One of the catecholamines, widely distributed in the central nervous system. Through a series of enzymatic reactions (see enzyme) it is formed from levodopa and converted to norepinephrine and then epinephrine. It is a central nervous system neurotransmitter essential to control of motion; it also acts as a hormone. Degeneration of certain dopamine-producing brain cells results in parkinsonism.
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Dopamine is a hormone and 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. 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.
Dopamine was discovered in 1952 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-dihydroxyphenylalanine (L-DOPA). 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.
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."
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.
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.
A common hypothesis, though not uncontroversial is that dopamine has a function of transmitting reward prediction error. 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.
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.
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.
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 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.
Dopamine is the primary neuroendocrine inhibitor 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.
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, sex, drugs, and neutral stimuli that become associated with them. This theory is often discussed in terms of drugs such as cocaine, nicotine, and amphetamines, which seem to directly or indirectly lead to an increase of dopamine in these areas, and in relation to neurobiological theories of chemical addiction, arguing that these dopamine pathways are pathologically altered in addicted persons. Recent studies indicate that aggression may also stimulate the release of dopamine in this way.
Cocaine and amphetamines inhibit the re-uptake of dopamine; however, they both 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.
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. 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.
In humans, however, drugs that reduce dopamine activity (neuroleptics, e.g. some antipsychotics) have been shown to reduce motivation, and to cause anhedonia a.k.a. the inability to experience pleasure. 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. (The Snaith-Hamilton-Pleasure-Scale (SHAPS), introduced in English in 1995, assesses self-reported anhedonia in psychiatric patients.)
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 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 hyperdopaminergic state in certain areas of the brain. In instances of bipolar disorder, manic subjects can become hypersocial, as well as hypersexual. This is also credited to an increase in dopamine, because mania can be reduced by dopamine-blocking anti-psychotics.
Dopamine has been demonstrated to play a role in pain processing in multiple levels of the central nervous system including the spinal cord , periaqueductal gray (PAG), thalamus , basal ganglia insular cortex and cingulate cortex. Accordingly, decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson's disease. Abnormalities in dopaminergic neurotransmission have also been demonstrated in painful clinical conditions, including burning mouth syndrome, fibromyalgia and restless legs syndrome. In general, the analgesic capacity of dopamine occurs as a result of dopamine D2 receptor activation; however, exceptions to this exist in the PAG, in which dopamine D1 receptor activation attenuates pain presumabley via activation of neurons involved in descending inhibition. In addition, D1 receptor activation in the insular cortex appears to attenuate subsequent pain-related behavior.
Dopamine may also have a role in the salience ('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.
One possible mechanism of paranoid thought architecture, both in schizophrenics and in amphetamine abusers (both groups are widely hypothesized to suffer from hyperabundance of dopamine), is as follows: hyperabundance of dopamine causes widespread salience: an impression of significance attendant to statements, events, things, etc. in the immediate environment. This heightened significance can frequently be disturbing since it may have no rational basis. The individual experiencing this heightened significance may attempt to account for it and in this way paranoid ideation begins as a theoretical structure designed to account for this disturbing impressionistic significance. On this model, the impression of heightened significance ("Meaning beyond meaning" or "things are not as they seem" as Carol North put it) is primary and gives rise to the theoretical efforts - the paranoid ideation. On this model, the paranoid ideation is engendered only indirectly by dopamine surfeit. If we follow this model, what is not clear, however, is the way in which exaggerated salience (supposing this to be a result of dopamine surfeit) gives rise to the sense of pervasive malfeasance which is a hallmark feature of paranoid schizophrenic and amphetamine-psychotic ideation. This sense of malfeasance need not be a direct product of salience; nor is it necessary that salience be a disquieting experience. It is neither a priori nor a posteriori true that salience leads inevitably to paranoid ideation. And the conviction of malfeasance may indeed have a non-sense-impressionistic source; i.e. there is no apparent reason (other than dogmatism) to follow the dictum that nothing is in the mind that was not first in the world of sense impressions. It may be that suspicion is engendered independently of impressions of salience. However, the two would seem philosophically linked in that it is hard to imagine an object of suspicion which is not also salient. The question then can be renewed: does the salience come first or the suspicion? It could be that they occur together but are distinct. In the case of paranoid ideation, it does not seem prima facie likely that this thought architecture would spring into existence simply because of salience. The sense of malefic conspiracy (a conspiracy which may be largely impersonal and theological, as in the case of Daniel Paul Schreber) is so consistent in paranoid ideation (of various kinds, in various individuals, of various origins) that it would seem to be a kind of mental capacity unto itself (albeit likely an exaggeration of this capacity, for vigilance or suspicion, e.g.), not something which is a product of a "suspicion-neutral" rational mind working to interpret irrational incidences of salience. That is, there is no reason to suppose that paranoid suspicion must be engendered by sense data of some kind (even of exaggerated salience) since this arbitrarily treats the suspicion as a learned response to certain sense data, rather than a capacity unto itself. (This would be analogous to treating human aggression as a learned response rather than as an innate capacity.) And indeed there would seem good reason to suppose the existence of an innate capacity for suspicion and vigilance, since these activities would tend toward individual survival.
Pharmacological blockade of brain dopamine receptors increases rather than decreases drug-taking behavior. 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.
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.
Abnormally high dopamine action has also been strongly linked to psychosis and schizophrenia, 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, for example, Risperidone, are designed to block dopamine function to varying degrees.
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.
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 (O2) 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.