopamine system and motor control

Main circuits of the basal ganglia. The dopaminergic pathway from the substantia nigra pars
compacta to the striatum is shown in light blue.
The substantia nigra is a component of the basal ganglia, a group of interconnected structures
in the forebrain and midbrain that play a central role in motor control. The precise nature of
that role has been difficult to work out, but one popular line of thought describes it as
"response selection". The response selection theory proposes that when a person or animal is
in a situation where several behaviors are possible, activity in the basal ganglia determines
which of them is executed, by releasing that response from inhibition. Thus the basal ganglia
are responsible for initiating behaviors but not for determining the details of how they are
carried out.
Dopamine is thought to modulate the response selection process in at least two important
ways. First, dopamine sets the "effort threshold" for initiating behaviors. The higher the level
of dopamine activity, the lower the impetus required to evoke a given behavior. As a
consequence, high levels of dopamine lead to high levels of motor activity and "impulsive"
behavior; low levels of dopamine lead to torpor and slowed reactions. Parkinson's disease, in
which dopamine levels in the substantia nigra circuit are greatly reduced, is characterized by
stiffness and greatly reduced movementhowever, when people with the disease are
confronted with strong stimuli such as a serious threat, their reactions can be as vigorous as
those of a healthy person. In the opposite direction, drugs that increase the effects of
dopamine, such as cocaine or amphetamine, produce heightened levels of activity, including
at the highest levels psychomotor agitation and stereotyped movements.
The second important effect of dopamine is as a "teaching" signal. When a motor response is
followed by an increase in dopamine activity, the basal ganglia circuit is altered in a way that

makes the same response easier to evoke when similar situations arise in the future. This is a
form of operant conditioning, in which dopamine plays the role of a reward signal.

Anatomy and physiology

The anatomy of the basal ganglia is extraordinarily complex, and the role of dopamine there is
correspondingly complex. On a macroscopic scale there is only one major dopamine
projection, from the substantia nigra pars compacta to the striatum, but the dopamine inputs
contact multiple types of neurons and have several distinct effects on their targets, activating
some via D1 receptors while inhibiting others via D2 receptors. A substantial number of
dopamine inputs are delivered to the necks of dendritic spines, where they are well-placed to
exert a gating effect on specific synaptic connections, often arising from the cerebral cortex.
There are two distinct pathways of signal flow arising from the striatum, known as the direct
pathway and indirect pathway. Dopamine is thought to promote action by upregulating the
direct pathway while suppressing the indirect pathway.
Many theoreticians believe that the mechanism underlying motor learning in the basal ganglia
involves a form of long-term potentiation that occurs in the striatum and is strongly
modulated by dopaminein other words, a mechanism by which dopamine activity induces
strengthening or weakening of synaptic connections inside the striatum.[20]

The ventral tegmental area, reward, and cognition

This article needs more medical references for verification or relies too heavily
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The ventral tegmental area (VTA) contains the largest group of dopamine neurons in the
human brain. They project to numerous brain areas, but the two largest projections are the
mesolimbic pathway, which targets the nucleus accumbens and other limbic structures, and
the mesocortical pathway, which targets the prefrontal and insular parts of the cerebral cortex.

Reward
The VTA dopamine system is strongly associated with the reward system of the brain.
Dopamine is released in areas such as the 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 pathways can itself serve as a
potent reward: animals will quickly learn to press a lever if it results in stimulation of
dopamine release, and often will continue pressing the lever for a long time, at steadily
increasing rates.[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, there has been a great deal of dispute about whether the function of dopamine should
be described as reward per se, or as some more complex construct that relates strongly to
reward. The difficulty arises mainly from two observations: (1) in addition to being

rewarding, dopamine is also arousing it produces a general increase in movement of all

sorts; (2) dopamine release can be caused by events that do not seem to have anything to do
with reward, most notably pain. One of the most popular alternatives to the reward theory is
the "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
reward prediction error, that is, the degree to which reward is surprising. According to this
hypothesis, which derives initially from recordings made by Wolfram Schultz, rewards that
are expected do not produce any activation of dopamine cells, but rewards that are greater
than expected produce a short-lasting increase in dopamine, whereas the omission of an
expected reward actually causes dopamine release to drop below its ordinary background
level. The "prediction error" hypothesis has drawn particular interest from computational
neuroscientists, because an influential computational-learning method known as temporal
difference 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 finds the reward neurons predominate in the ventromedial region of
the substantia nigra pars compacta, as well as in the 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 predominant in the 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 of
dopaminergic 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 of other cortical areas in primate have not been studied. It
has been appreciated for many years that exposure to even mild, uncontrollable stress
increases dopamine release in the rodent prefrontal cortex -e.g. reviewed in [26]- suggesting
that dopamine salience cells have a large influence on this cortical region.
"Seeking" versus "liking"
Kent Berridge and other researchers have argued for a distinction between reward, which is
defined in terms of motivation, and pleasure, which is defined in terms of emotional
expression. A simpler way of describing this is as a distinction between "seeking" and
"liking". "Seeking" occurs when an animal, given access to some stimulus such as food,
executes some type of active behavior in order to acquire it. "Liking" occurs when an animal
shows expressions of happiness or satisfaction while consuming something. There is
considerable evidence that the dopamine system is part of the brain system that mediates
seeking but not part of the system that mediates liking. Drugs that increase the effects of
dopamine (most notably stimulants such as methamphetamine or cocaine) produce
corresponding increases in seeking behaviors, but do not greatly alter expressions of pleasure.
Conversely, opiate drugs such as heroin or morphine produce increases in expressions of
pleasure but do not greatly alter seeking behaviors. Animals in which the VTA dopamine
system has been rendered inactive do not seek food, and will starve to death if left to

themselves, but if food is placed in their mouths they will consume it and show facial
expressions indicative of pleasure.[21]

Role in cognition
Dopamine's effects on higher cognitive function have been studied in monkeys and rodents.
This work began with the landmark study of Brozoski et al., 1979 showing that depletion of
catecholamines from the dorsolateral prefrontal cortex in monkeys impaired spatial working
memory to the same degree as removing the cortex itself.[27] It is now known that both
dopamine and norepinephrine have essential actions on prefrontal cortical function, and help
coordinate cognitive state with arousal state.[28] 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.[29] In the primate prefrontal cortex, dopamine D1 receptor
stimulation selectively influences the firing of "Delay" cells (also called "Memory" cells),
while dopamine D2 receptors selectively alter the firing of "Response cells".[30]

Diseases and disorders

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

Parkinson's disease
Parkinson's disease is a disorder characterized by stiffness of the body, slowing of movement,
and trembling of limbs when they are not in use. In advanced stages it progresses to dementia
and eventually death. The main symptoms are caused by massive loss of dopamine-secreting
cells in the substantia nigra. These dopamine cells are especially vulnerable to damage, and a
variety of insults, including encephalitis (as depicted in the book and movie "Awakenings"),
repeated sports-related concussions, and some forms of chemical poisoning (ex. MPTP), can
lead to substantial cell loss, producing a Parkinsonian syndrome that is similar in its main
features to Parkinson's disease. Most cases of Parkinson's disease, however, are "idiopathic",
meaning that the cause of cell death cannot be identified.
The most widely used treatment for Parkinsonism is administration of L-DOPA, the metabolic
precursor for dopamine. This treatment cannot restore the dopamine cells that have been lost,
but it causes the remaining cells to produce more dopamine, thereby compensating for the loss
to at least some degree. In advanced stages the treatment begins to fail because the cell loss is
so severe that the remaining ones cannot produce enough dopamine regardless of L-DOPA
levels. As this stage is approached, the metabolic regulatory mechanisms in the dopamine
cells, operating far above their normal level, become erratic, producing dopamine
dysregulation syndrome, in which patients fluctuate unpredictably between states of
hyperactivity and paralysis.[31]

Attention deficit hyperactivity disorder

Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder
(ADHD), a condition associated with impaired ability to regulate attention, behavior, and/or
impulses. There are some genetic links between dopamine receptors, the dopamine transporter

and ADHD,[32] in addition to links to other neurotransmitter receptors and transporters. The
most important relationship between dopamine and ADHD involves the drugs that are used to
treat ADHD. Some of the most effective therapeutic agents for ADHD are psychostimulants
such as methylphenidate (Ritalin) and amphetamine, drugs that increase both dopamine and
norepinephrine levels in brain.[33]

Drug addiction
Main article: FosB
Current models of addiction from chronic drug use involve alterations in gene expression in
the nucleus accumbens, in turn affecting dopaminergic neurotransmission.[34][35] The most
important transcription factors that produce these alterations are FosB, cyclic adenosine
monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa
B (NFB).[35] FosB is the most significant among these, since its overexpression in the
nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug
addiction;[35] it has been implicated in addictions to many types of drugs, including
cannabinoids, cocaine, nicotine, phenylcyclidine, and substituted amphetamines.[34][35] JunD
is the transcription factor which directly opposes FosB.[35] Increases in nucleus accumbens
JunD expression can reduce or, with a large increase, even block most of the neural
alterations seen in chronic drug abuse (i.e., the alterations mediated by FosB).[35] FosB also
plays an important role in regulating behavioral responses to natural rewards, such as
palatable food, sex, and exercise.[34][35] Since natural rewards, like drugs of abuse, induce
FosB, chronic acquisition of these rewards can result in a similar pathological addictive
state.[34][35] FosB inhibitors (drugs that oppose its action) may be an effective treatment for
addiction and addictive disorders.[36]

Pain
Dopamine has been demonstrated to play a role in pain processing in multiple levels of the
central nervous system 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 frequently occur in Parkinson's disease. Abnormalities
in dopaminergic neurotransmission have also been demonstrated in painful clinical
conditions, including burning mouth syndrome,[37] fibromyalgia, and restless legs syndrome.
In general, the analgesic capacity of dopamine occurs as a result of dopamine D2 receptor
activation; however, exceptions to this exist in the PAG, in which dopamine D1 receptor
activation attenuates pain presumably via activation of neurons involved in descending
inhibition.[38] In addition, D1 receptor activation in the insular cortex appears to attenuate
subsequent pain-related behavior.

Nausea
Nausea and vomiting are largely determined by activity in a brainstem area known as the
chemoreceptor trigger zone. This area contains a large population of type D2 dopamine
receptors. Consequently, drugs that activate D2 receptors have a high potential to cause
nausea. This group includes some medications that are administered for Parkinson's disease,
as well as other dopamine agonists such as apomorphine. In many cases, 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.
[39]
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.[40] Increased dopaminergic functional 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. The two
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 typical antipsychotics most commonly act on D2 receptors,[41]
while the atypical drugs also act on D1, D3 and D4 receptors, though they have a lower
affinity for dopamine receptors in general.[42] The finding that drugs such as amphetamines,
methamphetamine and cocaine, which can increase dopamine levels by more than tenfold,[43]
can temporarily cause psychosis, provides further evidence for this link.[44] However, many
non-dopaminergic drugs can induce acute and chronic psychosis.[45] The NMDA antagonists
Ketamine and PCP both are used in research to reproduce the positive and negative symptoms
commonly associated with schizophrenia.[46][47]
Dopaminergic dysregulation has also been linked to depressive disorders.[48] Early research in
humans used various methods of analyzing dopamine levels and function in depressed
patients. Studies have reported that there is decreased concentration of tyrosine, a precursor to
dopamine, in the blood plasma, ventricular spinal fluid, and lumbar spinal fluid of depressed
patients compared to control subjects.[49][50] One study measured the amount of homovanillic
acid, the major metabolite of dopamine in the CSF, as a marker for the dopamine pathway
turnover rate, and found decreased concentrations of homovanillic acid in the CSF of
depressed patients.[51] Postmordem real time reverse transcriptase-polymerase chain reaction
(RT-PCR) has also been used to find that gene expression of a specific subtype of dopamine
receptor was elevated in the amygdala of people suffering from depression as compared to
control subjects.[52]
The action of commonly used antidepressant drugs also has yielded information about
possible alterations of the dopaminergic pathway in treating depression. It has been reported
that many antidepressant drugs increase extracellular dopamine concentrations in the rat
prefrontal cortex,[53] but vary greatly in their effects on the striatum and nucleus accumbens.[54]
[55]
This can be compared to electro convulsive shock treatment (ECT), which has been shown
to have a multiple fold increase in striatal dopamine levels in rats.[56]
More recent research studies with rodents have found that depression-related behaviors are
associated with dopaminergic system dysregulation.[57] In rodents exposed to chronic mild
stress, decreased escape behavior and decreased forced swimming is reversed with activation
of the dopaminergic mesolimbic pathway.[57] Also, rodents that are susceptible to depressionrelated behavior after social defeat can have their behavior reversed with dopamine pathway
activation.[58] Depletion of dopamine in the caudate nucleus and nucleus accumbens has also
been reported in cases of learned helplessness in animals. These symptoms can be reversed

with dopamine agonists and antidepressant administration prior to the learned helplessness
protocol.[59]

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.[60] Perhaps more importantly, there are
types of bacteria that contain homologs of all the enzymes that animals use to synthesize
dopamine. It has even been proposed that animals derived their dopamine-synthesizing
machinery from bacteria, via horizontal gene transfer that may have occurred relatively late in
evolutionary time, perhaps as a result of the symbiotic incorporation of bacteria into
eukaryotic cells that gave rise to mitochondria.[61]

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;[62] however, dopamine has been reported in the nervous systems of numerous
radially symmetric species, including cnidaria (jellyfish, hydra, corals, etc.).[63] This dates the
emergence of dopamine as a neurotransmitter back to the earliest appearance of the nervous
system, over 500 million years ago in the Cambrian era. Among existing species, dopamine
functions as a neurotransmitter in vertebrates, echinoderms, arthropods, molluscs, and several
types of worms.[64][65]
In every type of animal that has been examined, dopamine acts to modify motor behavior.[66]
In the much-studied nematode worm Caenorhabditis elegans, it reduces locomotion and
increases food-exploratory movements; in planarian worms it produces "screw-like"
movements; in leeches it inhibits swimming and promotes crawling; etc. Across a wide range
of vertebrates, dopamine has an "activating" effect on behavior-switching and response
selection, comparable to its effect in mammals.[66]
Dopamine also consistently plays a role in reward learning, in all animal groups that have
been examined except arthropods. In nematodes, planarians, molluscs, and vertebrates,
animals can be trained to repeat an action if it is consistently followed by an increase in
dopamine levels.[66] Arthropods are an exception, though. In these species insects,
crustaceans, etc. dopamine has an aversive effect, and reward is instead mediated by
octopamine, a neurotransmitter that is not found in vertebrates but is thought to be closely
related to norepinephrine. In insects, dopamine increases aversion learning for olfactory
stimuli as well as visual stimuli, and reduces approach learning for stimuli that are followed
by rewards. It also improves recall for aversive memories and reduces recall for positive
memories.[66] The origin of the striking reversal between dopamine's effects in arthropods
versus all other types of animals has not been explained.

Plants

Dopamine can be found in the peel and fruit pulp of bananas

Many plants synthesize dopamine to varying degrees, including a variety of food plants. The
highest concentrations have been observed in bananas the fruit pulp of red and yellow
bananas contains dopamine at levels of 40 to 50 parts per million by weight. Potatoes,
avocados, broccoli, and Brussels sprouts may also contain dopamine at levels of 1 part per
million or more; oranges, tomatoes, spinach, beans, and other plants contain measurable
concentrations less than 1 part per million.[67] The dopamine in plants is synthesized from the
amino acid tyrosine, by biochemical mechanisms similar to those that animals use. It can be
metabolized in a number of ways, producing melanin and a variety of alkaloids as byproducts.
[67]
The functions of plant catecholamines have not been clearly established, but there is
evidence that they play a role in the response to stressors such as bacterial infection, act as
growth-promoting factors in some situations, and modify the way that sugars are metabolized.
The receptors that mediate these actions have not yet been identified, nor have the
intracellular mechanisms that they activate.[67]
Dopamine consumed in food cannot act on the brain, because it cannot cross the bloodbrain
barrier. However, there are also a variety of plants that contain L-DOPA, the metabolic
precursor of dopamine.[68] 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.[69] Another plant containing substantial amounts of LDOPA is Vicia faba, the plant that produces fava beans (also known as "broad beans"). The
level of L-DOPA in the beans, however, is much lower than in the pod shells and other parts
of the plant.[70] The seeds of Cassia and Bauhinia trees also contain substantial amounts of LDOPA.[68]
In the marine green alga Ulvaria obscura, which is a major component of some algal blooms,
dopamine is present in very high concentrations, estimated at 4.4% of dry weight. There is
evidence that this dopamine functions as an anti-herbivore defense, reducing consumption by
snails and isopods.[71]

As a precursor for melanin

Melanins are a family of dark-pigmented substances that are found in a wide range of
organisms. Their physical properties make them difficult to work with experimentally, and
consequently a number of aspects of their biochemistry are not well understood. Chemically
they are closely related to dopamine, and there is a type of melanin, known as "dopaminemelanin", that can be synthesized by oxidation of dopamine via the enzyme tyrosinase.[72] The
melanin that darkens human skin is not of this type: it is synthesized by a pathway that uses
L-DOPA as a precursor but not dopamine. 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.[73]

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. [74]
The complex patterns that appear on butterfly wings, as well as black-and-white stripes on the
bodies of insect larvae, are also thought to be caused by spatially structured accumulations of
dopamine-melanin.[75]

Pharmacology
Dopamine as an injectable drug
Under the trade names Intropin, Dopastat, Revimine, or other names, dopamine can be used
as a drug in injectable form. It is most commonly used in the treatment of severe hypotension,
bradycardia (slow heart rate), 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/beta dose" of 5 to 10 g/kg/min, dopamine acts through the
sympathetic nervous system to increase heart muscle contraction force and heart rate, thereby
increasing cardiac output and blood pressure. At a "pressor/alpha dose" of 10 to 20 g/kg/min,
dopamine also causes vasoconstriction that further increases blood pressure, but can produce
negative side effects such as an impairment of kidney function and cardiac arrhythmias.[76][77]
Older literature also describes a so-called "renal/dopaminergic dose" of 2 to 5 g/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.[78]

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

Psychostimulants
Pharmacodynamics of amphetamine enantiomers in a dopamine neuron

via AADC

Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.
Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When
amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the
cytosol (yellow-orange area). When amphetamine binds to TAAR1, it reduces dopamine
receptor firing rate via potassium channels and triggers protein kinase A (PKA) and protein
kinase C (PKC) signaling, resulting in DAT phosphorylation. PKA-phosphorylation causes
DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKCphosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT,
internalize and cease transport.
Cocaine and substituted amphetamines both increase dopamine neuronal activity; however,
they do so by very different mechanisms. Cocaine is a dopamine transporter and

norepinephrine transporter blocker. It non-competitively inhibits dopamine reuptake, resulting

in increased dopamine concentrations in the synaptic cleft. Like cocaine, substituted
amphetamines increase the concentration of dopamine in the synaptic cleft, but by a different,
more complex mechanism (see image).[79]

Antipsychotic drugs
A range of drugs that reduce dopamine activity have been found useful in the treatment of
schizophrenia and other disorders that produce psychosis. These antipsychotic drugs are also
sometimes known as neuroleptics or "major tranquilizers", in contrast to "minor tranquilizers"
such as Valium that are used to treat anxiety or sleep disorders. These drugs have a broadly
suppressive effect on most types of active behavior, and particularly reduce the delusional and
agitated behavior characteristic of overt psychosis. The introduction of the first widely used
antipsychotic drug, chlorpromazine (Thorazine), in the 1950s, led to the release of many
schizophrenia patients from institutions in the years that followed.
Even so, the widespread use of antipsychotic drugs has long been controversial. There are
several reasons for this. First, these drugs are perceived as very aversive by people who have
to take them, because they produce a general dullness of thought and suppress the ability to
experience pleasure.[80] Second, it is difficult to show that they act specifically against
psychotic behaviors rather than merely suppressing all types of active behavior. Third, they
can produce a range of serious side effects, including weight gain, diabetes, fatigue, sexual
dysfunction, hormonal changes, and a type of movement disorder known as tardive
dyskinesia. Some of these side effects may continue long after the cessation of drug use, or
even permanently.
The first drugs introduced specifically for the treatment of psychosis all had strong direct
effects on multiple aspects of dopamine function. Drugs of this type are known as "typical
antipsychotics". Because of the problems they cause, there has been wide interest in newer
types of drugs known as "atypical antipsychotics" or "second-generation antipsychotics",
which aim to target the specific types of dopamine receptors involved in psychosis, and
thereby reduce psychotic symptoms without producing as many undesirable side effects.
There remains substantial dispute, however, about how much of an improvement in the
patient experience these drugs produce.

Toxicity
The LD50, or dose which is expected to be lethal in 50% of the population, has been found to
be: 59 mg/kg (mouse; administered intravenously); 950 mg/kg (mouse; administered
intraperitoneally); 163 mg/kg (rat; administered intraperitoneally); 79 mg/kg (dog;
administered intravenously).[81]

Binding profile of dopamine[82]

Macromolecule Ki (nM)
5-HT1A
8248
5-HT7
>10000
D1
130
D2
598

D3
D4
D5
DAT
NET
TAAR1

32.5
182.6
228
67
323
422

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 is transported to synaptic sites and packaged into vesicles for
release, which occurs during synaptic transmission. After release, free dopamine is either
reabsorbed into the presynaptic terminal for reuse, or broken down by the enzymes
monoamine oxidase or COMT, producing a variety of degradation metabolites.

Biosynthesis
Human biosynthesis pathway for trace amines and catecholamines[85]

L-Phenylalanine
L-Tyrosine
L-Dopa
Epinephrine
Phenethylamine
p-Tyramine
Dopamine
Norepinephrine
N-Methylphenethylamine
N-Methyltyramine
p-Octopamine
Synephrine
3-Methoxytyramine
AADC
AADC
AADC
PNMT
PNMT
PNMT

PNMT
AAAH
AAAH
COMT
DBH
DBH

This is the biosynthesis of catecholamines, including dopamine, as well as

phenethylaminergic trace amines from the amino acid phenylalanine. Abbreviations used:
DBH: Dopamine -hydroxylase
AADC: Aromatic L-amino acid decarboxylase
AAAH: (Biopterin-dependent) aromatic amino acid hydroxylase
COMT: Catechol O-methyltransferase
PNMT: Phenylethanolamine N-methyltransferase
Dopamine is synthesized in a restricted set of cell types, mainly neurons and cells in the
medulla of the adrenal 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 acid phenylalanine or the non-essential amino acid tyrosine. These amino
acids are found in nearly every protein and as such are provided from ingestion of proteincontaining food, with tyrosine being the most common. Although dopamine itself is also
found in many types of food, it is incapable of crossing the bloodbrain barrier that surrounds
and protects the brain. It must therefore be synthesized inside the brain in order to perform its
neural actions.
L-Phenylalanine

is converted into L-tyrosine by the enzyme phenylalanine hydroxylase

(PAH), with molecular oxygen (O2) and tetrahydrobiopterin (THB) as cofactors. L-Tyrosine is
converted into L-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-amino acid decarboxylase (AADC; also known as DOPA decarboxylase
(DDC)), with pyridoxal phosphate (PLP) as the cofactor.
Dopamine itself is also used as precursor in the synthesis of the neurotransmitters
norepinephrine and epinephrine. Dopamine is converted into norepinephrine by the enzyme
dopamine -hydroxylase (DBH), with O2 and L-ascorbic acid as cofactors. Norepinephrine is
converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT)
with S-adenosyl-L-methionine (SAMe) as the cofactor.
It should be noted that some of the cofactors also require their own synthesis. Deficiency in
any required amino acid or cofactor will result in subsequent dopamine, norepinephrine, and
epinephrine biosynthesis impairment and deficiency.

Storage, release, and reuptake

Inside the brain dopamine functions as a neurotransmitter, and is controlled by a set of
mechanisms that are common to all neurotransmitters. After synthesis, dopamine is
transported from the cytosol[citation needed] into synaptic vesicles by the vesicular monoamine

transporter 2 (VMAT2). Dopamine is stored in and remains in these vesicles until an action
potential occurs and causes the contents of the vesicles to be ejected into the synaptic cleft.
Once in the synapse, dopamine binds to and activates dopamine receptors, which can be
located either on postsynaptic 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 are then absorbed back into the presynaptic cell, via reuptake mediated either
by the high-affinity dopamine transporter (DAT) or by the low-affinity plasma membrane
monoamine transporter (PMAT). Once back in the cytosol, dopamine is subsequently
repackaged into vesicles by VMAT2, making it available for future release.

Degradation

Dopamine 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. Both isoforms of MAO, MAO-A and MAO-B, are equally effective.
The metabolites produced by these processes are:

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, a partial TAAR1 agonist)

HVA (Homovanillic acid)

All of these are intermediate metabolites except MOPET and HVA, which are filtered from
the bloodstream by the kidneys and then excreted in the urine.
The specific reactions that make up these pathways are:

Dopamine DOPAL, mediated by MAO

DOPAL DOPAC, mediated by ALDH

DOPAL DOPET, mediated by aldose reductase (minor pathway)

DOPAC HVA, mediated by COMT

DOPET MOPET, mediated by COMT

Dopamine 3-MT, mediated by COMT

3-MT HVA, mediated by MAO

In most areas of the brain, including the striatum and basal ganglia, dopamine is inactivated
by reuptake via the DAT, then enzymatic breakdown by MAO into DOPAC. In the prefrontal
cortex, however, there are very few 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.[86] 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.[87] Dopamine that is not
broken down by enzymes is repackaged into vesicles for future release.

Chemistry

Dopamine structure

Phenethylamine structure

Catechol structure
Chemically, a dopamine molecule consists of a catechol structure (a benzene ring with two
hydroxyl side groups) with one amine group attached. As such, dopamine is the simplest
possible catecholamine, a family that also includes the neurotransmitters norepinephrine and
epinephrine. The presence of a benzene ring with an attached amine group makes it a
phenethylamine, a family that includes numerous psychoactive drugs.
Dopamine, like most amines, is an organic base. At neutral or acidic pH levels it is generally
protonated. The protonated form is highly water-soluble and relatively stable, though it is
capable of oxidizing if exposed to oxygen or other oxidants. At basic pH levels, dopamine
becomes deprotonated. In this free base form it is less soluble and also highly reactive and
easily oxidized. Because of this pH-dependence, dopamine is supplied for chemical or
pharmaceutical use in the form of dopamine hydochloride, that is, the hydrochloride salt that
is created when dopamine is combined with hydrochloric acid. In dry form, dopamine
hydrochloride is a fine colorless powder. When dissolved in distilled water it gives a solution
that is mildly acidic and therefore relatively stable. It cannot, however, be combined with
alkaline solutions such as a bicarbonate buffer 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.[88] The rate of
autoxidation can be increased by the presence of ferrous iron or other factors. The ability of
dopamine autoxidation to produce quinones and free radicals makes it a potent cell toxin, and
there is evidence that this mechanism may contribute to cell loss that occurs in Parkinson's
disease or other conditions.[89]

Polydopamine
Research motivated by mussel adhesive proteins led to the discovery in 2007 that a wide
variety of materials, if placed in a solution of dopamine at slightly basic pH, will become
coated with a layer of polymerized dopamine, often referred to as polydopamine.[90][91] This
polymerized dopamine forms by a spontaneous oxidation reaction, and is formally a type of
melanin.[92] Synthesis usually involves reaction of dopamine hydrochloride with Tris as a base
in water. The structure of polydopamine is unknown.[91]
Polydopamine coatings can form on objects ranging in size from nanoparticles to large
surfaces. Polydopamine layers have chemical properties that have the potential to be
extremely useful, and numerous studies have examined their possible applications. At the
simplest level, they can be used for protection against damage by light, or to form capsules for
drug delivery. At a more sophisticated level, their adhesive properties may make them useful
as substrates for biosensors or other biologically active macromolecules.[92]

History
Main article: History of catecholamine research
Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome
Laboratories in London, England.[93] It was named dopamine because it is a monoamine
whose precursor in the Barger-Ewens synthesis is 3,4-dihydroxyphenylalanine (levodopamine
or L-DOPA). Dopamine's function as a neurotransmitter was first recognized in 1958 by
Arvid Carlsson and Nils-ke Hillarp at the Laboratory for Chemical Pharmacology of the
National Heart Institute of Sweden.[94] Carlsson was awarded the 2000 Nobel Prize in
Physiology or Medicine for showing that dopamine is not only a precursor of norepinephrine
(noradrenaline) and epinephrine (adrenaline), but also a neurotransmitter.

See also

Addiction
Amphetamine

Antipsychotic

Catecholamine

Catechol-O-methyl transferase

Classical conditioning

Cocaine

Depression

Dopamine hypothesis of schizophrenia

Dopamine reuptake inhibitor

Epinine (N-methyldopamine)

Limbic system

Methylphenidate

N,N-Dimethyldopamine

Neurotransmitter

Operant conditioning

Parkinson's disease

Prolactinoma

Schizophrenia

Selegiline

Serotonin

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