Dopamine (contracted from 3,4-dihydroxyphenethylamine) is a hormone (also known as Prolactin Inhibiting Hormone/Factor – PIH or PIF) a neurotransmitter of the catecholamine and phenethylamine families that plays a number of important roles in the human brain and body. Its name derives from its chemical structure: it is an amine that is formed by removing a carboxyl group from a molecule of L-DOPA.
In the brain, dopamine functions as a neurotransmitter—a chemical released by nerve cells to send signals to other nerve cells. The brain includes several distinct dopamine pathways, one of which plays a major role in reward-motivated behavior.
Most types of reward increase the level of dopamine in the brain, and a variety of addictive drugs increase dopamine neuronal activity. Other brain dopamine systems are involved in motor control and in controlling the release of several other important hormones.
Several important diseases of the nervous system are associated with dysfunctions of the dopamine system. Parkinson’s disease, a degenerative condition causing tremor and motor impairment, has been related to the loss of dopamine-secreting neurons in the midbrain area called the substantia nigra.
Outside the nervous system, dopamine functions in several parts of the body as a local chemical messenger. In the blood vessels, it inhibits norepinephrine release and acts as a vasodilator; in the kidneys, it increases sodium excretion and urine output; in the pancreas, it reduces insulin production; in the digestive system, it reduces gastrointestinal motility and protects intestinal mucosa; and in the immune system, it reduces the activity of lymphocytes. With the exception of the blood vessels, dopamine in each of these peripheral systems has a “paracrine” function: it is synthesized locally and exerts its effects on cells that are located near the cells that release it.
A variety of important drugs work by altering the way the body makes or uses dopamine. Dopamine itself is available for intravenous injection: although it cannot reach the brain from the bloodstream, its peripheral effects make it useful in the treatment of heart failure or shock, especially in newborn babies. L-DOPA, the metabolic precursor of dopamine, does reach the brain and is the most widely used treatment for Parkinson’s disease.
Dopaminergic stimulants can be addictive in high doses, but some are used at lower doses to treat ADHD. Conversely, many antipsychotic drugs act by suppressing the effects of dopamine. Drugs that act against dopamine by a different mechanism are also some of the most effective anti-nausea agents.
Preparations containing dopamine hydrochloride are used in the treatment of acute heart failure, kidney failure, myocardial infarction, septic shock, etc. and are on the World Health Organization’s List of Essential Medicines, a list of medicines that are essential for a basic health system.
Physiological Effects of Dopamine
Major Dopamine pathways by NIDA, Quasihuman – Licensed under Public Domain via Wikimedia Commons
Inside the brain, dopamine plays important roles in motor control, motivation, arousal, cognition, and reward, as well as a number of basic lower-level functions including lactation, sexual gratification, and nausea.
Dopaminergic neurons (i.e., neurons whose primary neurotransmitter is dopamine) are comparatively few in number — a total of around 400,000 in the human brain — and their cell bodies are confined to a few relatively small brain areas, but they send projections to many other brain areas and exert powerful effects on their targets. These dopaminergic cell groups were first mapped in 1964 by Annica Dahlström and Kjell Fuxe, who assigned them labels starting with the letter “A” (for “aminergic”). In their scheme, areas A1 through A7 contain the neurotransmitter norepinephrine, whereas A8 through A14 contain dopamine. Here is a list of the dopaminergic areas they identified:
The substantia nigra, a small midbrain area that forms a component of the basal ganglia. The dopamine neurons are found mainly in a part of this structure called the pars compacta (cell group A8) and nearby (group A9). In humans, the projection of dopamine neurons from the substantia nigra pars compacta to the dorsal striatum, termed the nigrostriatal pathway, plays a significant role in the control of motor function and in learning new motor programs.
The name substantia nigra is Latin for “dark substance”, and refers to the fact that the dopaminergic neurons there are darkly pigmented. These neurons are especially vulnerable to damage, and when a large fraction of them die, the result is a Parkinsonian syndrome.
The ventral tegmental area (VTA), another midbrain area. This cell group (A10) is the largest group of dopaminergic cells in the human brain, though still quite small in absolute terms. The most prominent group of VTA dopamine neurons projects from the VTA to the prefrontal cortex via the mesocortical pathway and the nucleus accumbens via the mesolimbic pathway, and is collectively termed the mesocorticolimbic projection; the VTA also sends dopaminergic projections to the amygdala, cingulate gyrus, hippocampus, and olfactory bulb.
Mesocorticolimbic neurons play a central role in reward and other aspects of motivation. The nucleus accumbens is often considered to be the “limbic” part of the striatum. As such, it is the part of the striatum involved in the highest level aspects of motor control, which include motivation and decision-making.
Thus, the role of the VTA in motivation and decision-making is structurally analogous to the role of the substantia nigra in low-level motor control. In primates (i.e. monkeys and humans), the dopamine neurons from the regions of the substantia nigra and VTA project throughout most of the cortical mantle, with particularly dense innervation of the motor and premotor cortices. Thus, there are major species differences in cortical dopamine projections.
The posterior hypothalamus. These dopaminergic cells (group A11) project to the spinal cord, and their function is not well established. There is some evidence that pathology in this area plays a role in restless legs syndrome, a condition in which people have difficulty sleeping due to an overwhelming compulsion to constantly move parts of the body, especially the legs.
The arcuate nucleus (cell group A12) and periventricular nucleus (cell group A14) of the hypothalamus. An important projection from these dopaminergic neurons, termed the tuberoinfundibular pathway, goes to the pituitary gland, where it influences the secretion of the hormone prolactin. Dopamine is the primary neuroendocrine inhibitor of the secretion of prolactin from the anterior pituitary gland.
Dopamine produced by neurons in the arcuate nucleus 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.
The zona incerta. These cells (group A13) project to several areas of the hypothalamus, and participate in the control of gonadotropin-releasing hormone, which is necessary to activate the development of reproductive systems that occurs following puberty, both in males and females.
An additional group of dopamine-secreting neurons are located in the retina of the eye. These neurons are amacrine cells, meaning that they have no axons. They release dopamine into the extracellular medium, and are specifically active during daylight hours, becoming silent at night. This retinal dopamine acts to enhance the activity of cone cells in the retina while suppressing rod cells — the result is to increase sensitivity to color and contrast during bright light conditions, at the cost of reduced sensitivity when the light is dim.
Like many other biologically active substances, dopamine exerts its effects by binding to and activating receptors located on the surface of cells. In mammals, five subtypes of dopamine receptors have been identified, labeled D1 through D5. All of them function as G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system.
Glossing over the details, dopamine receptors in mammals can be divided into two families, known as D1-like and D2-like. The ultimate effect of D1-like receptors (D1 and D5) can be excitation (via opening of sodium channels) or inhibition (via opening of potassium channels); the ultimate effect of D2-like receptors (D2, D3, and D4) is usually inhibition of the target neuron.
Consequently, it is incorrect to describe dopamine itself as either excitatory or inhibitory. Its effect on a target neuron depends on which types of receptors are present on the membrane of that neuron and on the internal responses of that neuron to cyclic AMP. D1 receptors are the most numerous dopamine receptors in the central nervous system; D2 receptors are next; D3, D4, and D5 receptors are present at significantly lower levels.
The level of extracellular dopamine is modulated by two mechanisms: tonic and phasic dopamine transmission. Tonic dopamine transmission occurs when small amounts of dopamine are released independently of neuronal activity, and is regulated by the activity of other neurons and neurotransmitter reuptake. Phasic dopamine release results from the activity of the dopamine-containing cells themselves. This activity is characterized by irregular pacemaking activity of single spikes, and rapid bursts of typically 2–6 spikes in quick succession.
Substantia Nigra Dopamine System and Motor Control
The substantia nigra is a component of the basal ganglia, a group of interconnected structures in the forebrain and midbrain that play a central role in motor control. The precise nature of that role has been difficult to work out, but one popular line of thought describes it as “response selection”.
The response selection theory proposes that when a person or animal is in a situation where several behaviors are possible, activity in the basal ganglia determines which of them is executed, by releasing that response from inhibition. Thus the basal ganglia are responsible for initiating behaviors but not for determining the details of how they are carried out.
Dopamine is thought to modulate the response selection process in at least two important ways. First, dopamine sets the “effort threshold” for initiating behaviors. The higher the level of dopamine activity, the lower the impetus required to evoke a given behavior. As a consequence, high levels of dopamine lead to high levels of motor activity and “impulsive” behavior; low levels of dopamine lead to torpor and slowed reactions.
Parkinson’s disease, in which dopamine levels in the substantia nigra circuit are greatly reduced, is characterized by stiffness and greatly reduced movement—however, when people with the disease are confronted with strong stimuli such as a serious threat, their reactions can be as vigorous as those of a healthy person. In the opposite direction, drugs that increase the effects of dopamine, such as cocaine or amphetamine, produce heightened levels of activity, including at the highest levels psychomotor agitation and stereotyped movements.
The second important effect of dopamine is as a “teaching” signal. When a motor response is followed by an increase in dopamine activity, the basal ganglia circuit is altered in a way that makes the same response easier to evoke when similar situations arise in the future. This is a form of operant conditioning, in which dopamine plays the role of a reward signal.
Role in Cognition
Dopamine’s effects on higher cognitive function have been studied in monkeys and rodents. This work began with the landmark study of Brozoski et al., 1979 showing that depletion of catecholamines from the dorsolateral prefrontal cortex in monkeys impaired spatial working memory to the same degree as removing the cortex itself.
It is now known that both dopamine and norepinephrine have essential actions on prefrontal cortical function, and help coordinate cognitive state with arousal state. Dopamine has an “inverted U” influence on prefrontal function through its actions on D1 receptors, where either too little or too much impairs working memory function.
Pharmacology of Dopamine
Under the trade names Intropin, Dopastat, Revimine, or other names, dopamine has been used as a drug in injectable form. It is most commonly used in the treatment of severe hypotension, bradycardia (slow heart rate), circulatory shock, or cardiac arrest, especially in newborn infants. 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.
At a “cardiac/beta dose” of 5 to 10 μg/kg/min, dopamine acts through the sympathetic nervous system to increase heart muscle contraction force and heart rate, thereby increasing cardiac output and blood pressure. At a “pressor/alpha dose” of 10 to 20 μg/kg/min, dopamine also causes vasoconstriction that further increases blood pressure, but can produce negative side effects such as an impairment of kidney function and cardiac arrhythmias.
Older literature also describes a so-called “renal/dopaminergic dose” of 2 to 5 μg/kg/min thought to improve kidney function without other consequences, but recent reviews have concluded that doses at this low level are not clinically effective and may sometimes be harmful.
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.
A range of drugs that reduce dopamine activity have been found useful in the treatment of schizophrenia and other disorders that produce psychosis. These antipsychotic drugs are also sometimes known as neuroleptics or “major tranquilizers”, in contrast to “minor tranquilizers” such as Valium that are used to treat anxiety or sleep disorders.
“TAAR1 Dopamine” by Seppi333 – Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons –
These drugs have a broadly suppressive effect on most types of active behavior, and particularly reduce the delusional and agitated behavior characteristic of overt psychosis. The introduction of the first widely used antipsychotic drug, chlorpromazine (Thorazine), in the 1950s, led to the release of many schizophrenia patients from institutions in the years that followed.
Even so, the widespread use of antipsychotic drugs has long been controversial. There are several reasons for this. First, these drugs are perceived as very aversive by people who have to take them, because they produce a general dullness of thought and suppress the ability to experience pleasure.
Second, it is difficult to show that they act specifically against psychotic behaviors rather than merely suppressing all types of active behavior.
Third, they can produce a range of serious side effects, including weight gain, diabetes, fatigue, sexual dysfunction, hormonal changes, and a type of movement disorder known as tardive dyskinesia. Some of these side effects may continue long after the cessation of drug use, or even permanently.
The first drugs introduced specifically for the treatment of psychosis all had strong direct effects on multiple aspects of dopamine function. Drugs of this type are known as “typical antipsychotics”. Because of the problems they cause, there has been wide interest in newer types of drugs known as “atypical antipsychotics” or “second-generation antipsychotics”, which aim to target the specific types of dopamine receptors involved in psychosis, and thereby reduce psychotic symptoms without producing as many undesirable side effects. There remains substantial dispute, however, about how much of an improvement in the patient experience these drugs produce.
Dopamine-Related Diseases and Disorders
Parkinson’s disease is a disorder characterized by stiffness of the body, slowing of movement, and trembling of limbs when they are not in use. In advanced stages it progresses to dementia and eventually death. The main symptoms are caused by massive loss of dopamine-secreting cells in the substantia nigra.
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 (ex. MPTP), can lead to substantial cell loss, producing a Parkinsonian syndrome that is similar in its main features to Parkinson’s disease. Most cases of Parkinson’s disease, however, are “idiopathic”, meaning that the cause of cell death cannot be identified.
The most widely used treatment for Parkinsonism is administration of L-DOPA, the metabolic precursor for dopamine. This 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.
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. As this stage is approached, the metabolic regulatory mechanisms in the dopamine cells, operating far above their normal level, become erratic, producing dopamine dysregulation syndrome, in which patients fluctuate unpredictably between states of hyperactivity and paralysis.
Attention Deficit Hyperactivity Disorder
Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder (ADHD), a condition associated with impaired ability to regulate attention, behavior, and/or impulses. There are some genetic links between dopamine receptors, the dopamine transporter and ADHD, in addition to links to other neurotransmitter receptors and transporters.
The most important relationship between dopamine and ADHD involves the drugs that are used to treat ADHD. Some of the most effective therapeutic agents for ADHD are psychostimulants such as methylphenidate (Ritalin, Concerta) and amphetamine, drugs that increase both dopamine and norepinephrine levels in brain.
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, 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 presumably via activation of neurons involved in descending inhibition. In addition, D1 receptor activation in the insular cortex appears to attenuate subsequent pain-related behavior.
Abnormally high dopaminergic transmission has been linked to psychosis and schizophrenia. However, clinical studies relating schizophrenia to brain dopamine metabolism have ranged from controversial to negative, with HVA levels in the CSF the same for schizophrenics and controls. Increased dopaminergic functional activity, specifically in the mesolimbic pathway, is found in schizophrenic individuals.
Antipsychotic medications act largely as dopamine antagonists, inhibiting dopamine at the receptor level, and thereby blocking the effects of the neurochemical in a dose-dependent manner. The older, so-called typical antipsychotics most commonly act on D2 receptors, while the atypical drugs also act on D1, D3 and D4 receptors, though they have a lower affinity for dopamine receptors in general.
The finding that drugs such as amphetamines, methamphetamine and cocaine, which can increase dopamine levels by more than tenfold, can temporarily cause psychosis, provides further evidence for this link. However, many non-dopaminergic drugs can induce acute and chronic psychosis. The NMDA antagonists Ketamine and PCP both are used in research to reproduce the positive and negative symptoms commonly associated with schizophrenia.
Dopaminergic dysregulation has also been linked to depressive disorders. Early research in humans used various methods of analyzing dopamine levels and function in depressed patients. Studies have reported that there is decreased concentration of tyrosine, a precursor to dopamine, in the blood plasma, ventricular spinal fluid, and lumbar spinal fluid of depressed patients compared to control subjects.
One study measured the amount of homovanillic acid, the major metabolite of dopamine in the CSF, as a marker for the dopamine pathway turnover rate, and found decreased concentrations of homovanillic acid in the CSF of depressed patients. Postmortem real time reverse transcriptase-polymerase chain reaction (RT-PCR) has also been used to find that gene expression of a specific subtype of dopamine receptor was elevated in the amygdala of people suffering from depression as compared to control subjects.
The action of commonly used antidepressant drugs also has yielded information about possible alterations of the dopaminergic pathway in treating depression. It has been reported that many antidepressant drugs increase extracellular dopamine concentrations in the rat prefrontal cortex, but vary greatly in their effects on the striatum and nucleus accumbens. This can be compared to electro convulsive shock treatment (ECT), which has been shown to have a multiple fold increase in striatal dopamine levels in rats.
More recent research studies with rodents have found that depression-related behaviors are associated with dopaminergic system dysregulation. In rodents exposed to chronic mild stress, decreased escape behavior and decreased forced swimming is reversed with activation of the dopaminergic mesolimbic pathway.
Also, rodents that are susceptible to depression-related behavior after social defeat can have their behavior reversed with dopamine pathway activation. Depletion of dopamine in the caudate nucleus and nucleus accumbens has also been reported in cases of learned helplessness in animals. These symptoms can be reversed with dopamine agonists and antidepressant administration prior to the learned helplessness protocol.
Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England and first identified in the human brain by Kathleen Montagu in 1957. It was named dopamine because it is a monoamine whose precursor in the Barger-Ewens synthesis is 3,4-dihydroxyphenylalanine (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. 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.