Dopamine

Dopamine plays a major role in the brain system that is responsible for reward-driven learning. Every type of reward that has been studied increases the level of dopamine transmission in the brain, and a variety of highly addictive drugs, including [|stimulants] such as cocaine and methamphetamine, act directly on the dopamine system. There is evidence that people with [|extraverted] (reward-seeking) personality types tend to show higher levels of dopamine activity than people with introverted personalities. Several important diseases of the nervous system are associated with dysfunctions of the dopamine system. [|Parkinson's disease], an age-related degenerative condition causing tremor and motor impairment, is caused by loss of dopamine-secreting neurons in the//substantia nigra//. [|Schizophrenia] has been shown to involve elevated levels of dopamine activity in the [|mesolimbic pathway] and decreased levels of dopamine in the [|prefrontal cortex]. [|[1]][|[2]] [|Attention deficit hyperactivity disorder] (ADHD) is also believed to be associated with decreased dopamine activity. [|[3]] Dopamine is available as an intravenous medication acting 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] (the precursor of dopamine) is often given because it crosses the blood-brain barrier relatively easily
 * Dopamine**, a simple organic chemical in the [|catecholamine] family, plays a number of important physiological roles in the bodies of animals. Its name derives from its chemical structure, which consists of an [|amine] group (NH2) linked to a [|catechol] structure called dihydroxyphenylalanine (acronym DOPA). In the [|brain], dopamine functions as a [|neurotransmitter] —a chemical released by nerve cells to send signals to other nerve cells. The human brain uses five known types of [|dopamine receptors] , labeled [|D1] , [|D2] , [|D3] , [|D4] , and [|D5] . Dopamine is produced in several areas of the brain, including the // [|substantia nigra] // and the [|ventral tegmental area].

History
Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England. [|[4]] It was named dopamine because it is a [|monoamine] whose [|precursor] in the Barger-Ewens synthesis is 3,4-//d//ihydr//o//xy//p//henyl//a//lanine (levodopamine 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]. [|[5]] Carlsson was awarded the 2000 [|Nobel Prize in Physiology or Medicine] for showing that dopamine is not only a precursor of [|norepinephrine] (noradrenaline) and [|epinephrine] (adrenaline), but also a neurotransmitter.

Chemistry


Dopamine //(right)// 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 medicinal agent, dopamine is synthesized by [|demethylation] of 2-(3,4-dimethoxyphenyl)ethylamine //(left)// using [|hydrogen bromide]. [|[6]][|[7]]

Biochemistry
   Biosynthesis of dopamine

[ [|edit] ] Classification
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.

[ [|edit] ] 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].

Functions in the brain
   Dopamine pathways. In the brain, dopamine plays an important role in the regulation of reward and movement. As part of the reward pathway, dopamine is manufactured in nerve cell bodies located within the ventral tegmental area (VTA) and is released in the nucleus accumbens and the prefrontal cortex. Its motor functions are linked to a separate pathway, with cell bodies in the substantia nigra that manufacture and release dopamine into the striatum. Dopamine has many functions in the brain, including important roles in behavior and [|cognition], [|voluntary movement] , [|motivation] , [|punishment] and [|reward] , inhibition of [|prolactin] production (involved in [|lactation] and [|sexual gratification] ), [|sleep] , [|mood] , [|attention] , [|working memory] , 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. [|[10]] 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 maximizing 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.[// [|citation needed] //] The reward system in insects uses [|octopamine], which is the presumed arthropod homolog of [|norepinephrine] , [|[11]] rather than dopamine. In insects, dopamine acts instead as a punishment signal and is necessary to form aversive memories. [|[12]][|[13]]

Motor control
Dopamine reduces the influence of the indirect pathway while increasing the actions of the direct pathway within the [|basal ganglia] .[// [|citation needed] //] Insufficient dopamine [|biosynthesis] in the dopaminergic neurons can cause [|Parkinson's disease], a condition in which one loses the ability to execute smooth, controlled movements.[// [|citation needed] //] Parkinson's disease is a motor disease.

Regulating prolactin secretion
Dopamine is the primary [|neuroendocrine] inhibitor of the secretion of [|prolactin] from the [|anterior pituitary] gland. [|[20]] 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.

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 [|[21]] as well as D4 receptors [|[22]] are responsible for the cognitive-enhancing effects of dopamine, whereas D2 receptors are more specific for motor actions.

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].

Effects of drugs that reduce dopamine activity
In humans, drugs that reduce dopamine activity ( [|neuroleptics], e.g. [|antipsychotics] ) have been shown to impair concentration, reduce motivation, cause [|anhedonia] (inability to experience pleasure), and long-term use has been associated with [|tardive dyskinesia] , an irreversible movement disorder. [|[23]] Antipsychotics have significant effects on gonadal hormones including significantly lower levels of estradiol and progesterone in women, whereas men display significantly lower levels of testosterone and [|DHEA] when undergoing antipsychotic drug treatment compared to controls. Antipsychotics are known to cause [|hyperprolactinaemia] leading to [|amenorrhea], cessation of normal cyclic ovarian function, loss of libido, occasional [|hirsutism] , false positive pregnancy tests, and long-term risk of osteoporosis in women. The effects of hyperprolactinemia in men are [|gynaecomastia], [|lactation] , [|impotence] , loss of [|libido] , and [|hypospermatogenesis]. [|[24]] Furthermore, antipsychotic drugs are associated with [|weight gain], [|diabetes] , [|drooling] , [|dysphoria] (abnormal depression and discontent), [|fatigue] , [|sexual dysfunction] , [|heart rhythm] problems, [|stroke] and [|heart attack]. Selective D2/D3 agonists [|pramipexole] and [|ropinirole], used to treat [|restless legs syndrome] (RLS), have limited anti-anhedonic properties as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). [|[25]]

Opioid and cannabinoid transmission
[|Opioid] and [|cannabinoid] transmission instead of dopamine may modulate consummatory pleasure and food palatability (liking). [|[26]] 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. [|[27]] Libido can be increased by drugs that affect dopamine, but not by drugs that affect [|opioid peptides] or other neurotransmitters.

Learning, reinforcement, and reward-seeking behavior
Dopamine is commonly associated with the [|reward system] of the brain, providing feelings of enjoyment and [|reinforcement] to motivate a person to perform certain activities. Dopamine is released (particularly in areas such as the [|nucleus accumbens] and [|prefrontal cortex] ) by [|rewarding] experiences such as [|food], [|sex] , [|drugs] , and [|neutral stimuli] that become [|associated] with them. [|[28]] Recent studies indicate that [|aggression] may also stimulate the release of dopamine in this way. [|[29]] This theory can be 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] (not to be confused with [|psychological dependence] ), arguing that this [|dopamine pathway] is pathologically altered in addicted persons. [|[30]] In recent studies, cholinergic inactivation of the nucleus accumbens was able to disrupt the acquisition of drug reinforced behaviors, suggesting that dopamine has a more limited involvement in the acquisition of both drug self-administration and drug-conditioned place-preference behaviors than previously thought. [|[31]][|[32]] Dopaminergic neurons of the midbrain are the main source of dopamine in the brain. [|[28]] Dopamine has been shown to be involved in the control of movements, the signaling of error in prediction of reward, motivation, and cognition. Cerebral dopamine depletion is the hallmark of Parkinson's disease. [|[28]] Other pathological states have also been associated with dopamine dysfunction, such as schizophrenia, autism, and attention deficit hyperactivity disorder, as well as drug abuse. Dopamine is closely associated with reward-seeking behaviors, such as approach, consumption, and addiction. [|[28]] Recent researches suggest that the firing of dopaminergic neurons is a motivational substance as a consequence of reward-anticipation. This hypothesis is based on the evidence that, when a reward is greater than expected, the firing of certain dopaminergic neurons increases, which consequently increases desire or motivation towards the reward. [|[28]] 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. [|[33]] 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 to reward values. [|[33]] The nonreward neurons are predominate in the dorsolateral area of the substantia nigra pars compacta which projects to the [|dorsal striatum] and may relate to orienting behaviour. [|[33]] 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]. [|[33]]

[ [|edit] ] 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. [|[28]] With this large reduction in dopamine, the rats would no longer eat of 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 eat. In another study, mutant hyperdopaminergic (increased dopamine) mice show higher "wanting" but not "liking" of sweet rewards. [|[34]] Dopamine and Drugs Dopamine is the main chemical released by the brain while on most "recreational" drugs. This is the reason addiction is so prevalent and it is so hard to beat. Dopamine is responsible for the euphoric feelings while abusing drugs and alcohol, and the brain begins to get used to the amount of dopamine that is in it, therefore a tollerance and need for the substance is built when the brain is unable to secrete efficient dopamine while not under the influence.

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