Dopamine (DA, a contraction of 3,4-
dihydr
oxy
phenethyl
amine) is a
neuromodulatory
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second m ...
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
that plays several important roles in cells. It is an
organic chemical
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The st ...
of the
catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a subst ...
and
phenethylamine
Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...
families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
synthesized by removing a
carboxyl group
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
from a molecule of its
precursor chemical
In chemistry, a precursor is a compound that participates in a chemical reaction that produces another compound.
In biochemistry, the term "precursor" often refers more specifically to a chemical compound preceding another in a metabolic pathway, ...
,
L-DOPA
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
, which is
synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
—a chemical released by
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s (nerve cells) to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct
dopamine pathways
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...
, one of which plays a major role in the motivational component of
reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many
addictive
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...
drugs
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
increase dopamine release or block its
reuptake
Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transm ...
into neurons following release.
Other brain dopamine pathways are involved in
motor control
Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement.
To control movement, the nervous system must integrate multimodal sensory information (both f ...
and in controlling the release of various hormones. These pathways and
cell groups
The cell group is a form of church organization that is used in many Christian churches. Cell groups are generally intended to teach the Bible and personalize Christian fellowship. They are always used in cell churches, but also occur in parachu ...
form a dopamine system which is
neuromodulatory
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second m ...
.
In popular culture and media, dopamine is often portrayed as the main chemical of pleasure, but the current opinion in pharmacology is that dopamine instead confers
motivational salience
Motivational salience is a cognitive process and a form of attention that ''motivates'' or propels an individual's behavior towards or away from a particular object, perceived event or outcome. Motivational salience regulates the intensity of be ...
;
in other words, dopamine signals the perceived motivational prominence (i.e., the desirability or aversiveness) of an outcome, which in turn propels the organism's behavior toward or away from achieving that outcome.
Outside the central nervous system, dopamine functions primarily as a local
paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...
messenger. In blood vessels, it inhibits
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
release and acts as a
vasodilator
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
(at normal concentrations); 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 Gastrointestinal physiology is the branch of human physiology that addresses the physical function of the gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical and chemical means, extract nutrients and ...
and protects
intestinal mucosa
The gastrointestinal wall of the gastrointestinal tract is made up of four layers of specialised tissue. From the inner cavity of the gut (the lumen) outwards, these are:
# Mucosa
# Submucosa
# Muscular layer
# Serosa or adventitia
The mucosa is ...
; and in the immune system, it reduces the activity of
lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
. With the exception of the blood vessels, dopamine in each of these peripheral systems is synthesized locally and exerts its effects near the cells that release it.
Several important diseases of the nervous system are associated with dysfunctions of the dopamine system, and some of the key medications used to treat them work by altering the effects of dopamine.
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, a degenerative condition causing
tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the
midbrain
The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...
called the
substantia nigra
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...
. Its metabolic precursor L-DOPA can be manufactured; ''Levodopa'', a pure form of L-DOPA, is the most widely used treatment for Parkinson's. There is evidence that
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
involves altered levels of dopamine activity, and most
antipsychotic drugs
Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of oth ...
used to treat this are
dopamine antagonist
A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have fo ...
s which reduce dopamine activity. Similar dopamine antagonist drugs are also some of the most effective
anti-nausea agents.
Restless legs syndrome
Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...
and
attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...
(ADHD) are associated with decreased dopamine activity.
Dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...
stimulants
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
can be addictive in high doses, but some are used at lower doses to treat ADHD.
Dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
itself is available as a manufactured medication for
intravenous injection
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutri ...
: although it
cannot reach the brain from the bloodstream, its peripheral effects make it useful in the treatment of
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
or
shock
Shock may refer to:
Common uses Collective noun
*Shock, a historic commercial term for a group of 60, see English numerals#Special names
* Stook, or shock of grain, stacked sheaves
Healthcare
* Shock (circulatory), circulatory medical emerge ...
, especially in newborn babies.
Structure
A dopamine molecule consists of a
catechol
Catechol ( or ), also known as pyrocatechol or 1,2-dihydroxybenzene, is a toxic organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amoun ...
structure (a
benzene
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...
ring with two
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
side groups) with one
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
group attached via an
ethyl
Ethyl may refer to:
Arts and entertainment
* Cold Ethyl, a Swedish rock band
*Ethyl Sinclair, a character in the ''Dinosaurs'' television show
Science and technology
* Ethyl group, an organic chemistry moiety
* Ethyl alcohol (or ethanol)
* E ...
chain.
As such, dopamine is the simplest possible
catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a subst ...
, a family that also includes the
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
and
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
.
The presence of a benzene ring with this amine attachment makes it a
substituted phenethylamine
Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative compounds of phenethylamine which can be formed by ...
, a family that includes numerous
psychoactive drug
A psychoactive drug, psychopharmaceutical, psychoactive agent or psychotropic drug is a chemical substance, that changes functions of the nervous system, and results in alterations in perception, mood, consciousness, cognition or behavior. ...
s.
Like most amines, dopamine is an
organic base
An organic base is an organic compound which acts as a base. Organic bases are usually, but not always, proton acceptors. They usually contain nitrogen atoms, which can easily be protonated. For example, amines or nitrogen-containing heterocyclic ...
.
As a
base, it is generally
protonated
In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid, i ...
in
acid
In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...
ic environments (in an
acid-base reaction).
[ The protonated form is highly water-soluble and relatively stable, but can become ]oxidized
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
if exposed to oxygen or other oxidants
An oxidizing agent (also known as an oxidant, oxidizer, electron recipient, or electron acceptor) is a substance in a redox chemical reaction that gains or " accepts"/"receives" an electron from a (called the , , or ). In other words, an oxi ...
.[ In basic environments, dopamine is not protonated.][ In this ]free base
Free base (freebase, free-base) is the conjugate base (deprotonated) form of an amine, as opposed to its conjugate acid (protonated) form. The amine is often an alkaloid, such as nicotine, cocaine, morphine, and ephedrine, or derivatives thereo ...
form, it is less water-soluble and also more highly reactive.[ Because of the increased stability and water-solubility of the protonated form, dopamine is supplied for chemical or pharmaceutical use as dopamine ]hydrochloride
In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative na ...
—that is, the hydrochloride
In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative na ...
salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...
that is created when dopamine is combined with hydrochloric acid
Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid
Acid strength is the tendency of an acid, symbol ...
.[ In dry form, dopamine hydrochloride is a fine powder which is white to yellow in color.
]
Biochemistry
Synthesis
Dopamine is synthesized in a restricted set of cell types, mainly neurons and cells in the medulla
Medulla or Medullary may refer to:
Science
* Medulla oblongata, a part of the brain stem
* Renal medulla, a part of the kidney
* Adrenal medulla, a part of the adrenal gland
* Medulla of ovary, a stroma in the center of the ovary
* Medulla of th ...
of the adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
s.[ The primary and minor ]metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
s respectively are:
:Primary: L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine
:Minor: L-Phenylalanine → L-Tyrosine → ''p''-Tyramine → Dopamine
:Minor: L-Phenylalanine → ''m''-Tyrosine → ''m''-Tyramine → Dopamine
Reaction diagram
/ref>
Reaction diagram
/ref>
The direct precursor of dopamine, L-DOPA, can be synthesized indirectly from the essential amino acid
An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come from the diet. Of the 21 amino acids common to all life form ...
phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
or directly from the non-essential amino acid tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
.[ These ]amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s are found in nearly every protein and so are readily available in food, with tyrosine being the most common. Although dopamine is also found in many types of food, it is incapable of crossing the blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
that surrounds and protects the brain. It must therefore be synthesized inside the brain to perform its neuronal activity
Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
.
L-Phenylalanine is converted into L-tyrosine by the enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
phenylalanine hydroxylase
Phenylalanine hydroxylase. (PAH) () is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a class ...
, with molecular oxygen
There are several known allotropes of oxygen. The most familiar is molecular oxygen (O2), present at significant levels in Earth's atmosphere and also known as dioxygen or triplet oxygen. Another is the highly reactive ozone (O3). Others are:
*A ...
(O2) and tetrahydrobiopterin
Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...
as cofactors
Cofactor may also refer to:
* Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed
* A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and t ...
, with tetrahydrobiopterin, O2, and iron (Fe2+) as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (also known as DOPA decarboxylase), with pyridoxal phosphate
Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent ac ...
as the cofactor.[
Dopamine itself is used as precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine.][ Dopamine is converted into norepinephrine by the enzyme ]dopamine β-hydroxylase
Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme () that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine.
The three substrates of ...
, with O2 and L-ascorbic acid as cofactors.[ Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine ''N''-methyltransferase with ''S''-adenosyl-L-methionine as the cofactor.][
Some of the cofactors also require their own synthesis.][ Deficiency in any required amino acid or cofactor can impair the synthesis of dopamine, norepinephrine, and epinephrine.][
]
Degradation
Dopamine is broken down into inactive metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s by a set of enzymes—monoamine oxidase
Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...
(MAO), catechol-''O''-methyl transferase (COMT), and aldehyde dehydrogenase
Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have be ...
(ALDH), acting in sequence. Both isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
of monoamine oxidase, MAO-A
Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, s ...
and MAO-B
Monoamine oxidase B, also known as MAOB, is an enzyme that in humans is encoded by the ''MAOB'' gene.
The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. ...
, effectively metabolize dopamine.[ Different breakdown pathways exist but the main end-product is ]homovanillic acid
Homovanillic acid (HVA) is a major catecholamine metabolite that is produced by a consecutive action of monoamine oxidase and catechol-O-methyltransferase on dopamine. Homovanillic acid is used as a reagent to detect oxidative enzymes, and is ...
(HVA), which has no known biological activity.[ From the bloodstream, homovanillic acid is filtered out by the kidneys and then excreted in the urine.][ The two primary metabolic routes that convert dopamine into HVA are:
* Dopamine → DOPAL → ]DOPAC
3,4-Dihydroxyphenylacetic acid (DOPAC) is a metabolite of the neurotransmitter dopamine. Dopamine can be metabolized into one of three substances. One such substance is DOPAC. Another is 3-methoxytyramine (3-MT). Both of these substances are ...
→ HVA – catalyzed by MAO, ALDH, and COMT respectively
* Dopamine → 3-Methoxytyramine
3-Methoxytyramine (3-MT), also known as 3-methoxy-4-hydroxyphenethylamine, is a human trace amine that occurs as a metabolite of the neurotransmitter dopamine. It is formed by the introduction of a methyl group to dopamine by the enzyme catecho ...
→ HVA – catalyzed by COMT and MAO+ALDH respectively
In clinical research on schizophrenia, measurements of homovanillic acid in plasma
Plasma or plasm may refer to:
Science
* Plasma (physics), one of the four fundamental states of matter
* Plasma (mineral), a green translucent silica mineral
* Quark–gluon plasma, a state of matter in quantum chromodynamics
Biology
* Blood pla ...
have been used to estimate levels of dopamine activity in the brain. A difficulty in this approach however, is separating the high level of plasma homovanillic acid contributed by the metabolism of norepinephrine.
Although dopamine is normally broken down by an oxidoreductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...
enzyme, it is also susceptible to oxidation by direct reaction with oxygen, yielding quinone
The quinones are a class of organic compounds that are formally "derived from aromatic compounds uch as benzene or naphthalene
Uch ( pa, ;
ur, ), frequently referred to as Uch Sharīf ( pa, ;
ur, ; ''"Noble Uch"''), is a historic city in the southern part of Pakistan's Punjab province. Uch may have been founded as Alexandria on the Indus, a town founded by Alexand ...
by conversion of an even number of –CH= groups into –C(=O)– groups with any necessary rearrangement of double ...
s plus various free radicals
In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron.
With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spont ...
as products. The rate of oxidation can be increased by the presence of ferric
In chemistry, iron(III) refers to the element iron in its +3 oxidation state. In ionic compounds (salts), such an atom may occur as a separate cation (positive ion) denoted by Fe3+.
The adjective ferric or the prefix ferri- is often used to spe ...
iron or other factors. Quinones and free radicals produced by autoxidation of dopamine can poison cells, and there is evidence that this mechanism may contribute to the cell loss that occurs in Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
and other conditions.
Functions
Cellular effects
Dopamine exerts its effects by binding to and activating cell surface receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...
s.[ In humans, dopamine has a high ]binding affinity
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mol ...
at dopamine receptor
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...
s and human trace amine-associated receptor 1
Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily exp ...
(hTAAR1). In mammals, five subtypes of dopamine receptor
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...
s have been identified, labeled from D1 to D5. All of them function as metabotropic
A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor, is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity. The nervous system utilizes two types of receptors: met ...
, G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s, meaning that they exert their effects via a complex second messenger system
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
. These receptors can be divided into two families, known as D1-like and D2-like.[ For receptors located on neurons in the nervous system, the ultimate effect of D1-like activation (D1 and D5) can be excitation (via opening of ]sodium channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
s) or inhibition (via opening of potassium channel
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
s); the ultimate effect of D2-like activation (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 the second messenger ]cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
.[ D1 receptors are the most numerous dopamine receptors in the human nervous system; D2 receptors are next; D3, D4, and D5 receptors are present at significantly lower levels.][
]
Storage, release, and reuptake
Inside the brain, dopamine functions as a neurotransmitter and neuromodulator
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second m ...
, and is controlled by a set of mechanisms common to all monoamine neurotransmitter
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromaticity, aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.
All mo ...
s.[ After synthesis, dopamine is transported from the ]cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
into synaptic vesicles
In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impul ...
by a solute carrier—a vesicular monoamine transporter
The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, ...
, VMAT2
The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the ''SLC18A2'' gene. SLC18A2 is an integral membrane protein that transports monoamines—particul ...
. Dopamine is stored in these vesicles until it is ejected into the synaptic cleft
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...
. In most cases, the release of dopamine occurs through a process called exocytosis
Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use o ...
which is caused by action potential
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
s, but it can also be caused by the activity of an intracellular trace amine-associated receptor
Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerab ...
, TAAR1
Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily exp ...
. TAAR1 is a high-affinity receptor for dopamine, trace amine
Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the ...
s, and certain substituted amphetamine
Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with sub ...
s that is located along membranes in the intracellular milieu of the presynaptic cell; activation of the receptor can regulate dopamine signaling by inducing dopamine reuptake inhibition
Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of trans ...
and efflux as well as by inhibiting neuronal firing through a diverse set of mechanisms.
Once in the synapse, dopamine binds to and activates dopamine receptors. These can be postsynaptic
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous sys ...
dopamine receptors, which are located on dendrite
Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the n ...
s (the postsynaptic neuron), or presynaptic autoreceptor
An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the aut ...
s (e.g., the D2sh and presynaptic D3 receptors), which are located on the membrane of an axon terminal
Axon terminals (also called synaptic boutons, terminal boutons, or end-feet) are distal terminations of the telodendria (branches) of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell, or neuron, that condu ...
(the presynaptic neuron). After the postsynaptic neuron elicits an action potential, dopamine molecules quickly become unbound from their receptors. They are then absorbed back into the presynaptic cell, via reuptake
Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transm ...
mediated either by the dopamine transporter
The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopam ...
or by the plasma membrane monoamine transporter
The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the ''SLC29A4'' gene. It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). Unlike othe ...
. Once back in the cytosol, dopamine can either be broken down by a monoamine oxidase
Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...
or repackaged into vesicles by VMAT2, making it available for future release.[
In the brain the level of extracellular dopamine is modulated by two mechanisms: phasic and tonic transmission.] Phasic dopamine release, like most neurotransmitter release in the nervous system, is driven directly by action potentials in the dopamine-containing cells.[ Tonic dopamine transmission occurs when small amounts of dopamine are released without being preceded by presynaptic action potentials.][ Tonic transmission is regulated by a variety of factors, including the activity of other neurons and neurotransmitter reuptake.][
]
Central nervous system
Inside the brain, dopamine plays important roles in executive function
In cognitive science and neuropsychology, executive functions (collectively referred to as executive function and cognitive control) are a set of cognitive processes that are necessary for the cognitive control of behavior: selecting and succe ...
s, motor control
Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement.
To control movement, the nervous system must integrate multimodal sensory information (both f ...
, motivation
Motivation is the reason for which humans and other animals initiate, continue, or terminate a behavior at a given time. Motivational states are commonly understood as forces acting within the agent that create a disposition to engage in goal-dire ...
, arousal
Arousal is the physiological and psychological state of being awoken or of sense organs stimulated to a point of perception. It involves activation of the ascending reticular activating system (ARAS) in the brain, which mediates wakefulness, th ...
, reinforcement
In behavioral psychology, reinforcement is a consequence applied that will strengthen an organism's future behavior whenever that behavior is preceded by a specific antecedent stimulus. This strengthening effect may be measured as a higher freq ...
, and reward
Reward may refer to:
Places
* Reward (Shelltown, Maryland), a historic home in Shelltown Maryland
* Reward, California (disambiguation)
* Reward-Tilden's Farm, a historic home in Chestertown Maryland
Arts, entertainment, and media
* "Rewa ...
, as well as lower-level functions including lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The proces ...
, sexual gratification
Orgasm (from Greek , ; "excitement, swelling") or sexual climax is the sudden discharge of accumulated sexual excitement during the sexual response cycle, resulting in rhythmic, involuntary muscular contractions in the pelvic region charac ...
, and nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
. The dopaminergic cell groups
Dopaminergic cell groups, DA cell groups, or dopaminergic nuclei are collections of neurons in the central nervous system that synthesize the neurotransmitter dopamine. In the 1960s, dopaminergic neurons or ''dopamine neurons'' were first identifi ...
and pathways make up the dopamine system which is neuromodulatory
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second m ...
.
Dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...
neurons (dopamine-producing nerve cells) are comparatively few in number—a total of around 400,000 in the human brain—and their cell bodies
The soma (pl. ''somata'' or ''somas''), perikaryon (pl. ''perikarya''), neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. The word 'soma' comes from the Greek '' σῶ ...
are confined in groups to a few relatively small brain areas.[ However their ]axon
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
s project to many other brain areas, and they exert powerful effects on their targets.[ These dopaminergic cell groups were first mapped in 1964 by ]Annica Dahlström
Annica Dahlström (born 1941) is a Swedish physician and Professor Emerita of Histology and Neuroscience at the Department of Medical Chemistry and Cell Biology at Gothenburg University.
Dahlström's research focuses on how nerve cells store and t ...
and Kjell Fuxe, who assigned them labels starting with the letter "A" (for "aminergic"). In their scheme, areas A1 through A7 contain the neurotransmitter norepinephrine, whereas A8 through A14 contain dopamine. The dopaminergic areas they identified are the substantia nigra (groups 8 and 9); the ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...
(group 10); the posterior hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
(group 11); the arcuate nucleus
The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...
(group 12); the zona incerta
The zona incerta (ZI) is a horizontally elongated region of gray matter in the subthalamus below the thalamus. Its connections project extensively over the brain from the cerebral cortex down into the spinal cord.
Its function is unknown, though ...
(group 13) and the periventricular nucleus
The periventricular nucleus is a thin sheet of small neurons located in the wall of the third ventricle, a composite structure of the hypothalamus. It functions in analgesia.
It is located in the rostral, intermediate, and caudal regions of t ...
(group 14).[
The substantia nigra is a small midbrain area that forms a component of the ]basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...
. This has two parts—an input area called the pars compacta
The pars compacta (SNpc) is a portion of the ''substantia nigra'', located in the midbrain. It is formed by dopaminergic neurons and located medial to the pars reticulata. Parkinson's disease is characterized by the death of dopaminergic neurons ...
and an output area the pars reticulata
The pars reticulata (SNpr) is a portion of the substantia nigra and is located lateral to the pars compacta. Most of the neurons that project out of the pars reticulata are inhibitory GABAergic neurons (i.e., these neurons release GABA, which is ...
. The dopaminergic neurons are found mainly in the pars compacta (cell group A8) and nearby (group A9). In humans, the projection of dopaminergic neurons from the substantia nigra pars compacta to the dorsal striatum, termed the ''nigrostriatal pathway The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum (i.e., the caudate nucleus and putamen) in the forebrain. It is one of the fou ...
'', plays a significant role in the control of motor function and in learning new motor skill
A motor skill is a function that involves specific movements of the body's muscles to perform a certain task. These tasks could include walking, running, or riding a bike. In order to perform this skill, the body's nervous system, muscles, and br ...
s. These neurons are especially vulnerable to damage, and when a large number of them die, the result is a parkinsonian syndrome
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...
.
The ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...
(VTA) is another midbrain area. The most prominent group of VTA dopaminergic neurons projects to the prefrontal cortex via the mesocortical pathway
The mesocortical pathway is a dopaminergic pathway that connects the ventral tegmentum to the prefrontal cortex. It is one of the four major dopamine pathways in the brain. It is essential to the normal cognitive function of the dorsolateral prefr ...
and another smaller group projects to the nucleus accumbens via the mesolimbic pathway
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral ...
. Together, these two pathways are collectively termed the ''mesocorticolimbic projection
Dopaminergic pathways (dopamine pathways, dopaminergic projections) in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. ...
''. The VTA also sends dopaminergic projections to the amygdala
The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...
, cingulate gyrus
The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the ci ...
, hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
, and olfactory bulb
The olfactory bulb (Latin: ''bulbus olfactorius'') is a grey matter, neural structure of the vertebrate forebrain involved in olfaction, the sense of odor, smell. It sends olfactory information to be further processed in the amygdala, the orbitof ...
. Mesocorticolimbic neurons play a central role in reward and other aspects of motivation. Accumulating literature shows that dopamine also plays a crucial role in aversive learning through its effects on a number of brain regions.
The posterior hypothalamus has dopamine neurons that project to the spinal cord, but 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.]
The arcuate nucleus and the periventricular nucleus of the hypothalamus have dopamine neurons that form an important projection—the ''tuberoinfundibular pathway
The tuberoinfundibular pathway refers to a population of dopamine neurons that project from the arcuate nucleus ( the "infundibular nucleus") in the tuberal region of the hypothalamus to the median eminence. It is one of the four major dopamine p ...
'' which goes to the pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
, where it influences the secretion of the hormone prolactin
Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...
.[ Dopamine is the primary ]neuroendocrine
Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules ( hormones) into the blood. In this way they b ...
inhibitor of the secretion of prolactin
Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...
from the anterior pituitary
A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the p ...
gland.[ Dopamine produced by neurons in the arcuate nucleus is secreted into the ]hypophyseal portal system
The hypophyseal portal system is a system of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus with the anterior pituitary. Its main function is to quickly transport and exchange hormones between the hypo ...
of the median eminence
The median eminence, part of the inferior boundary of the hypothalamus in the brain, is attached to the infundibulum. The median eminence is a small swelling on the tuber cinereum, posterior to and atop the pituitary stalk; it lies in the area rou ...
, which supplies the pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
.[ The ]prolactin cell
A lactotropic cell (also known as prolactin cell, epsilon acidophil, lactotrope, lactotroph, mammatroph, mammotroph) is a cell in the anterior pituitary which produces prolactin in response to hormonal signals including dopamine which is inhibit ...
s that produce prolactin, in the absence of dopamine, secrete prolactin continuously; dopamine inhibits this secretion.[ In the context of regulating prolactin secretion, dopamine is occasionally called prolactin-inhibiting factor, prolactin-inhibiting hormone, or prolactostatin.]
The zona incerta, grouped between the arcuate and periventricular nuclei, projects to several areas of the hypothalamus, and participates in the control of gonadotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...
, which is necessary to activate the development of the male
Male (symbol: ♂) is the sex of an organism that produces the gamete (sex cell) known as sperm, which fuses with the larger female gamete, or ovum, in the process of fertilization.
A male organism cannot reproduce sexually without access to ...
and female reproductive system
The female reproductive system is made up of the internal and external sex organs that function in the reproduction of new offspring. In humans, the female reproductive system is immature at birth and develops to maturity at puberty to be able ...
s, following puberty.[
An additional group of dopamine-secreting neurons is found in the ]retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
of the eye.[ These neurons are ]amacrine cells
Amacrine cells are interneurons in the retina. They are named from the Greek roots ''a–'' ("non"), ''makr–'' ("long") and ''in–'' ("fiber"), because of their short neuronal processes. Amacrine cells are inhibitory neurons, and they proje ...
, 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 cell
Cone cells, or cones, are photoreceptor cells in the retinas of vertebrate eyes including the human eye. They respond differently to light of different wavelengths, and the combination of their responses is responsible for color vision. Cone ...
s in the retina while suppressing rod cell
Rod cells are photoreceptor cells in the retina of the eye that can function in lower light better than the other type of visual photoreceptor, cone cells. Rods are usually found concentrated at the outer edges of the retina and are used in per ...
s—the result is to increase sensitivity to color and contrast during bright light conditions, at the cost of reduced sensitivity when the light is dim.
Basal ganglia
The largest and most important sources of dopamine in the vertebrate brain are the substantia nigra and ventral tegmental area.[ These structures are closely related to each other and functionally similar in many respects.][ Both are components of the mid brain.][ The largest component of the basal ganglia is the striatum.] The substantia nigra sends a dopaminergic projection to the dorsal striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
, while the ventral tegmental area sends a similar type of dopaminergic projection to the ventral striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
.[
Progress in understanding the functions of the basal ganglia has been slow.] The most popular hypotheses, broadly stated, propose that the basal ganglia play a central role in action selection Action selection is a way of characterizing the most basic problem of intelligent systems: what to do next. In artificial intelligence and computational cognitive science, "the action selection problem" is typically associated with intelligent agen ...
. The action selection theory in its simplest form proposes that when a person or animal is in a situation where several behaviors are possible, activity in the basal ganglia determines which of them is executed, by releasing that response from inhibition while continuing to inhibit other motor systems that if activated would generate competing behaviors. Thus the basal ganglia, in this concept, are responsible for initiating behaviors, but not for determining the details of how they are carried out. In other words, they essentially form a decision-making system.[
The basal ganglia can be divided into several sectors, and each is involved in controlling particular types of actions.] The ventral sector of the basal ganglia (containing the ventral striatum and ventral tegmental area) operates at the highest level of the hierarchy, selecting actions at the whole-organism level.[ The dorsal sectors (containing the dorsal striatum and substantia nigra) operate at lower levels, selecting the specific muscles and movements that are used to implement a given behavior pattern.][
Dopamine contributes to the action selection process in at least two important ways. First, it sets the "threshold" for initiating actions.][ 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
In psychology, impulsivity (or impulsiveness) is a tendency to act on a whim, displaying behavior characterized by little or no forethought, reflection, or consideration of the consequences. Impulsive actions are typically "poorly conceived, pre ...
; low levels of dopamine lead to torpor
Torpor is a state of decreased physiological activity in an animal, usually marked by a reduced body temperature and metabolic rate. Torpor enables animals to survive periods of reduced food availability. The term "torpor" can refer to the time ...
and slowed reactions.[ Parkinson's disease, in which dopamine levels in the substantia nigra circuit are greatly reduced, is characterized by stiffness and difficulty initiating movement—however, when people with the disease are confronted with strong stimuli such as a serious threat, their reactions can be as vigorous as those of a healthy person.][ In the opposite direction, drugs that increase dopamine release, such as cocaine or amphetamine, can produce heightened levels of activity, including, at the extreme, ]psychomotor agitation
Psychomotor agitation is a symptom in various disorders and health conditions. It is characterized by unintentional and purposeless motions and restlessness, often but not always accompanied by emotional distress. Typical manifestations include ...
and stereotyped movements.
The second important effect of dopamine is as a "teaching" signal.[ When an action is followed by an increase in dopamine activity, the basal ganglia circuit is altered in a way that makes the same response easier to evoke when similar situations arise in the future.][ This is a form of ]operant conditioning
Operant conditioning, also called instrumental conditioning, is a learning process where behaviors are modified through the association of stimuli with reinforcement or punishment. In it, operants—behaviors that affect one's environment—are c ...
, in which dopamine plays the role of a reward signal.[
]
Reward
In the language used to discuss the reward system, ''reward'' is the attractive and motivational property of a stimulus that induces appetitive behavior
The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and clas ...
(also known as approach behavior) and consummatory behavior
The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and class ...
. A rewarding stimulus is one that can induce the organism to approach it and choose to consume it. Pleasure
Pleasure refers to experience that feels good, that involves the enjoyment of something. It contrasts with pain or suffering, which are forms of feeling bad. It is closely related to value, desire and action: humans and other conscious anima ...
, learning
Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, attitudes, and preferences. The ability to learn is possessed by humans, animals, and some machine learning, machines ...
(e.g., classical and operant conditioning
Operant conditioning, also called instrumental conditioning, is a learning process where behaviors are modified through the association of stimuli with reinforcement or punishment. In it, operants—behaviors that affect one's environment—are c ...
), and approach behavior are the three main functions of reward. As an aspect of reward, ''pleasure'' provides a definition of reward; however, while all pleasurable stimuli are rewarding, not all rewarding stimuli are pleasurable (e.g., extrinsic rewards like money). The motivational or desirable aspect of rewarding stimuli is reflected by the approach behavior that they induce, whereas the pleasure from intrinsic rewards results from consuming them after acquiring them. A neuropsychological model which distinguishes these two components of an intrinsically rewarding stimulus is the incentive salience
Motivational salience is a cognitive process and a form of attention that ''motivates'' or propels an individual's behavior towards or away from a particular stimulus (psychology), object, perceived event or outcome. Motivational salience regulat ...
model, where "wanting" or desire (less commonly, "seeking") corresponds to appetitive or approach behavior while "liking" or pleasure corresponds to consummatory behavior. In human drug addicts
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use of ...
, "wanting" becomes dissociated with "liking" as the desire to use an addictive drug increases, while the pleasure obtained from consuming it decreases due to drug tolerance
Drug tolerance or drug insensitivity is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further ...
.
Within the brain, dopamine functions partly as a global reward signal. An initial dopamine response to a rewarding stimulus encodes information about the salience, value, and context of a reward. In the context of reward-related learning, dopamine also functions as a ''reward prediction error'' signal, that is, the degree to which the value of a reward is unexpected.[ According to this hypothesis proposed by Montague, Dayan, and Sejnowski, rewards that are expected do not produce a second phasic dopamine response in certain dopaminergic cells, but rewards that are unexpected, or greater than expected, produce a short-lasting increase in synaptic dopamine, whereas the omission of an expected reward actually causes dopamine release to drop below its background level.][ The "prediction error" hypothesis has drawn particular interest from computational neuroscientists, because an influential computational-learning method known as ]temporal difference learning
Temporal difference (TD) learning refers to a class of model-free reinforcement learning methods which learn by bootstrapping from the current estimate of the value function. These methods sample from the environment, like Monte Carlo methods, a ...
makes heavy use of a signal that encodes prediction error.[ This confluence of theory and data has led to a fertile interaction between neuroscientists and computer scientists interested in ]machine learning
Machine learning (ML) is a field of inquiry devoted to understanding and building methods that 'learn', that is, methods that leverage data to improve performance on some set of tasks. It is seen as a part of artificial intelligence.
Machine ...
.[
Evidence from ]microelectrode
A microelectrode is an electrode used in electrophysiology either for recording neural signals or for the electrical stimulation of nervous tissue (they were first developed by Ida Hyde in 1921). Pulled glass pipettes with tip diameters of 0. ...
recordings from the brains of animals shows that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra are strongly activated by a wide variety of rewarding events. These reward-responsive dopamine neurons in the VTA and substantia nigra are crucial for reward-related cognition and serve as the central component of the reward system. The function of dopamine varies in each axonal projection
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
from the VTA and substantia nigra; for example, the VTA–nucleus accumbens shell
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypotha ...
projection assigns incentive salience ("want") to rewarding stimuli and its associated cues, the VTA–prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46, ...
projection updates the value of different goals in accordance with their incentive salience, the VTA–amygdala and VTA–hippocampus projections mediate the consolidation of reward-related memories, and both the VTA–nucleus accumbens core
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypotha ...
and substantia nigra–dorsal striatum pathways are involved in learning motor responses that facilitate the acquisition of rewarding stimuli. Some activity within the VTA dopaminergic projections appears to be associated with reward prediction as well.
Pleasure
While dopamine has a central role in causing "wanting," associated with the appetitive or approach behavioral responses to rewarding stimuli, detailed studies have shown that dopamine cannot simply be equated with hedonic "liking" or pleasure, as reflected in the consummatory behavioral response.[ Dopamine neurotransmission is involved in some but not all aspects of pleasure-related cognition, since ]pleasure center
The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and class ...
s have been identified both within the dopamine system (i.e., nucleus accumbens shell) and outside the dopamine system (i.e., ventral pallidum
The ventral pallidum (VP) is a structure within the basal ganglia of the brain. It is an output nucleus whose fibres project to thalamic nuclei, such as the ventral anterior nucleus, the ventral lateral nucleus, and the medial dorsal nucleus.
The ...
and parabrachial nucleus
The parabrachial nuclei, also known as the parabrachial complex, are a group of nuclei in the dorsolateral pons that surrounds the superior cerebellar peduncle as it enters the brainstem from the cerebellum. They are named from the Latin term for ...
). For example, direct electrical stimulation of dopamine pathways, using electrodes implanted in the brain, is experienced as pleasurable, and many types of animals are willing to work to obtain it.[ ]Antipsychotic drug
Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of oth ...
s reduce dopamine levels and tend to cause anhedonia
Anhedonia is a diverse array of deficits in hedonic function, including reduced motivation or ability to experience pleasure. While earlier definitions emphasized the inability to experience pleasure, anhedonia is currently used by researchers t ...
, a diminished ability to experience pleasure. Many types of pleasurable experiences—such as sexual intercourse, eating, and playing video games—increase dopamine release. All addictive drugs directly or indirectly affect dopamine neurotransmission in the nucleus accumbens;[ these drugs increase drug "wanting", leading to compulsive drug use, when repeatedly taken in high doses, presumably through the sensitization of incentive-salience.] Drugs that increase synaptic dopamine concentrations include psychostimulant
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
s such as methamphetamine and cocaine. These produce increases in "wanting" behaviors, but do not greatly alter expressions of pleasure or change levels of satiation. However, opiate
An opiate, in classical pharmacology, is a substance derived from opium. In more modern usage, the term ''opioid'' is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain (including antagonis ...
drugs such as heroin and morphine produce increases in expressions of "liking" and "wanting" behaviors.[ Moreover, animals in which the ventral tegmental dopamine system has been rendered inactive do not seek food, and will starve to death if left to themselves, but if food is placed in their mouths they will consume it and show expressions indicative of pleasure.
A clinical study from January 2019 that assessed the effect of a dopamine precursor (]levodopa
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
), dopamine antagonist (risperidone
Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It is taken either by mouth or by injection (subcutaneous or intramuscular). The injectable versions ...
), and a placebo on reward responses to music – including the degree of pleasure experienced during musical chills, as measured by changes in electrodermal activity
Electrodermal activity (EDA) is the property of the human body that causes continuous variation in the electrical characteristics of the skin. Historically, EDA has also been known as skin conductance, galvanic skin response (GSR), electrodermal ...
as well as subjective ratings – found that the manipulation of dopamine neurotransmission bidirectionally regulates pleasure cognition (specifically, the hedonic impact of music) in human subjects. This research demonstrated that increased dopamine neurotransmission acts as a ''sine qua non
''Sine qua non'' (, ) or ''condicio sine qua non'' (plural: ''condiciones sine quibus non'') is an indispensable and essential action, condition, or ingredient. It was originally a Latin legal term for " conditionwithout which it could not be" ...
'' condition for pleasurable hedonic reactions to music in humans.
Outside the central nervous system
Dopamine does not cross the blood–brain barrier, so its synthesis and functions in peripheral areas are to a large degree independent of its synthesis and functions in the brain. 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 ]sulfate
The sulfate or sulphate ion is a polyatomic anion with the empirical formula . Salts, acid derivatives, and peroxides of sulfate are widely used in industry. Sulfates occur widely in everyday life. Sulfates are salts of sulfuric acid and many ar ...
, a conjugate produced by the enzyme sulfotransferase 1A3/1A4 acting on free dopamine.[ The bulk of this dopamine sulfate is produced in the ]mesentery
The mesentery is an organ that attaches the intestines to the posterior abdominal wall in humans and is formed by the double fold of peritoneum. It helps in storing fat and allowing blood vessels, lymphatics, and nerves to supply the intestines ...
that surrounds parts of the digestive system.[ The production of dopamine sulfate is thought to be a mechanism for detoxifying dopamine that is ingested as food or produced by the digestive process—levels in the plasma typically rise more than fifty-fold after a meal.][ Dopamine sulfate has no known biological functions and is excreted in urine.][
The relatively small quantity of unconjugated dopamine in the bloodstream may be produced by the ]sympathetic nervous system
The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of th ...
, 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
Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme () that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine.
The three substrates of ...
, which is released into the bloodstream by the adrenal medulla.[ Some dopamine receptors are located in the walls of arteries, where they act as a ]vasodilator
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
and an inhibitor of norepinephrine release. These responses might be activated by dopamine released from the carotid body
The carotid body is a small cluster of chemoreceptor cells, and supporting sustentacular cells. The carotid body is located in the adventitia, in the bifurcation (fork) of the common carotid artery, which runs along both sides of the neck.
The ca ...
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
Exocrine glands are glands that secrete substances on to an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous. Exocrine glands are one of two ...
or paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...
function.[ The peripheral systems in which dopamine plays an important role include the ]immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
, the kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
s and the pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...
.
Immune system
In the immune system dopamine acts upon receptors present on immune cells, especially lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s. Dopamine can also affect immune cells in the spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . , bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
, and circulatory system
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
. In addition, dopamine can be synthesized and released by immune cells themselves.[ The main effect of dopamine on lymphocytes is to reduce their activation level. The functional significance of this system is unclear, but it affords a possible route for interactions between the nervous system and immune system, and may be relevant to some autoimmune disorders.]
Kidneys
The renal dopaminergic system is located in the cells of the nephron
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
in the kidney, where all subtypes of dopamine receptors are present. Dopamine is also synthesized there, by tubule
In biology, a tubule is a general term referring to small tube or similar type of structure. Specifically, tubule can refer to:
* a small tube or fistular structure
* a minute tube lined with glandular epithelium
* any hollow cylindrical body stru ...
cells, and discharged into the tubular fluid Tubular fluid is the fluid in the tubules of the kidney. It starts as a renal ultrafiltrate in the glomerulus, changes composition through the nephron, and ends up as urine leaving through the ureters.
Composition table
The composition of tubular ...
. Its actions include increasing the blood supply to the kidneys, increasing the glomerular filtration rate
Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood p ...
, and increasing the excretion of sodium in the urine. Hence, defects in renal dopamine function can lead to reduced sodium excretion and consequently result in the development of high blood pressure
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
. There is strong evidence that faults in the production of dopamine or in the receptors can result in a number of pathologies including oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
, edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
, and either genetic or essential hypertension. Oxidative stress can itself cause hypertension. Defects in the system can also be caused by genetic factors or high blood pressure.
Pancreas
In the pancreas the role of dopamine is somewhat complex. The pancreas consists of two parts, an exocrine
Exocrine glands are glands that secrete substances on to an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous. Exocrine glands are one of two ...
and an endocrine
The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...
component. The exocrine part synthesizes and secretes digestive enzymes
Digestive enzymes are a group of enzymes that break down polymeric macromolecules into their smaller building blocks, in order to facilitate their absorption into the cells of the body. Digestive enzymes are found in the digestive tracts of anim ...
and other substances, including dopamine, into the small intestine.[ 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 Gastrointestinal physiology is the branch of human physiology that addresses the physical function of the gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical and chemical means, extract nutrients and ...
(the rate at which content moves through the digestive system).
The pancreatic islets make up the endocrine part of the pancreas, and synthesize and secrete hormones including insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
into the bloodstream.[ There is evidence that the ]beta cell
Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...
s in the islets 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.][
]
Medical uses
Dopamine as a manufactured medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
is sold under the trade names Intropin, Dopastat, and Revimine, among others. It is on the World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. It is most commonly used as a stimulant drug in the treatment of severe low blood pressure
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...
, slow heart rate
Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...
, and cardiac arrest
Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...
. It is especially important in treating these in newborn infants. It is given intravenously. Since the half-life of dopamine in plasma is very short—approximately one minute in adults, two minutes in newborn infants and up to five minutes in preterm infants—it is usually given in a continuous intravenous drip rather than a single injection.
Its effects, depending on dosage, include an increase in sodium excretion by the kidneys, an increase in urine output, an increase in heart rate
Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). The heart rate can vary according to the body's physical needs, including the need to absorb oxygen and excr ...
, and an increase in blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
.[ At low doses it acts through the sympathetic nervous system to increase heart muscle contraction force and heart rate, thereby increasing ]cardiac output
In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: t ...
and blood pressure. Higher doses also cause vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vessel ...
that further increases blood pressure. Older literature also describes very low doses thought to improve kidney function without other consequences, but recent reviews have concluded that doses at such low levels are not effective and may sometimes be harmful. While some effects result from stimulation of dopamine receptors, the prominent cardiovascular effects result from dopamine acting at α1, β1, and β2 adrenergic receptor
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
s.
Side effects
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
of dopamine include negative effects on kidney function and irregular heartbeats
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
. The LD50, or lethal dose which is expected to prove fatal in 50% of the population, has been found to be: 59 mg/kg (mouse; administered intravenously
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
); 95 mg/kg (mouse; administered intraperitoneally
Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity). It is more often applied to animals than to humans. In general, it is preferred when large amounts of blood replacement fluids are needed ...
); 163 mg/kg (rat; administered intraperitoneally); 79 mg/kg (dog; administered intravenously).
A fluorinated
In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a chemical compound, compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the prod ...
form of L-DOPA known as fluorodopa
Fluorodopa, also known as FDOPA, is a fluorinated form of L-DOPA primarily synthesized as its fluorine-18 isotopologue for use as a radiotracer in positron emission tomography (PET).
The most common side effects are injection site pain.
Medi ...
is available for use in positron emission tomography
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...
to assess the function of the nigrostriatal pathway.
Disease, disorders, and pharmacology
The dopamine system plays a central role in several significant medical conditions, including Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...
, Tourette syndrome
Tourette syndrome or Tourette's syndrome (abbreviated as TS or Tourette's) is a common neurodevelopmental disorder that begins in childhood or adolescence. It is characterized by multiple movement (motor) tics and at least one vocal (phonic) ...
, schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
, bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
, and addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...
. Aside from dopamine itself, there are many other important drugs that act on dopamine systems in various parts of the brain or body. Some are used for medical or recreational purposes, but neurochemist
Neurochemistry is the study of chemicals, including neurotransmitters and other molecules such as psychopharmaceuticals and neuropeptides, that control and influence the physiology of the nervous system. This particular field within neuroscience ...
s have also developed a variety of research drugs, some of which bind with high affinity to specific types of dopamine receptors and either agonize or antagonize their effects, and many that affect other aspects of dopamine physiology, including dopamine transporter
The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopam ...
inhibitors, VMAT inhibitors, and enzyme inhibitors
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...
.
Aging brain
A number of studies have reported an age-related decline in dopamine synthesis and dopamine receptor density (i.e., the number of receptors) in the brain. This decline has been shown to occur in the striatum and extrastriatal regions. Decreases in the D1, D2, and D3 receptors are well documented. The reduction of dopamine with aging is thought to be responsible for many neurological symptoms that increase in frequency with age, such as decreased arm swing and increased rigidity. Changes in dopamine levels may also cause age-related changes in cognitive flexibility.
Other neurotransmitters, such as serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
and glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
also show a decline in output with aging.
Multiple sclerosis
Studies reported that dopamine imbalance influences the fatigue in multiple sclerosis. In patients with multiple sclerosis, dopamine inhibits production of IL-17 and IFN-γ by peripheral blood mononuclear cells.
Parkinson's disease
Parkinson's disease is an age-related disorder characterized by movement disorder
Movement disorder refers to any clinical syndrome with either an excess of movement or a paucity of voluntary and involuntary movements, unrelated to weakness or spasticity. Movement disorders are synonymous with basal ganglia or extrapyramidal d ...
s such as stiffness of the body, slowing of movement, and trembling of limbs when they are not in use. In advanced stages it progresses to dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
and eventually death.[ The main symptoms are caused by the loss of dopamine-secreting cells in the substantia nigra.] These dopamine cells are especially vulnerable to damage, and a variety of insults, including encephalitis
Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations, ...
(as depicted in the book and movie "Awakenings
''Awakenings'' is a 1990 American drama film directed by Penny Marshall. It is written by Steven Zaillian, who based his screenplay on Oliver Sacks's 1973 memoir ''Awakenings''. It tells the story of neurologist Dr. Malcolm Sayer (Robin Williams ...
"), repeated sports-related concussion
A concussion, also known as a mild traumatic brain injury (mTBI), is a head injury that temporarily affects brain functioning. Symptoms may include loss of consciousness (LOC); memory loss; headaches; difficulty with thinking, concentration, ...
s, and some forms of chemical poisoning such as MPTP
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a prodrug to the neurotoxin MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study d ...
, can lead to substantial cell loss, producing a parkinsonian syndrome
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...
that is similar in its main features to Parkinson's disease. Most cases of Parkinson's disease, however, are idiopathic
An idiopathic disease is any disease with an unknown cause or mechanism of apparent wikt:spontaneous, spontaneous origin. From Ancient Greek, Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approxi ...
, 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.] L-DOPA is converted to dopamine in the brain and various parts of the body by the enzyme DOPA decarboxylase.[ L-DOPA is used rather than dopamine itself because, unlike dopamine, it is capable of crossing the ]blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
. It is often co-administered with an enzyme inhibitor
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...
of peripheral decarboxylation
Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
such as carbidopa
Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–bra ...
or benserazide
Benserazide (also called Serazide or Ro 4-4602) is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier.
It is on the World Health Organization's List of E ...
, to reduce the amount converted to dopamine in the periphery and thereby increase the amount of L-DOPA that enters the brain. When L-DOPA is administered regularly over a long time period, a variety of unpleasant side effects such as dyskinesia
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...
often begin to appear; even so, it is considered the best available long-term treatment option for most cases of Parkinson's disease.
L-DOPA treatment cannot restore the dopamine cells that have been lost, but it causes the remaining cells to produce more dopamine, thereby compensating for the loss to at least some degree. 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. Other drugs that enhance dopamine function, such as bromocriptine
Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic maligna ...
and pergolide
Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced do ...
, are also sometimes used to treat Parkinsonism, but in most cases L-DOPA appears to give the best trade-off between positive effects and negative side-effects.
Dopaminergic medications that are used to treat Parkinson's disease are sometimes associated with the development of a dopamine dysregulation syndrome
Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It typically occurs in people with Parkinson's disease (PD) who have taken dop ...
, which involves the overuse of dopaminergic medication and medication-induced compulsive engagement in natural reward
Behavioral addiction is a form of addiction that involves a compulsion to engage in a rewarding non- substance-related behavior – sometimes called a natural reward – despite any negative consequences to the person's physical, mental, social ...
s like gambling and sexual activity. The latter behaviors are similar to those observed in individuals with a behavioral addiction
Behavioral addiction is a form of addiction that involves a compulsion to engage in a rewarding non- substance-related behavior – sometimes called a natural reward – despite any negative consequences to the person's physical, mental, social o ...
.
Drug addiction and psychostimulants
Cocaine
Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...
, substituted amphetamines (including methamphetamine
Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...
), Adderall
Adderall and Mydayis are trade names for a combination drug called mixed amphetamine salts containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio bet ...
, methylphenidate
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, ...
(marketed as Ritalin
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...
or Concerta
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, ...
), and other psychostimulants
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
exert their effects primarily or partly by increasing dopamine levels in the brain by a variety of mechanisms.[ Cocaine and methylphenidate are dopamine transporter blockers or ]reuptake inhibitor
Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmit ...
s; they non-competitively inhibit dopamine reuptake, resulting in increased dopamine concentrations in the synaptic cleft. Like cocaine, substituted amphetamines and amphetamine also increase the concentration of dopamine in the synaptic cleft
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...
, but by different mechanisms.[
The effects of psychostimulants include increases in heart rate, body temperature, and sweating; improvements in alertness, attention, and endurance; increases in pleasure produced by rewarding events; but at higher doses agitation, anxiety, or even loss of contact with reality.] Drugs in this group can have a high addiction potential, due to their activating effects on the dopamine-mediated reward system in the brain.[ However some can also be useful, at lower doses, for treating attention deficit hyperactivity disorder (ADHD) and ]narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
.[ An important differentiating factor is the onset and duration of action.][ Cocaine can take effect in seconds if it is injected or inhaled in free base form; the effects last from 5 to 90 minutes.] This rapid and brief action makes its effects easily perceived and consequently gives it high addiction potential.[ Methylphenidate taken in pill form, in contrast, can take two hours to reach peak levels in the bloodstream,] and depending on formulation the effects can last for up to 12 hours. These longer acting formulations have the benefit of reducing the potential for abuse, and improving adherence for treatment by using more convenient dosage regimens.
A variety of addictive drugs produce an increase in reward-related dopamine activity.[ Stimulants such as ]nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
, cocaine and methamphetamine promote increased levels of dopamine which appear to be the primary factor in causing addiction. For other addictive drugs such as the opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
heroin, the increased levels of dopamine in the reward system may play only a minor role in addiction. When people addicted to stimulants go through withdrawal, they do not experience the physical suffering associated with alcohol withdrawal
Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. M ...
or withdrawal
Withdrawal means "an act of taking out" and may refer to:
* Anchoresis (withdrawal from the world for religious or ethical reasons)
* ''Coitus interruptus'' (the withdrawal method)
* Drug withdrawal
* Social withdrawal
* Taking of money from a ban ...
from opiates; instead they experience craving, an intense desire for the drug characterized by irritability, restlessness, and other arousal symptoms, brought about by psychological dependence
Psychological dependence is a cognitive disorder that involves emotional–motivational withdrawal symptoms—e.g. anxiety and anhedonia—upon cessation of prolonged drug abuse or certain repetitive behaviors. It develops through frequent expo ...
.
The dopamine system plays a crucial role in several aspects of addiction. At the earliest stage, genetic differences that alter the expression of dopamine receptors in the brain can predict whether a person will find stimulants appealing or aversive. Consumption of stimulants produces increases in brain dopamine levels that last from minutes to hours.[ Finally, the chronic elevation in dopamine that comes with repetitive high-dose stimulant consumption triggers a wide-ranging set of structural changes in the brain that are responsible for the behavioral abnormalities which characterize an addiction.] Treatment of stimulant addiction is very difficult, because even if consumption ceases, the craving that comes with psychological withdrawal does not.[ Even when the craving seems to be extinct, it may re-emerge when faced with stimuli that are associated with the drug, such as friends, locations and situations.][ Association networks in the brain are greatly interlinked.
]
Psychosis and antipsychotic drugs
Psychiatrists in the early 1950s discovered that a class of drugs known as typical antipsychotic
Typical antipsychotics (also known as major tranquilizers, and first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia). Typical antipsychotics ma ...
s (also known as major tranquilizer
A tranquilizer is a drug that is designed for the treatment of anxiety, fear, tension, agitation, and disturbances of the mind, specifically to reduce states of anxiety and tension.
Etymology
Tranquilizer, as a term, was first used by F.F. Yonk ...
s), were often effective at reducing the psychotic
Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
symptoms of schizophrenia.[ The introduction of the first widely used antipsychotic, ]chlorpromazine
Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar dis ...
(Thorazine), in the 1950s, led to the release of many patients with schizophrenia from institutions in the years that followed.[ By the 1970s researchers understood that these typical antipsychotics worked as ]antagonists
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
on the D2 receptors. This realization led to the so-called dopamine hypothesis of schizophrenia
The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model that attributes the positive symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the ...
, which postulates that schizophrenia is largely caused by hyperactivity of brain dopamine systems. The dopamine hypothesis drew additional support from the observation that psychotic symptoms were often intensified by dopamine-enhancing stimulants such as methamphetamine, and that these drugs could also produce psychosis in healthy people if taken in large enough doses.[ In the following decades other ]atypical antipsychotics
The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...
that had fewer serious side effects were developed.[ Many of these newer drugs do not act directly on dopamine receptors, but instead produce alterations in dopamine activity indirectly.] These drugs were also used to treat other psychoses. Antipsychotic drugs
Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of oth ...
have a broadly suppressive effect on most types of active behavior, and particularly reduce the delusional and agitated behavior characteristic of overt psychosis.[
Later observations, however, have caused the dopamine hypothesis to lose popularity, at least in its simple original form.][ For one thing, patients with schizophrenia do not typically show measurably increased levels of brain dopamine activity.][ Even so, many psychiatrists and neuroscientists continue to believe that schizophrenia involves some sort of dopamine system dysfunction.][ As the "dopamine hypothesis" has evolved over time, however, the sorts of dysfunctions it postulates have tended to become increasingly subtle and complex.][
]Psychopharmacologist
Psychopharmacology (from Greek grc, ψῡχή, psȳkhē, breath, life, soul, label=none; grc, φάρμακον, pharmakon, drug, label=none; and grc, -λογία, -logia, label=none) is the scientific study of the effects drugs have on mo ...
Stephen M. Stahl suggested in a review of 2018 that in many cases of psychosis, including schizophrenia, three interconnected networks based on dopamine, serotonin, and glutamate – each on its own or in various combinations – contributed to an overexcitation of dopamine D2 receptors in the ventral striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
.
Attention deficit hyperactivity disorder
Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder (ADHD), a condition associated with impaired cognitive control
In cognitive science and neuropsychology, executive functions (collectively referred to as executive function and cognitive control) are a set of cognitive processes that are necessary for the cognitive control of behavior: selecting and succe ...
, in turn leading to problems with regulating attention (attentional control
Attentional control, colloquially referred to as concentration, refers to an individual's capacity to choose what they pay attention to and what they ignore. It is also known as endogenous attention or executive attention. In lay terms, attenti ...
), inhibiting behaviors (inhibitory control
Inhibitory control, also known as response inhibition, is a cognitive process – and, more specifically, an executive function – that permits an individual to inhibit their impulses and natural, habitual, or dominant behavioral res ...
), and forgetting things or missing details (working memory
Working memory is a cognitive system with a limited capacity that can hold information temporarily. It is important for reasoning and the guidance of decision-making and behavior. Working memory is often used synonymously with short-term memory, ...
), among other problems. There are genetic links between dopamine receptors, the dopamine transporter, and ADHD, 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, Concerta) and ]amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
(Evekeo, Adderall, Dexedrine), drugs that increase both dopamine and norepinephrine levels in the brain. The clinical effects of these psychostimulants in treating ADHD are mediated through the indirect activation of dopamine and norepinephrine receptors, specifically dopamine receptor D1 and adrenoceptor α2, in the prefrontal cortex.
Pain
Dopamine plays a role in pain
Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
processing in multiple levels of the central nervous system including the spinal cord, periaqueductal gray
The periaqueductal gray (PAG, also known as the central gray) is a brain region that plays a critical role in autonomic function, motivated behavior and behavioural responses to threatening stimuli. PAG is also the primary control center for d ...
, thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
, basal ganglia, and cingulate cortex
The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the ci ...
. Decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson's disease. Abnormalities in dopaminergic neurotransmission also occur in several painful clinical conditions, including burning mouth syndrome
Burning mouth syndrome (BMS) is a burning, tingling or scalding sensation in the mouth, lasting for at least four to six months, with no underlying known dental or medical cause. No related signs of disease are found in the mouth. People with ...
, fibromyalgia
Fibromyalgia (FM) is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hyp ...
, and restless legs syndrome.
Nausea
Nausea and vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose.
Vomiting can be the result of ailments like Food-poisoning, foo ...
are largely determined by activity in the area postrema
The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its dual role to detect circulating chemical messengers in the blood and ...
in the medulla
Medulla or Medullary may refer to:
Science
* Medulla oblongata, a part of the brain stem
* Renal medulla, a part of the kidney
* Adrenal medulla, a part of the adrenal gland
* Medulla of ovary, a stroma in the center of the ovary
* Medulla of th ...
of the brainstem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...
, in a region known as the chemoreceptor trigger zone
The chemoreceptor trigger zone (CTZ) is an area of the medulla oblongata that receives inputs from blood-borne drugs or hormones, and communicates with other structures in the vomiting center to initiate vomiting. The CTZ is located within the area ...
. 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
A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
such as apomorphine
Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antagon ...
. In some cases, D2-receptor antagonists such as metoclopramide
Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesoph ...
are useful as anti-nausea drugs
An antiemetic is a medication, drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the Adverse effect (medicine), side effects of opioid analgesics, general anaesthetics, and chemothera ...
.[
]
Comparative biology and evolution
Microorganisms
There are no reports of dopamine in archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
, but it has been detected in some types of bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
and in the protozoa
Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...
n called ''Tetrahymena
''Tetrahymena'', a Unicellular organism, unicellular eukaryote, is a genus of free-living ciliates. The genus Tetrahymena is the most widely studied member of its phylum. It can produce, store and react with different types of hormones. Tetrah ...
''. Perhaps more importantly, there are types of bacteria that contain homologs
A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same locus (genetics), loci where they pr ...
of all the enzymes that animals use to synthesize dopamine.[ It has been proposed that animals derived their dopamine-synthesizing machinery from bacteria, via ]horizontal gene transfer
Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between Unicellular organism, unicellular and/or multicellular organisms other than by the ("vertical") transmission of DNA from parent to offsprin ...
that may have occurred relatively late in evolutionary time, perhaps as a result of the symbiotic
Symbiosis (from Greek , , "living together", from , , "together", and , bíōsis, "living") is any type of a close and long-term biological interaction between two different biological organisms, be it mutualistic, commensalistic, or parasit ...
incorporation of bacteria into eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
cells that gave rise to mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
.
Animals
Dopamine is used as a neurotransmitter in most multicellular animals.[ In ]sponge
Sponges, the members of the phylum Porifera (; meaning 'pore bearer'), are a basal animal clade as a sister of the diploblasts. They are multicellular organisms that have bodies full of pores and channels allowing water to circulate through t ...
s there is only a single report of the presence of dopamine, with no indication of its function; however, dopamine has been reported in the nervous systems of many other radially symmetric species, including the cnidarian
Cnidaria () is a phylum under kingdom Animalia containing over 11,000 species of aquatic animals found both in freshwater and marine environments, predominantly the latter.
Their distinguishing feature is cnidocytes, specialized cells that th ...
jellyfish
Jellyfish and sea jellies are the informal common names given to the medusa-phase of certain gelatinous members of the subphylum Medusozoa, a major part of the phylum Cnidaria. Jellyfish are mainly free-swimming marine animals with umbrella- ...
, hydra
Hydra generally refers to:
* Lernaean Hydra, a many-headed serpent in Greek mythology
* ''Hydra'' (genus), a genus of simple freshwater animals belonging to the phylum Cnidaria
Hydra or The Hydra may also refer to:
Astronomy
* Hydra (constel ...
and some coral
Corals are marine invertebrates within the class Anthozoa of the phylum Cnidaria. They typically form compact colonies of many identical individual polyps. Coral species include the important reef builders that inhabit tropical oceans and sec ...
s. 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
The Cambrian Period ( ; sometimes symbolized C with bar, Ꞓ) was the first geological period of the Paleozoic Era, and of the Phanerozoic Eon. The Cambrian lasted 53.4 million years from the end of the preceding Ediacaran Period 538.8 million ...
Period. Dopamine functions as a neurotransmitter in vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s, echinoderm
An echinoderm () is any member of the phylum Echinodermata (). The adults are recognisable by their (usually five-point) radial symmetry, and include starfish, brittle stars, sea urchins, sand dollars, and sea cucumbers, as well as the sea ...
s, arthropod
Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and Arth ...
s, molluscs
Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000 extant taxon, extant species of molluscs are recognized. The number of fossil sp ...
, and several types of worm
Worms are many different distantly related bilateral animals that typically have a long cylindrical tube-like body, no limbs, and no eyes (though not always).
Worms vary in size from microscopic to over in length for marine polychaete wor ...
.
In every type of animal that has been examined, dopamine has been seen to modify motor behavior. In the model organism
A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...
, nematode
The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-Parasitism, parasitic nematodes also known as eelworms. They are a diverse animal phylum inhab ...
''Caenorhabditis elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
'', it reduces locomotion
Locomotion means the act or ability of something to transport or move itself from place to place.
Locomotion may refer to:
Motion
* Motion (physics)
* Robot locomotion, of man-made devices
By environment
* Aquatic locomotion
* Flight
* Locomoti ...
and increases food-exploratory movements; in flatworm
The flatworms, flat worms, Platyhelminthes, or platyhelminths (from the Greek πλατύ, ''platy'', meaning "flat" and ἕλμινς (root: ἑλμινθ-), ''helminth-'', meaning "worm") are a phylum of relatively simple bilaterian, unsegment ...
s it produces "screw-like" movements; in leech
Leeches are segmented parasitic or predatory worms that comprise the subclass Hirudinea within the phylum Annelida. They are closely related to the oligochaetes, which include the earthworm, and like them have soft, muscular segmented bodie ...
es it inhibits swimming and promotes crawling. Across a wide range of vertebrates, dopamine has an "activating" effect on behavior-switching and response selection, comparable to its effect in mammals.[
Dopamine has also consistently been shown to play a role in reward learning, in all animal groups.][ As in all vertebrates – ]invertebrate
Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
s such as roundworms
The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a broa ...
, flatworm
The flatworms, flat worms, Platyhelminthes, or platyhelminths (from the Greek πλατύ, ''platy'', meaning "flat" and ἕλμινς (root: ἑλμινθ-), ''helminth-'', meaning "worm") are a phylum of relatively simple bilaterian, unsegment ...
s, mollusc
Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000 extant species of molluscs are recognized. The number of fossil species is esti ...
s and common fruit flies can all be trained to repeat an action if it is consistently followed by an increase in dopamine levels. In fruit flies
Fruit fly may refer to:
Organisms
* Drosophilidae, a family of small flies, including:
** ''Drosophila'', the genus of small fruit flies and vinegar flies
** ''Drosophila melanogaster'' or common fruit fly
** ''Drosophila suzukii'' or Asian fruit ...
, distinct elements for reward learning suggest a modular structure to the insect reward processing system that broadly parallels that in the mammalian one. For example, dopamine regulates short- and long-term learning in monkeys; in fruit flies, different groups of dopamine neurons mediate reward signals for short- and long-term memories.
It had long been believed that arthropods were an exception to this with dopamine being seen as having an adverse effect. Reward was seen to be mediated instead by octopamine
Octopamine (molecular formula C8H11NO2; also known as OA, and also norsynephrine, ''para''-octopamine and others) is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is ofte ...
, a neurotransmitter closely related to norepinephrine.[ More recent studies, however, have shown that dopamine does play a part in reward learning in fruit flies. It has also been found that the rewarding effect of octopamine is due to its activating a set of dopaminergic neurons not previously accessed in the research.]
Plants
Many plants, including a variety of food plants, synthesize dopamine to varying degrees.[ The highest concentrations have been observed in bananas—the fruit pulp of ]red
Red is the color at the long wavelength end of the visible spectrum of light, next to orange and opposite violet. It has a dominant wavelength of approximately 625–740 nanometres. It is a primary color in the RGB color model and a secondar ...
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.] 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 variety of ways, producing melanin and a variety of alkaloids as byproducts.][ 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.][
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. 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. Another plant containing substantial amounts of L-DOPA is ''Vicia faba'', the plant that produces fava beans (also known as "broad beans"). The level of L-DOPA in the beans, however, is much lower than in the pod shells and other parts of the plant. The seeds of ''Cassia (genus), Cassia'' and ''Bauhinia'' trees also contain substantial amounts of L-DOPA.[
In a species of seawater, marine green algae ''Ulvaria obscura'', 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 isopoda, isopods.]
As a precursor for melanin
Melanins are a family of dark-pigmented substances found in a wide range of organisms.[ Chemically they are closely related to dopamine, and there is a type of melanin, known as dopamine-melanin, that can be synthesized by oxidation of dopamine via the enzyme tyrosinase.] 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.
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. 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.
]
History and development
Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Trust, Wellcome Laboratories in London, England and first identified in the human brain by Katharine Montagu in 1957. It was named dopamine because it is a monoamine whose precursor in the Barger-Ewens synthesis is 3,4-dihydroxyphenylalanine (levodopa or L-DOPA). Dopamine's function as a neurotransmitter was first recognized in 1958 by Arvid Carlsson and Nils-Åke Hillarp at the Laboratory for Chemical Pharmacology of the National Heart Institute of Sweden. Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not only a precursor of norepinephrine (noradrenaline) and epinephrine (adrenaline), but is also itself a neurotransmitter.
Polydopamine
Research motivated by bioadhesive, adhesive polyphenolic proteins in mussels 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. This polymerized dopamine forms by a spontaneous oxidation reaction, and is formally a type of melanin. Furthermore, dopamine self-polymerization can be used to modulate the mechanical properties of peptide-based gels. Synthesis of polydopamine usually involves reaction of dopamine hydrochloride with Tris as a base in water. The structure of polydopamine is unknown.
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.][
]
See also
* Dopamine fasting
* Breastfeeding and fertility
References
External links
*
*
{{Authority control
Dopamine,
Amphetamine
Cardiac stimulants
Catecholamines
Dopamine agonists
Hormones of the hypothalamus
Hormones of the hypothalamic-pituitary-prolactin axis
Phenethylamines
Inotropic agents
Motivation
Neurotransmitters
Norepinephrine-dopamine releasing agents
TAAR1 agonists
Biology of attention deficit hyperactivity disorder
Peripherally selective drugs
Human female endocrine system