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{{Chembox new|ImageFile=Dopamin - Dopamine.svg|ImageSize=|ImageFile2=Dopamine-3d-CPK.png|ImageSize2=150px|IUPACName=4-(2-aminoethyl)benzene-1,2-diol|OtherNames=2-(3,4-dihydroxyphenyl)ethylamine; 3,4-dihydroxyphenethylamine; 3-hydroxytyramine; DA; Intropin Revivan; Oxytyramine|Section1= {{Chembox Identifiers| CASNo=51-61-6| PubChem=681| SMILES=C1=CC(=C(C=C1CCN)O)O --> |Section2= {{Chembox Properties| Formula=C8H11NO2| MolarMass=153.178| Appearance=| Density=| MeltingPt=128 °C (401 K)| BoilingPt=| Solubility=60.0 g/100 ml (? °C), solid --> |Section3= {{Chembox Hazards| MainHazards=| FlashPt=| Autoignition=| RSPhrases = List of R-phrases: 36/37/38
List of S-phrases: 26-36 --> -->Dopamine is a hormone and neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In chemical structure, it is a phenethylamine.

In the human brain, dopamine functions as a neurotransmitter, activating the five types of dopamine receptor - D1, D2, D3, D4 and D5, and their variants. Dopamine is produced in several areas of the brain, including the substantia nigra. 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 nervous system, producing effects such as increased heart rate and blood pressure. However, since 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.

History Dopamine was discovered by Arvid Carlsson and Nils-Åke Hillarp at the Laboratory for Chemical Pharmacology of the National Heart Institute of Sweden, in 1952. It was named Dopamine because it was a monoamine, and its synthetic precursor was 3,4-dihydroxyphenylalanine (L-DOPA). Benes, F.M. Carlsson and the discovery of dopamine. Trends in Pharmacological Sciences, Volume 22, Issue 1, 1 January 2001, Pages 46-47. Arvid Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not just a precursor of noradrenaline and adrenaline but a neurotransmitter, as well.

Biochemistry Name and family Dopamine has the chemical formula C6H3(OH)2-CH2-CH2-NH2. 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 adrenal medulla of the adrenal glands) first by the hydration 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 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 Vesicle (biology), which are then released in response to the 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.

Dopamine may also simply diffuse away from the synapse.

Functions in the brain Dopamine has many functions in the brain, including important roles in behavior and cognition, motor activity, motivation and reward system, regulation of milk production, sleep, Mood (psychology), 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, substantia nigra, and arcuate nucleus of the hypothalamus.

The VTA and nucleus accumbens are central to the brain reward system. Schultz, Cambridge university, UK Dopamine neurons in the primate brain are found in the substantia nigra pars compacta and the ventral tegmental area. The phasic responses of dopamine neurons are observed when an unexpected reward is presented. These responses transfer to the onset of a Classical conditioning 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 by many 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 Quantitative structure-activity relationship of dopamine.

Movement Via the dopamine receptors D1, D2, D3, D4 and D5, 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. The phasic dopaminergic activation seems to be crucial with respect to a lasting internal encoding of motor skills (Beck, 2005).

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. On the converse, however, anti-psychotic medications act as dopamine antagonists and are used in the treatment of positive symptoms in schizophrenia.

Regulating prolactin secretion Dopamine is the primary neuroendocrine regulator of the secretion of prolactin from the anterior pituitary gland. 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 (sex).

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 ventral tegmental area) by naturally rewarding experiences such as food, Human sexual behaviour, use of certain drugs and neutral stimulus that become Classical conditioning with them. This theory is often discussed in terms of drugs such as cocaine and amphetamines, which seem to directly or indirectly lead to the increase of dopamine in these areas, and in relation to neurobiology theories of chemical addiction, arguing that these dopamine pathways are pathologically altered in addicted persons.

Reuptake inhibition, expulsion However, cocaine and amphetamine 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%) 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. When entering inside the presynaptic neuron, amphetamines force the dopamine molecules out of their storage vesicles and expel them into the synaptic gap by making the dopamine transporters work in reverse.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 is not released when unpleasant or aversive stimuli are encountered, and so motivates towards the pleasure of avoiding or removing the unpleasant stimuli.

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% in the nucleus accumbens and neostriatum using 6-hydroxydopamine. 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.

Dopamine reducing drugs in humans In humans, however, drugs that reduce dopamine activity (neuroleptics, e.g., some antipsychotics) have been shown to reduce motivation, as well as cause anhedonia (the inability to experience pleasure). Conversely the selective D2/D3 agonists pramipexole and ropinirole have anti-anhedonic properties as measured by the Snaith-Hamilton Pleasure Scale. (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). 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. 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, manic subjects can become hypersocial, as well as hypersexual. This is also credited to an increase in dopamine, because mania alleviates from dopamine-blocking antipsychotics.

Salience Dopamine may also have a role in the Salience (neuroscience) ('noticeableness') of perceived objects and events, with potentially important stimuli such as: 1) rewarding things or 2) dangerous or threatening things seeming more noticeable or important. 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 Pharmacological blockade of brain dopamine receptors increases rather than decreases drug-taking behaviour. Since blocking dopamine decreases desire, the increase in drug-taking behaviour may be seen as not a chemical desire but as a deeply psychological desire to just 'feel something'.

Deficits in dopamine levels are implicated in Attention-deficit hyperactivity disorder(ADHD), and stimulant medications used to successfully treat the disorder increase dopamine neurotransmitter levels, leading to decreased symptoms.

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.

Links to psychosis Disruption to the dopamine system has also been strongly linked to psychosis and schizophrenia,{{cite web |publisher=St. Jude Children's Research Hospital |title=Disruption of gene interaction linked to schizophrenia | accessdate=2006-07-06 | url=http://www.innovations-report.com/html/reports/life_sciences/report-52499.html--> with abnormally high dopamine action apparently leading to these conditions. 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 D2 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. Because of this, most modern antipsychotic medications are designed to block dopamine function to varying degrees.

Therapeutic use L-DOPA is a dopamine precursor used in various forms to treat Parkinson's disease. It is typically co-administered with an inhibitor of peripheral decarboxylation (DDC, Aromatic-L-amino-acid 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.

Dopamine is also used as an inotrope in patients with Shock (medical) to increase cardiac output and blood pressure.

Major pathways

Mesocortical pathway
Mesolimbic pathway
Nigrostriatal pathway
Tuberoinfundibular pathway

Dopamine and fruit browning Polyphenol oxidases (PPOs) are a family of enzymes responsible for the Browning (chemical process) of fresh fruits and vegetables when they are cut or bruised. These enzymes use molecular oxygen (O2) to redox various diphenol 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 polymerisation and condense with amino acids and proteins to form brown biological pigment known as melanins. The quinones and melanins derived from dopamine may help protect damaged fruit and vegetables against growth of bacteria and fungi.

References See also

Addiction
Amphetamine
Antipsychotic
Catecholamine
Catechol-O-methyl transferase
Classical conditioning
Operant conditioning
Cocaine
Dopamine hypothesis of schizophrenia
Dopamine reuptake inhibitors
Methylphenidate
Neurotransmitter
Parkinson's disease
Prolactinoma
Schizophrenia
Selegiline

External links

The dopamine connection
Dopamine: what does it do? ... Dopamine: Pharmacologic and Therapeutic Aspects by Velasco M, Luchsinger A

Dopamine
What is dopamine?

Dopamine - Wikipedia, the free encyclopedia
Dopamine is a hormone and neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In chemical structure, it is a phenethylamine.

Dopamine
Dopamine: a key regulator to adapt action, emotion, motivation and cognition by Nieoullon A, Coquerel A. Neurobiology Unit, CNRS, Universite de La Mediterranee,

MDMA and dopamine
How does MAMA work? ... Acute psychological and physiological effects of MDMA ("Ecstasy") after haloperidol pretreatment in healthy humans

Dopamine: the pleasure and the pain
Is dopamine the brain's pleasure chemical? ... Date: August 1999 Pain, Itself, Elicits Pain Relief, And Does So Through "Reward" Pathway"

Dopamine
Dopamine hydrochloride. Dopamine hydrochloride - Medicine Guide. Dopamine hydrochloride (Dope-am-een hi-droh-clor-ride ) is a medicine which is used in heart failure, hypotension ...

Definition: dopamine from Online Medical Dictionary
The Online Medical Dictionary is a searchable dictionary of definitions from medicine, science and technology.

The dopamine hypothesis of depression
Uptake inhibition of biogenic amines by newer antidepressant drugs: relevance to the dopamine hypothesis of depression by Randrup A, Braestrup C.

Understanding Addiction
One of the neurotransmitters playing a major role in addiction is dopamine. Many of the concepts that apply to dopamine apply to other neurotransmitters as well.