Материал: все о дофамине
Within the brain, dopamine functions partly as a global reward signal. An initial dopamine response to a rewarding stimulus encodes information about the salience, value, and context of a reward.[52] In the context of reward-related learning, dopamine also functions as a reward prediction error signal, that is, the degree to which the value of a reward is unexpected.[52] According to this hypothesis proposed by Montague, Dayan, and Sejnowski,[56] rewards that are expected do not produce a second phasic dopamine response in certain dopaminergic cells, but rewards that are unexpected, or greater than expected, produce a short-lasting increase in synaptic dopamine, whereas the omission of an expected reward actually causes dopamine release to drop below its background level.[52] The "prediction error" hypothesis has drawn particular interest from computational neuroscientists, because an influential computational-learning method known as temporal difference learning makes heavy use of a signal that encodes prediction error.[52] This confluence of theory and data has led to a fertile interaction between neuroscientists and computer scientists interested in machine learning.[52]
Evidence from microelectrode recordings from the brains of animals shows that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra are strongly activated by a wide variety of rewarding events.[52] These reward-responsive dopamine neurons in the VTA and substantia nigra are crucial for reward-related cognition and serve as the central component of the reward system.[4][57][58] The function of dopamine varies in each axonal projection from the VTA and substantia nigra;[4] for example, the VTA–nucleus accumbens shell projection assigns incentive salience ("want") to rewarding stimuli and its associated cues, the VTA–prefrontal cortex projection updates the value of different goals in accordance with their incentive salience, the VTA–amygdala and VTA–hippocampus projections mediate the consolidation of reward-related memories, and both the VTA–nucleus accumbens core and substantia nigra–dorsal striatum pathways are involved in learning motor responses that facilitate the acquisition of rewarding stimuli.[4][59] Some activity within the VTA dopaminergic projections appears to be associated with reward prediction as well.[4][59]
Pleasure
While dopamine has a central role in causing "wanting," associated with the appetitive or approach behavioral responses to rewarding stimuli, detailed studies have shown that dopamine cannot simply be equated with hedonic "liking" or pleasure, as reflected in the consummatory behavioral response.[53] Dopamine neurotransmission is involved in some but not all aspects of pleasure-related cognition, since pleasure centers have been identified both within the dopamine system (i.e., nucleus accumbens shell) and outside the dopamine system (i.e., ventral pallidum and parabrachial nucleus).[53][55][60] For example, direct electrical stimulation of dopamine pathways, using electrodes implanted in the brain, is experienced as pleasurable, and many types of animals are willing to work to obtain it.[61] Antipsychotic drugs reduce dopamine levels and tend to cause anhedonia, a diminished ability to experience pleasure.[62] Many types of pleasurable experiences—such as sex, eating, and playing video games—increase dopamine release.[63] All addictive drugs directly or indirectly affect dopamine neurotransmission in the nucleus accumbens;[4][61] these drugs increase drug "wanting", leading to compulsive drug use, when repeatedly taken in high doses, presumably through the sensitization of incentive-salience.[55] Drugs that increase synaptic dopamine concentrations include psychostimulants such as methamphetamine and cocaine. These produce increases in "wanting" behaviors, but do not greatly alter expressions of pleasure or change levels of satiation.[55][61] However, opiate drugs such as heroin and morphine produce increases in expressions of "liking" and "wanting" behaviors.[55] Moreover, animals in which the ventral tegmental dopamine system has been rendered inactive do not seek food, and will starve to death if left to themselves, but if food is placed in their mouths they will consume it and show expressions indicative of pleasure.[64]
A clinical study from January 2019 that assessed the effect of a dopamine precursor (levodopa), dopamine antagonist (risperidone), and a placebo on reward responses to music – including the degree of pleasure experienced during musical chills, as measured by changes in electrodermal activity as well as subjective ratings – found that the manipulation of dopamine neurotransmission bidirectionally regulates pleasure cognition (specifically, the hedonic impact of music) in human subjects.[65][66] This research demonstrated that increased dopamine neurotransmission acts as a sine qua non condition for pleasurable hedonic reactions to music in humans.[65][66]
Outside the nervous system
Dopamine does not cross the blood–brain barrier, so its synthesis and functions in peripheral areas are to a large degree independent of its synthesis and functions in the brain.[22] A substantial amount of dopamine circulates in the bloodstream, but its functions there are not entirely clear.[23] Dopamine is found in blood plasma at levels comparable to those of epinephrine, but in humans, over 95% of the dopamine in the plasma is in the form of dopamine sulfate, a conjugate produced by the enzyme sulfotransferase 1A3/1A4 acting on free dopamine.[23] The bulk of this dopamine sulfate is produced in the mesentery that surrounds parts of the digestive system.[23] The production of dopamine sulfate is thought to be a mechanism for detoxifying dopamine that is ingested as food or produced by the digestive process—levels in the plasma typically rise more than fifty-fold after a meal.[23] Dopamine sulfate has no known biological functions and is excreted in urine.[23]
The relatively small quantity of unconjugated dopamine in the bloodstream may be produced by the sympathetic nervous system, the digestive system, or possibly other organs.[23] It may act on dopamine receptors in peripheral tissues, or be metabolized, or be converted to norepinephrine by the enzyme dopamine beta hydroxylase, which is released into the bloodstream by the adrenal medulla.[23] Some dopamine receptors are located in the walls of arteries, where they act as a vasodilator and an inhibitor of norepinephrine release.[67] These responses might be activated by dopamine released from the carotid body under conditions of low oxygen, but whether arterial dopamine receptors perform other biologically useful functions is not known.[67]
Beyond its role in modulating blood flow, there are several peripheral systems in which dopamine circulates within a limited area and performs an exocrine or paracrine function.[23] The peripheral systems in which dopamine plays an important role include the immune system, the kidneys and the pancreas.
Immune system
In the immune system dopamine acts upon receptors present on immune cells, especially lymphocytes.[68] Dopamine can also affect immune cells in the spleen, bone marrow, and circulatory system.[69] In addition, dopamine can be synthesized and released by immune cells themselves.[68] The main effect of dopamine on lymphocytes is to reduce their activation level. The functional significance of this system is unclear, but it affords a possible route for interactions between the nervous system and immune system, and may be relevant to some autoimmune disorders.[69]
Kidneys
The renal dopaminergic system is located in the cells of the nephron in the kidney, where all subtypes of dopamine receptors are present.[70] Dopamine is also synthesized there, by tubule cells, and discharged into the tubular fluid. Its actions include increasing the blood supply to the kidneys, increasing the glomerular filtration rate, and increasing the excretion of sodium in the urine. Hence, defects in renal dopamine function can lead to reduced sodium excretion and consequently result in the development of high blood pressure. There is strong evidence that faults in the production of dopamine or in the receptors can result in a number of pathologies including oxidative stress, edema, and either genetic or essential hypertension. Oxidative stress can itself cause hypertension.[71] Defects in the system can also be caused by genetic factors or high blood pressure.[72]
Pancreas
In the pancreas the role of dopamine is somewhat complex. The pancreas consists of two parts, an exocrine and an endocrine component. The exocrine part synthesizes and secretes digestive enzymes and other substances, including dopamine, into the small intestine.[73] The function of this secreted dopamine after it enters the small intestine is not clearly established—the possibilities include protecting the intestinal mucosa from damage and reducing gastrointestinal motility (the rate at which content moves through the digestive system).[73]
The pancreatic islets make up the endocrine part of the pancreas, and synthesize and secrete hormones including insulin into the bloodstream.[73] There is evidence that the beta cells in the islets that synthesize insulin contain dopamine receptors, and that dopamine acts to reduce the amount of insulin they release.[73] The source of their dopamine input is not clearly established—it may come from dopamine that circulates in the bloodstream and derives from the sympathetic nervous system, or it may be synthesized locally by other types of pancreatic cells.[73]
Medical uses
Main article: Dopamine (medication)
Dopamine HCl preparation, single dose vial for intravenous administration
Dopamine as a manufactured medication is sold under the trade names Intropin, Dopastat, and Revimine, among others. It is on the World Health Organization's List of Essential Medicines.[74] It is most commonly used as a stimulant drug in the treatment of severe low blood pressure, slow heart rate, and cardiac arrest. It is especially important in treating these in newborn infants.[75] It is given intravenously. Since the half-life of dopamine in plasma is very short—approximately one minute in adults, two minutes in newborn infants and up to five minutes in preterm infants—it is usually given in a continuous intravenous drip rather than a single injection.[76]
Its effects, depending on dosage, include an increase in sodium excretion by the kidneys, an increase in urine output, an increase in heart rate, and an increase in blood pressure.[76] At low doses it acts through the sympathetic nervous system to increase heart muscle contraction force and heart rate, thereby increasing cardiac output and blood pressure.[77] Higher doses also cause vasoconstriction that further increases blood pressure.[77][78] Older literature also describes very low doses thought to improve kidney function without other consequences, but recent reviews have concluded that doses at such low levels are not effective and may sometimes be harmful.[79] While some effects result from stimulation of dopamine receptors, the prominent cardiovascular effects result from dopamine acting at α1, β1, and β2 adrenergic receptors.[80][81]
Side effects of dopamine include negative effects on kidney function and irregular heartbeats.[77] The LD50, or lethal dose which is expected to prove fatal in 50% of the population, has been found to be: 59 mg/kg (mouse; administered intravenously); 95 mg/kg (mouse; administered intraperitoneally); 163 mg/kg (rat; administered intraperitoneally); 79 mg/kg (dog; administered intravenously).[82]
A fluorinated form of L-DOPA known as fluorodopa is available for use in positron emission tomography to assess the function of the nigrostriatal pathway.[83]
Disease, disorders, and pharmacology
See also: List of dopaminergic drugs
The dopamine system plays a central role in several significant medical conditions, including Parkinson's disease, attention deficit hyperactivity disorder, Tourette syndrome, schizophrenia, bipolar disorder, and addiction. Aside from dopamine itself, there are many other important drugs that act on dopamine systems in various parts of the brain or body. Some are used for medical or recreational purposes, but neurochemists have also developed a variety of research drugs, some of which bind with high affinity to specific types of dopamine receptors and either agonize or antagonize their effects, and many that affect other aspects of dopamine physiology,[84] including dopamine transporter inhibitors, VMAT inhibitors, and enzyme inhibitors.
Aging brain
Main article: Aging brain
A number of studies have reported an age-related decline in dopamine synthesis and dopamine receptor density (i.e., the number of receptors) in the brain.[85] This decline has been shown to occur in the striatum and extrastriatal regions.[86] Decreases in the D1, D2, and D3 receptors are well documented.[87][88][89] The reduction of dopamine with aging is thought to be responsible for many neurological symptoms that increase in frequency with age, such as decreased arm swing and increased rigidity.[90] Changes in dopamine levels may also cause age-related changes in cognitive flexibility.[90]
Other neurotransmitters, such as serotonin and glutamate also show a decline in output with aging.[89][91]
Multiple sclerosis
Studies reported that dopamine imbalance influences the fatigue in multiple sclerosis.[92] In patients with multiple sclerosis, dopamine inhibits production of IL-17 and IFN-γ by peripheral blood mononuclear cells.[93]
Parkinson's disease
Parkinson's disease is an age-related disorder characterized by movement disorders such as stiffness of the body, slowing of movement, and trembling of limbs when they are not in use.[50] In advanced stages it progresses to dementia and eventually death.[50] The main symptoms are caused by the loss of dopamine-secreting cells in the substantia nigra.[94] These dopamine cells are especially vulnerable to damage, and a variety of insults, including encephalitis (as depicted in the book and movie "Awakenings"), repeated sports-related concussions, and some forms of chemical poisoning such as MPTP, can lead to substantial cell loss, producing a parkinsonian syndrome that is similar in its main features to Parkinson's disease.[95] Most cases of Parkinson's disease, however, are idiopathic, meaning that the cause of cell death cannot be identified.[95]
The most widely used treatment for parkinsonism is administration of L-DOPA, the metabolic precursor for dopamine.[22] L-DOPA is converted to dopamine in the brain and various parts of the body by the enzyme DOPA decarboxylase.[21] L-DOPA is used rather than dopamine itself because, unlike dopamine, it is capable of crossing the blood-brain barrier.[22] It is often co-administered with an enzyme inhibitor of peripheral decarboxylation such as carbidopa or benserazide, to reduce the amount converted to dopamine in the periphery and thereby increase the amount of L-DOPA that enters the brain.[22] When L-DOPA is administered regularly over a long time period, a variety of unpleasant side effects such as dyskinesia often begin to appear; even so, it is considered the best available long-term treatment option for most cases of Parkinson's disease.[22]
L-DOPA treatment cannot restore the dopamine cells that have been lost, but it causes the remaining cells to produce more dopamine, thereby compensating for the loss to at least some degree.[22] In advanced stages the treatment begins to fail because the cell loss is so severe that the remaining ones cannot produce enough dopamine regardless of L-DOPA levels.[22] Other drugs that enhance dopamine function, such as bromocriptine and pergolide, are also sometimes used to treat Parkinsonism, but in most cases L-DOPA appears to give the best trade-off between positive effects and negative side-effects.[22]
Dopaminergic medications that are used to treat Parkinson's disease are sometimes associated with the development of a dopamine dysregulation syndrome, which involves the overuse of dopaminergic medication and medication-induced compulsive engagement in natural rewards like gambling and sexual activity.[96][97] The latter behaviors are similar to those observed in individuals with a behavioral addiction.[96]
Drug addiction and psychostimulants
Main article: Addiction
Cocaine increases dopamine levels by blocking dopamine transporters (DAT), which transport dopamine back into a synaptic terminal after it has been emitted.
Cocaine, substituted amphetamines (including methamphetamine), Adderall, methylphenidate (marketed as Ritalin or Concerta), and other psychostimulants exert their effects primarily or partly by increasing dopamine levels in the brain by a variety of mechanisms.[98] Cocaine and methylphenidate are dopamine transporter blockers or reuptake inhibitors;[99] they non-competitively inhibit dopamine reuptake, resulting in increased dopamine concentrations in the synaptic cleft.[100][101]: 54–58 Like cocaine, substituted amphetamines and amphetamine also increase the concentration of dopamine in the synaptic cleft, but by different mechanisms.[31][101]: 147–150
The effects of psychostimulants include increases in heart rate, body temperature, and sweating; improvements in alertness, attention, and endurance; increases in pleasure produced by rewarding events; but at higher doses agitation, anxiety, or even loss of contact with reality.[98] Drugs in this group can have a high addiction potential, due to their activating effects on the dopamine-mediated reward system in the brain.[98] However some can also be useful, at lower doses, for treating attention deficit hyperactivity disorder (ADHD) and narcolepsy.[102][103] An important differentiating factor is the onset and duration of action.[98] Cocaine can take effect in seconds if it is injected or inhaled in free base form; the effects last from 5 to 90 minutes.[104] This rapid and brief action makes its effects easily perceived and consequently gives it high addiction potential.[98] Methylphenidate taken in pill form, in contrast, can take two hours to reach peak levels in the bloodstream,[102] and depending on formulation the effects can last for up to 12 hours.[105] These longer acting formulations have the benefit of reducing the potential for abuse, and improving adherence for treatment by using more convenient dosage regimens.[106]
Methamphetamine hydrochloride also known as crystal meth
A variety of addictive drugs produce an increase in reward-related dopamine activity.[98] Stimulants such as nicotine, cocaine and methamphetamine promote increased levels of dopamine which appear to be the primary factor in causing addiction. For other addictive drugs such as the opioid heroin, the increased levels of dopamine in the reward system may play only a minor role in addiction.[107] When people addicted to stimulants go through withdrawal, they do not experience the physical suffering associated with alcohol withdrawal or withdrawal from opiates; instead they experience craving, an intense desire for the drug characterized by irritability, restlessness, and other arousal symptoms,[108] brought about by psychological dependence.
The dopamine system plays a crucial role in several aspects of addiction. At the earliest stage, genetic differences that alter the expression of dopamine receptors in the brain can predict whether a person will find stimulants appealing or aversive.[109] Consumption of stimulants produces increases in brain dopamine levels that last from minutes to hours.[98] Finally, the chronic elevation in dopamine that comes with repetitive high-dose stimulant consumption triggers a wide-ranging set of structural changes in the brain that are responsible for the behavioral abnormalities which characterize an addiction.[110] Treatment of stimulant addiction is very difficult, because even if consumption ceases, the craving that comes with psychological withdrawal does not.[108] Even when the craving seems to be extinct, it may re-emerge when faced with stimuli that are associated with the drug, such as friends, locations and situations.[108] Association networks in the brain are greatly interlinked.[111]