Dopamine
is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this phenethylamine functions as a neurotransmitter, activating the five types of dopamine receptors — D1, D2, D3, D4, and D5, and their variants. Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area. [1] Dopamine is also a neurohormone released by the hypothalamus. Its main function as a hormone is to inhibit the release of prolactin from the anterior lobe of the pituitary.
Dopamine can be supplied as a medication that acts on the sympathetic nervous system, producing effects such as increased heart rate and blood pressure. However, because dopamine cannot cross the blood-brain barrier, dopamine given as a drug does not directly affect the central nervous system. To increase the amount of dopamine in the brains of patients with diseases such as Parkinson's disease and dopa-responsive dystonia, L-DOPA (levodopa), which is the precursor of dopamine, can be given because it can cross the blood-brain barrier.
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THE DOPAMINES TICKETS
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History
The function of dopamine as a neurotransmitter was discovered in 1958 by
Arvid Carlsson and Nils-Åke Hillarp at the Laboratory for Chemical Pharmacology of the National Heart Institute of
Sweden. It was named dopamine because it was a
monoamine, and its synthetic precursor was 3,4-
d
ihydr
o
xy
p
henyl
a
lanine (
L-DOPA).
[2] Arvid Carlsson was awarded the 2000
Nobel Prize in Physiology or Medicine for showing that dopamine is not just a precursor of
norepinephrine (noradrenaline) and
epinephrine (adrenaline) but a neurotransmitter, as well.
Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England.
[3]
Biochemistry
Name and family
Dopamine has the chemical formula C
6H
3(OH)
2-CH
2-CH
2-NH
2. Its chemical name is "4-(2-aminoethyl)benzene-1,2-diol" and its abbreviation is "DA."
As a member of the
catecholamine family, dopamine is a precursor to
norepinephrine (noradrenaline) and then
epinephrine (adrenaline) in the biosynthetic pathways for these neurotransmitters.
Biosynthesis
Dopamine is biosynthesized in the body (mainly by nervous tissue and the
medulla of the
adrenal glands) first by the hydroxylation of the amino acid
L-tyrosine to L-DOPA via the enzyme tyrosine 3-monooxygenase, also known as
tyrosine hydroxylase, and then by the
decarboxylation of
L-DOPA by
aromatic L-amino acid decarboxylase (which is often referred to as dopa decarboxylase). In some neurons, dopamine is further processed into
norepinephrine by
dopamine beta-hydroxylase.
In
neurons, dopamine is packaged after synthesis into
vesicles, which are then released into the
synapse in response to a presynaptic
action potential.
Inactivation and degradation
Dopamine is inactivated by
reuptake via the
dopamine transporter, then enzymatic breakdown by
catechol-O-methyl transferase (COMT) and
monoamine oxidase (MAO). Dopamine that is not broken down by enzymes is repackaged into vesicles for reuse.
Functions in the brain
Dopamine has many functions in the brain, including important roles in behavior and
cognition,
voluntary movement,
motivation and
reward, inhibition of
prolactin production (involved in
lactation),
sleep,
mood,
attention, and
learning. Dopaminergic neurons (i.e., neurons whose primary neurotransmitter is dopamine) are present chiefly in the
ventral tegmental area (VTA) of the
midbrain, the
substantia nigra pars compacta, and the
arcuate nucleus of the hypothalamus.
It has been hypothesized that dopamine transmits reward prediction error, although this has been questioned.
[4] According to this hypothesis, the phasic responses of dopamine neurons are observed when an unexpected reward is presented. These responses transfer to the onset of a
conditioned stimulus after repeated pairings with the reward. Further, dopamine neurons are depressed when the expected reward is omitted. Thus, dopamine neurons seem to
encode the prediction error of rewarding outcomes. In nature, we learn to repeat behaviors that lead to maximize rewards. Dopamine is therefore believed to provide a teaching signal to parts of the brain responsible for acquiring new behavior.
Temporal difference learning provides a computational model describing how the prediction error of dopamine neurons is used as a teaching signal.
In insects, a similar reward system exists, using
octopamine, a
chemical relative of dopamine.
[5]
Anatomy
Dopaminergic neurons form a
neurotransmitter system which originates in
substantia nigra pars compacta,
ventral tegmental area (VTA), and
hypothalamus. These project
axons to large areas of the brain through four major pathways:
- Mesocortical pathway
- Mesolimbic pathway
- Nigrostriatal pathway
- Tuberoinfundibular pathway
This innervation explains many of the effects of activating this dopamine system. For instance, the
mesolimbic pathway connects the VTA and
nucleus accumbens; both are central to the brain
reward system.
[6]
Movement
Via the
dopamine receptors, D
1-5, dopamine reduces the influence of the indirect pathway, and increases the actions of the direct pathway within the
basal ganglia. Insufficient dopamine
biosynthesis in the dopaminergic neurons can cause
Parkinson's disease, in which a person loses the ability to execute smooth, controlled movements.
Cognition and frontal cortex
In the
frontal lobes, dopamine controls the flow of information from other areas of the brain. Dopamine disorders in this region of the brain can cause a decline in
neurocognitive functions, especially
memory,
attention, and
problem-solving. Reduced dopamine concentrations in the prefrontal cortex are thought to contribute to
attention deficit disorder. It has been found that D1 receptors
[7] as well as D4 receptors
[8] are responsible for the cognitive-enhancing effects of dopamine. On the converse, however,
anti-psychotic medications act as dopamine antagonists and are used in the treatment of positive symptoms in
schizophrenia, although the older, so-called "typical" antipsychotics most commonly act on D2 receptors
[9], while the atypical drugs also act on D1, D3 and D4 receptors
[10] [11].
Regulating prolactin secretion
Dopamine is the primary
neuroendocrine inhibitor of the secretion of
prolactin from the
anterior pituitary gland.
[12] Dopamine produced by neurons in the
arcuate nucleus of the hypothalamus is secreted into the hypothalamo-hypophysial blood vessels of the
median eminence, which supply the
pituitary gland. The lactotrope cells that produce
prolactin, in the absence of dopamine, secrete prolactin continuously; dopamine inhibits this secretion. Thus, in the context of regulating prolactin secretion, dopamine is occasionally called
prolactin-inhibiting factor
(
PIF
),
prolactin-inhibiting hormone
(
PIH
), or
prolactostatin
. Prolactin also seems to inhibit dopamine release, such as after
orgasm, and is chiefly responsible for the
refractory period.
Motivation and pleasure
Reinforcement
Dopamine is commonly associated with the
pleasure system
of the brain, providing feelings of enjoyment and
reinforcement to motivate a person proactively to perform certain activities. Dopamine is released (particularly in areas such as the
nucleus accumbens and
prefrontal cortex) by naturally
rewarding experiences such as
food,
sex, drugs, and
neutral stimuli that become
associated with them. Recent studies indicate that
aggression may also stimulate the release of dopamine in this way. This theory is often discussed in terms of drugs such as
cocaine,
nicotine, and
amphetamines, which directly or indirectly lead to an increase of dopamine in the
mesolimbic reward pathway of the brain, and in relation to
neurobiological theories of chemical
addiction, arguing that this dopamine pathway is pathologically altered in addicted persons.
[13] [14] [15]
Reuptake inhibition, expulsion
Cocaine and amphetamines inhibit the
re-uptake of dopamine; however, they influence separate mechanisms of action. Cocaine is a
dopamine transporter blocker that competitively inhibits dopamine uptake to increase the lifetime of dopamine and augments an overabundance of dopamine (an increase of up to 150 percent) within the parameters of the dopamine neurotransmitters.
Like cocaine, amphetamines increase the concentration of dopamine in the
synaptic gap, but by a different mechanism. Amphetamines are similar in structure to dopamine, and so can enter the terminal button of the presynaptic neuron via its dopamine transporters as well as by diffusing through the
neural membrane directly. By entering the presynaptic neuron, amphetamines force dopamine molecules out of their storage
vesicles and expel them into the synaptic gap by making the dopamine transporters work in reverse.
Incentive salience
Dopamine's role in experiencing pleasure has been questioned by several researchers. It has been argued that dopamine is more associated with anticipatory desire and motivation (commonly referred to as "wanting") as opposed to actual consummatory pleasure (commonly referred to as "liking").
Dopamine, learning, and reward-seeking behavior
Dopaminergic neurons of the midbrain are the main source of dopamine in the brain.
[17] Other pathological states have also been associated with dopamine dysfunction, such as schizophrenia, autism, and attention deficit hyperactivity disorder in children, as well as drug abuse.
Dopamine is closely associated with reward-seeking behaviors, such as approach, consumption, and addiction.
However, recent research finds that while some dopaminergic neurons react in the way expected of reward neurons, others do not and seem to respond in regard to unpredictability.
[19] This research finds the reward neurons predominate in the ventromedial region in the
substantia nigra pars compacta as well as the
ventral tegmental area. Neurons in these areas project mainly to the
ventral striatum and thus might transmit value-related information in regard reward values.
The nonreward neurons are predominate in the dorsolateral area of the substantia nigra pars compacta which projects to the
dorsal striatum and may relate orienting behaviour.
It has been suggested that the difference between these two types of dopaminergic neurons arises from their input: reward linked ones have input from the
basal forebrain while the nonreward related ones from the
lateral habenula.
Animal studies
Clues to dopamine's role in motivation, desire, and pleasure have come from studies performed on animals. In one such study, rats were depleted of dopamine by up to 99 percent in the
nucleus accumbens and
neostriatum using 6-hydroxydopamine.
[20]
With this large reduction in dopamine, the rats would no longer eat by their own volition. The researchers then force-fed the rats food and noted whether they had the proper facial expressions indicating whether they liked or disliked it. The researchers of this study concluded that the reduction in dopamine did not reduce the rat's consummatory pleasure, only the desire to actually eat. In another study, mutant hyperdopaminergic (increased dopamine) mice show higher "wanting" but not "liking" of sweet rewards.
[21]
The effects of drugs that reduce dopamine levels in humans
In humans, drugs that reduce dopamine activity (
neuroleptics, e.g. some
antipsychotics) have been shown to reduce motivation, and to cause
anhedonia (the inability to experience pleasure).
[22]
Selective D2/D3 agonists
pramipexole and
ropinirole, used to treat
Restless legs syndrome, have limited anti-anhedonic properties as measured by the Snaith-Hamilton Pleasure Scale.
[23]
(The Snaith-Hamilton-Pleasure-Scale (SHAPS), introduced in English in 1995, assesses self-reported
anhedonia in psychiatric patients.)
Opioid and cannabinoid transmission
Opioid and
cannabinoid transmission instead of dopamine may modulate consummatory pleasure and food palatability (liking).
[24]
This could explain why animals' "liking" of food is independent of brain dopamine concentration. Other consummatory pleasures, however, may be more associated with dopamine. One study found that both anticipatory and consummatory measures of sexual behavior (male rats) were disrupted by DA receptor antagonists.
[25]
Libido can be increased by drugs that affect dopamine, but not by drugs that affect opioid peptides or other neurotransmitters.
Sociability
Sociability is also closely tied to dopamine neurotransmission. Low D2 receptor-binding is found in people with
social anxiety. Traits common to negative schizophrenia (
social withdrawal,
apathy,
anhedonia) are thought to be related to a hypodopaminergic state in certain areas of the brain. In instances of
bipolar disorder,
manic subjects can become hypersocial, as well as
hypersexual. This is credited to an increase in dopamine, because mania can be reduced by dopamine-blocking anti-psychotics.
[26]
Processing of pain
Dopamine has been demonstrated to play a role in
pain processing in multiple levels of the
central nervous system including the
spinal cord [27],
periaqueductal gray (PAG)
[28],
thalamus [29],
basal ganglia [30] [31] insular cortex [32] [33] and
cingulate cortex.
[34] Accordingly, decreased levels of dopamine have been associated with painful symptoms that frequently occur in
Parkinson's disease.
[35] Abnormalities in dopaminergic neurotransmission have also been demonstrated in painful clinical conditions, including
burning mouth syndrome,
[36] fibromyalgia [37] [38] and
restless legs syndrome.
[39] In general, the analgesic capacity of dopamine occurs as a result of dopamine D2 receptor activation; however, exceptions to this exist in the PAG, in which dopamine D1 receptor activation attenuates pain presumably
via
activation of neurons involved in descending inhibition.
[40] In addition, D1 receptor activation in the insular cortex appears to attenuate subsequent pain-related behavior.
Salience
Dopamine may also have a role in the
salience of potentially important stimuli, such as sources of reward or of danger.
[41] This hypothesis argues that dopamine assists decision-making by influencing the priority, or level of desire, of such stimuli to the person concerned.
Behavior disorders
Deficient dopamine neurotransmission is implicated in
attention-deficit hyperactivity disorder, and stimulant medications used to successfully treat the disorder increase dopamine neurotransmission, leading to decreased symptoms.
[42]
The long term use of
levodopa in
Parkinson's disease has been linked to the so-called
dopamine dysregulation syndrome.
[43]
Latent inhibition and creative drive
Dopamine in the
mesolimbic pathway increases general
arousal and goal directed behaviors and decreases
latent inhibition; all three effects increase the creative drive of idea generation. This has led to a three-factor model of
creativity involving the
frontal lobes, the
temporal lobes, and mesolimbic dopamine.
[44]
Chemoreceptor trigger zone
Dopamine is one of the neurotransmitters implicated in the control of
nausea and
vomiting via interactions in the
chemoreceptor trigger zone.
Metoclopramide is a D2-receptor antagonist that functions as a
prokinetic/
antiemetic.
Links to psychosis
Abnormally high dopamine action has also been strongly linked to
psychosis and
schizophrenia,
[45]
Dopamine neurons in the
mesolimbic pathway are particularly associated with these conditions. Evidence comes partly from the discovery of a class of drugs called the
phenothiazines (which block D
2 dopamine receptors) that can reduce psychotic symptoms, and partly from the finding that drugs such as
amphetamine and
cocaine (which are known to greatly increase dopamine levels) can cause psychosis.
[46] Because of this, most modern
antipsychotic medications, for example,
risperidone, are designed to block dopamine function to varying degrees.
Therapeutic use
Levodopa is a dopamine precursor used in various forms to treat
Parkinson's disease and dopa-responsive
dystonia. It is typically co-administered with an inhibitor of peripheral decarboxylation (DDC,
dopa decarboxylase), such as
carbidopa or
benserazide. Inhibitors of alternative metabolic route for dopamine by
catechol-O-methyl transferase are also used. These include
entacapone and
tolcapone.
Peripheral effects
Dopamine also has effects when administered through an
IV line outside the CNS. The brand name of this preparation is known as
Intropin. The effects in this form are dose dependent.
- Dosages from 2 to 5 µg/kg/min are considered the "renal dose." [47] At this low dosage, dopamine binds D1 receptors, dilating blood vessels, increasing blood flow to renal, mesenteric, and coronary arteries; and increasing overall renal perfusion. [48] Dopamine therefore has a diuretic effect, potentially increasing urine output from 5 ml/kg/hr to 10 ml/kg/hr.
- Intermediate dosages from 5 to 10 µg/kg/min additionally have a positive inotropic and chronotropic effect through increased ß1 receptor activation. It is used in patients with shock or heart failure to increase cardiac output and blood pressure.
Dopamine begins to affect the heart at the lower doses, from about 3 µg/kg/min IV. [49]
- High doses from 10 to 20 µg/kg/min is the "pressor" dose. This dose causes vasoconstriction, increases systemic vascular resistance, and increases blood pressure through a1 receptor activation;
but can cause the vessels in the kidneys to constrict to the point where they will become non-functional.
Dopamine and fruit browning
Polyphenol oxidases (PPOs) are a family of enzymes responsible for the
browning of fresh fruits and vegetables when they are cut or bruised. These enzymes use molecular
oxygen (O
2) to
oxidise various
1,2-diphenols to their corresponding
quinones. The natural substrate for PPOs in
bananas is dopamine. The product of their oxidation, dopamine quinone, spontaneously oxidises to other quinones. The quinones then
polymerise and
condense with
amino acids and
proteins to form brown
pigments known as
melanins. The quinones and melanins derived from dopamine may help protect damaged fruit and vegetables against growth of
bacteria and
fungi.
[50]
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