Dopamine

Dopamine is a neurotransmitter that occurs 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, which is the precursor of dopamine, can be given because it can cross the blood-brain barrier.

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-dihydroxyphenylalanine (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 noradrenaline and 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
Biosynthesis of dopamine -Biodegradation of dopamine

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 noradrenaline and then 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 COMT and MAO. Dopamine that is not broken down by enzymes is repackaged into vesicles for reuse.[citation needed]

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 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.

The reward system in insects uses octopamine, which is the presumed arthropod homolog of norepinephrine,[5] rather than dopamine. In insects, dopamine acts instead as a punishment signal and is necessary to form aversive memories.[6][7]

Anatomy
Dopaminergic pathways Dopaminergic neurons form a neurotransmitter system which originates in substantia nigra pars compacta, 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.

Movement
Via the dopamine receptors, D1-5, 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. [8]

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 ADD. It has been found that D1 receptors[9] as well as D4 receptors[10] 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[11], while the atypical drugs also act on D1, D3 and D4 receptors[12][13].

Regulating prolactin secretion
Dopamine is the primary neuroendocrine inhibitor of the secretion of prolactin from the anterior pituitary gland. [14] 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 PIF, PIH, or prolactostatin.

Motivation
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 (not to be confused with psychological dependence), arguing that this dopamine pathway is pathologically altered in addicted persons.[15][16][17]

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.[18] 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.[18] Other pathological states have also been associated with dopamine dysfunction, such as schizophrenia, autism, and ADHD, as well as drug abuse.

Dopamine is closely associated with reward-seeking behaviors, such as approach, consumption, and addiction.[18] 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.[18] 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.[19] The nonreward neurons are predominant in the dorsolateral area of the substantia nigra pars compacta which projects to the dorsal striatum and may relate orienting behaviour.[19] 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.[19]

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.[18] 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.[20]

The effects of drugs that reduce dopamine levels in humans
In humans, drugs that reduce dopamine activity (neuroleptics, e.g. antipsychotics) have been shown to reduce motivation, cause anhedonia (inability to experience pleasure), and long-term use has been associated with irreversible tardive dyskinesia (movement disorder).[21] Selective D2/D3 agonists pramipexole and ropinirole, used to treat Restless legs syndrome, have limited anti-anhedonic properties as measured by the SHAPS.[22]

Opioid and cannabinoid transmission
Opioid and cannabinoid transmission instead of dopamine may modulate consummatory pleasure and food palatability (liking).[23] 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.[24] 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.[25]

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,[26] PAG,[27] thalamus,[28] basal ganglia,[29][30] insular cortex,[31][32] and cingulate cortex.[33] Accordingly, decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson's disease.[34] Abnormalities in dopaminergic neurotransmission have also been demonstrated in painful clinical conditions, including burning mouth syndrome,[35] fibromyalgia,[36][37] and restless legs syndrome.[38] 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.[39] 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.[40] 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.[41] Consistent with this hypothesis, dopaminergic pathways have a role in inhibitory action control and the inhibition of the tendency to make unwanted actions.[42]

The long term use of levodopa in Parkinson's disease has been linked to dopamine dysregulation syndrome.[43]

Latent inhibition and creative drive
Dopamine in the mesolimbicpathway 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. MetoclopramideD2-receptor antagonist that functions as a prokinetic/antiemetic.

Links to Psychosis
Dopamine hypothesis of schizophrenia Abnormally high dopaminergic transmission has been linked to psychosis and schizophrenia.[45] Increased dopaminergic functional activity, specifically in the mesolimbic pathway, is found in schizophrenic individuals. Both the typical and the atypical antipsychotics work largely by inhibiting dopamine at the receptor level, thereby blocking the effects of the neurochemical in a dose-dependant manner. The finding that drugs such as mphetamines and cocaine, which can increase dopamine levels by more than tenfold,[46] can temporarily cause psychosis, provides further evidence for this link.[47]

Therapeutic use
L-DOPA 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 (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."[48] 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.[49] Dopamine therefore has a diuretic effect, potentially increasing urine output from 5 ml/kg/hr to 10 ml/kg/hr.[citation needed] Intermediate dosages from 5 to 10 μg/kg/min additionally have a positive inotropic and chronotropic effect through increased β1 receptor activation. It is used in patients with shock or heart failure to increase cardiac output and blood pressure.[49] Dopamine begins to affect the heart at the lower doses, from about 3 μg/kg/min IV.[50] High doses from 10 to 20 μg/kg/min is the "pressor" dose.[citation needed] This dose causes vasoconstriction, increases systemic vascular resistance, and increases blood pressure through α1 receptor activation;[49] but can cause the vessels in the kidneys to constrict to the point where they will become non-functional.[citation needed]

Dopamine and fruit browning
PPOs are a family of enzymes responsible for the browning of fresh fruits and vegetables when they are cut or bruised. These enzyme use molecular oxygen (O2) to oxidize 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 oxidizes 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.[51]