Dopamine (DA, short for 3,4-dihydroxyphenethylamine) is a chemical that helps control the activity of cells. It belongs to two groups of chemicals called catecholamines and phenethylamines. Dopamine is made by removing a part of a molecule called L-DOPA, which is created in the brain and kidneys. It is also made in plants and most animals. In the brain, dopamine acts as a neurotransmitter, meaning it is released by nerve cells to send messages to other nerve cells. The brain has several pathways that use dopamine, one of which is important for motivation and reward-related behavior. When people expect a reward, dopamine levels in the brain increase. Many drugs that cause addiction increase dopamine release or stop it from being reabsorbed by nerve cells. Other dopamine pathways help control movement and hormone release. These pathways and cells together form the dopamine system, which helps regulate nerve activity.

In popular culture, dopamine is often described as the main chemical linked to pleasure. However, scientists now believe dopamine is more about signaling the importance of a goal, such as how desirable or unpleasant an outcome is, which influences behavior to achieve or avoid that outcome.

Outside the brain, dopamine mainly acts as a local messenger between nearby cells. In blood vessels, it stops the release of another chemical called norepinephrine and helps widen blood vessels. In the kidneys, it increases salt removal and urine production. In the pancreas, it reduces insulin production. In the digestive system, it slows stomach and intestinal movement and protects the lining of the intestines. In the immune system, it reduces activity in certain white blood cells. Except for blood vessels, dopamine is made locally in these systems and works near the cells that release it.

Dysfunctions in the dopamine system are linked to several nervous system diseases. Parkinson’s disease, a condition that causes shaking and movement problems, happens when nerve cells that make dopamine in a part of the brain called the substantia nigra are lost. A chemical called L-DOPA, which is made in the body, can be used to treat this disease. Levodopa, a pure form of L-DOPA, is the most common treatment for Parkinson’s. Schizophrenia, a mental disorder, is associated with changes in dopamine activity. Many medicines used to treat schizophrenia block dopamine activity. These same medicines are also effective for treating nausea. Restless legs syndrome and attention deficit hyperactivity disorder (ADHD) are linked to lower dopamine activity. Some drugs that increase dopamine activity are used to treat ADHD at low doses but can be addictive at higher doses. Dopamine itself is available as a medicine for injection and is used to treat severe heart failure or shock in newborns.

Structure

Dopamine is made up of a catechol structure, which is a benzene ring with two hydroxyl groups attached to it. One amine group is connected to this structure through an ethyl chain. Because of this structure, dopamine is the simplest type of catecholamine, a group of molecules that also includes the neurotransmitters norepinephrine and epinephrine. The combination of a benzene ring and an amine group makes dopamine a substituted phenethylamine, a category that includes many psychoactive drugs.

Like most amines, dopamine is an organic base. In acidic environments, it reacts by accepting a proton, becoming protonated. This protonated form dissolves easily in water and is more stable, but it can react with oxygen or other oxidants. In basic environments, dopamine does not accept a proton and remains in its free base form. This form is less water-soluble and more reactive. Because the protonated form is more stable and water-soluble, dopamine is commonly provided as dopamine hydrochloride. This compound forms when dopamine combines with hydrochloric acid. In its dry form, dopamine hydrochloride appears as a fine powder that is white to yellow in color.

Biochemistry

Dopamine is made in specific types of cells, mainly neurons and cells in the medulla of the adrenal glands. The main and less common ways dopamine is broken down are:

The direct source of dopamine, called L-DOPA, can be made indirectly from the essential amino acid phenylalanine or directly from the non-essential amino acid tyrosine. These amino acids are found in nearly all proteins and are easily available in food, with tyrosine being the most common. Although dopamine is also found in many foods, it cannot pass through the blood–brain barrier that protects the brain. Therefore, dopamine must be made inside the brain to function properly.

L-Phenylalanine is changed into L-tyrosine by the enzyme phenylalanine hydroxylase, which needs molecular oxygen (O₂) and tetrahydrobiopterin as helpers. L-Tyrosine is changed into L-DOPA by the enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin, oxygen, and iron (Fe) as helpers. L-DOPA is then changed into dopamine by the enzyme aromatic L-amino acid decarboxylase (also called DOPA decarboxylase), which uses pyridoxal phosphate as a helper.

Dopamine is used to make the neurotransmitters norepinephrine and epinephrine. Dopamine becomes norepinephrine through the enzyme dopamine β-hydroxylase, which needs oxygen and L-ascorbic acid as helpers. Norepinephrine becomes epinephrine through the enzyme phenylethanolamine N-methyltransferase, which uses S-adenosyl-L-methionine as a helper.

Some helpers also need to be made themselves. A lack of any required amino acid or helper can slow the production of dopamine, norepinephrine, and epinephrine.

Dopamine is broken down into inactive substances by enzymes—monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH)—in a series of steps. Both forms of monoamine oxidase, MAO-A and MAO-B, effectively break down dopamine. Different breakdown paths exist, but the main final product is homovanillic acid (HVA), which has no known biological function. From the bloodstream, homovanillic acid is filtered by the kidneys and removed through urine. The two main ways dopamine is converted into HVA are:

• Dopamine → DOPAL → DOPAC → HVA – each step is helped by MAO, ALDH, and COMT, respectively
• Dopamine → 3-Methoxytyramine → HVA – helped by COMT and then MAO+ALDH, respectively

In research on schizophrenia, measuring homovanillic acid in blood has been used to estimate dopamine activity in the brain. However, a challenge is separating the high levels of homovanillic acid in blood that come from the breakdown of norepinephrine.

Although dopamine is usually broken down by an oxidoreductase enzyme, it can also react directly with oxygen, forming quinones and free radicals. This reaction happens faster in the presence of ferric iron or other factors. Quinones and free radicals from dopamine’s breakdown can harm cells. Evidence suggests this process may contribute to cell loss seen in Parkinson’s disease and other conditions.

Functions

Dopamine works by attaching to and activating receptors on the surface of cells. In humans, dopamine strongly binds to dopamine receptors and a receptor called human trace amine-associated receptor 1 (hTAAR1). In mammals, five types of dopamine receptors have been identified, labeled D1 through D5. All of these receptors are metabotropic, G protein-coupled receptors, meaning they use a complex system of signals inside the cell to produce their effects. These receptors are grouped into two families: D1-like (D1 and D5) and D2-like (D2, D3, and D4). When D1-like receptors are activated on neurons, they can either excite neurons (by opening sodium channels) or inhibit them (by opening potassium channels). When D2-like receptors are activated, they usually inhibit the target neuron. Therefore, dopamine itself is not inherently excitatory or inhibitory; its effect depends on the type of receptors present on the neuron and how the neuron responds to the signal cAMP. D1 receptors are the most common in the human nervous system, followed by D2 receptors, while D3, D4, and D5 receptors are found in much smaller amounts.

Inside the brain, dopamine acts as a neurotransmitter and neuromodulator, controlled by mechanisms shared by all monoamine neurotransmitters. After being made, dopamine is moved from the cell’s cytosol into storage vesicles, including synaptic vesicles and large dense core vesicles, using a protein called the vesicular monoamine transporter (VMAT2). Dopamine remains in these vesicles until it is released into the synaptic cleft. Most dopamine is released through a process called exocytosis, which happens when electrical signals called action potentials occur. However, dopamine release can also be triggered by a receptor called TAAR1, which is sensitive to dopamine, trace amines, and certain amphetamines. TAAR1 is located inside the presynaptic cell and helps control dopamine signaling by reducing its reuptake, increasing its release, and decreasing neuronal activity.

Once in the synapse, dopamine binds to dopamine receptors. These receptors can be postsynaptic (located on dendrites of the receiving neuron) or presynaptic autoreceptors (found on the axon terminal of the sending neuron). After the receiving neuron generates an action potential, dopamine detaches from its receptors and is taken back into the presynaptic cell through reuptake, which is managed by the dopamine transporter or the plasma membrane monoamine transporter. Once inside the cell, dopamine is either broken down by an enzyme called monoamine oxidase or repackaged into vesicles by VMAT2 for future use.

In the brain, dopamine levels are controlled by two processes: phasic and tonic transmission. Phasic dopamine release occurs when action potentials in dopamine-producing cells directly trigger the release of dopamine. Tonic transmission involves the release of small amounts of dopamine without action potentials, and it is influenced by other neurons and reuptake processes.

Dopamine plays important roles in the brain, including controlling executive functions, motor skills, motivation, alertness, reward, and basic functions like lactation, sexual satisfaction, and nausea. The network of dopamine-producing neurons and their connections form the dopamine system, which acts as a neuromodulator.

Dopamine-producing neurons are relatively few in number—about 400,000 in the human brain—and are located in specific small brain regions. However, their long axons connect to many other brain areas, allowing them to influence widespread functions. These neurons were first mapped in 1964 by Annica Dahlström and Kjell Fuxe, who labeled them with letters starting with "A" (for "aminergic"). Areas A1 through A7 contain norepinephrine, while A8 through A14 contain dopamine. The dopamine-producing regions include the substantia nigra (groups A8 and A9), the ventral tegmental area (group A10), the posterior hypothalamus (group A11), the arcuate nucleus (group A12), the zona incerta (group A13), and the periventricular nucleus (group A14).

The substantia nigra is a small brain region part of the basal ganglia, divided into the pars reticulata (input area) and the pars compacta (output area). Most dopamine-producing neurons are found in the pars compacta (group A8) and nearby (group A9). In humans, the connection between the substantia nigra pars compacta and the dorsal striatum, called the nigrostriatal pathway, is vital for motor control and learning new movements. These neurons are especially vulnerable to damage, and their loss can lead to Parkinson’s disease.

The ventral tegmental area (VTA) is another midbrain region. The most prominent dopamine-producing neurons in the VTA send signals to the prefrontal cortex via the mesocortical pathway and to the nucleus accumbens via the mesolimbic pathway. Together, these are called the mesocorticolimbic projection. These neurons also connect to the amygdala, cingulate gyrus, hippocampus, and olfactory bulb. These pathways are central to reward and motivation. Research shows dopamine also helps with learning from negative experiences through its effects on brain regions.

The posterior hypothalamus contains dopamine neurons that connect to the spinal cord, though their exact role is unclear. Some evidence suggests issues in this area may contribute to restless legs syndrome, a condition causing an urge to move limbs, especially legs, during sleep.

The arcuate nucleus and periventricular nucleus of the hypothalamus have dopamine neurons that form the tuberoinfundibular pathway, which connects to the pituitary gland. This pathway influences the release of prolactin, a hormone that produces milk. Dopamine from the arcuate nucleus is sent through the hypophyseal portal system to the pituitary gland. Without dopamine, prolactin is released constantly, but dopamine stops this process.

The zona incerta, located between the arcuate and periventricular nuclei, connects to the hypothalamus and helps control gonadotropin-releasing hormone, which is essential for reproductive system development after puberty.

Another group of dopamine-producing neurons is found in the retina of the eye. These are amacrine cells, which lack axons. They release dopamine into the space around them and are active during the day but inactive at night. This dopamine helps cone cells in the retina function better during daylight and reduces rod cell activity.

Medical uses

Dopamine, when made into medicine, is sold under names such as Intropin, Dopastat, and Revimine. It is listed on the World Health Organization's List of Essential Medicines. It is most often used as a stimulant to treat severe low blood pressure, slow heart rate, and cardiac arrest. It is especially important for treating these conditions in newborn infants. Dopamine is given through a vein. Because dopamine leaves the blood very quickly—about one minute in adults, two minutes in newborns, and up to five minutes in preterm infants—it is usually given in a continuous intravenous drip instead of a single injection.

Depending on the dose, dopamine can increase sodium removal by the kidneys, increase urine production, increase heart rate, and raise blood pressure. At low doses, it activates the sympathetic nervous system to strengthen heart muscle contractions and increase heart rate, which improves cardiac output and blood pressure. Higher doses cause blood vessels to narrow, further raising blood pressure. Older studies suggested very low doses might improve kidney function without harm, but recent research has found these low doses may not work and could sometimes be harmful. While some effects come from dopamine binding to dopamine receptors, the main effects on the heart and blood vessels occur when dopamine acts as a weak activator on α1, β1, and β2 adrenergic receptors.

Side effects of dopamine include harm to kidney function and irregular heartbeats. The LD50, or the dose expected to kill 50% of a population, has been reported as: 59 mg/kg (mouse, given through a vein); 95 mg/kg (mouse, given into the abdomen); 163 mg/kg (rat, given into the abdomen); 79 mg/kg (dog, given through a vein).

Disease, disorders, and pharmacology

The dopamine system is important in many serious medical conditions, such as Parkinson's disease, attention deficit hyperactivity disorder (ADHD), Tourette syndrome, schizophrenia, bipolar disorder, and addiction. In addition to dopamine itself, many other drugs affect the dopamine system in the brain or body. Some of these drugs are used for medical or recreational purposes, but scientists have also created research drugs that attach strongly to certain dopamine receptors. These drugs either help or block the receptors' effects, and others influence other parts of dopamine function, such as drugs that stop dopamine from being removed from nerve cells, drugs that stop dopamine from being stored in cells, and drugs that stop enzymes from working.

Studies have found that as people age, the brain makes less dopamine and has fewer dopamine receptors. This change happens in areas of the brain called the striatum and extrastriatal regions. The number of D1, D2, and D3 receptors decreases with age. This loss of dopamine is believed to cause many neurological problems that become more common as people grow older, such as less movement in the arms and more stiffness. Changes in dopamine levels may also affect how well the brain can adapt to new situations.

Research has shown that an imbalance in dopamine levels can affect fatigue in people with multiple sclerosis. In these patients, dopamine stops certain immune cells from producing IL-17 and IFN-γ.

Parkinson's disease is a condition that happens as people age and causes movement problems, such as stiff muscles, slow movement, and shaking in the limbs when they are not moving. In later stages, it can lead to dementia and death. The main symptoms are caused by the loss of brain cells that produce dopamine in an area called the substantia nigra. These cells are especially at risk of damage, and events like brain infections, repeated head injuries from sports, and exposure to certain chemicals, such as MPTP, can cause significant cell loss, leading to symptoms similar to Parkinson's disease. Most cases of Parkinson's disease are idiopathic, meaning the cause of the cell loss is unknown.

The most common treatment for Parkinson's disease is a drug called L-DOPA, which is a chemical that the brain turns into dopamine. L-DOPA can cross the blood–brain barrier, unlike dopamine itself, which cannot. To help more L-DOPA reach the brain, it is often given with drugs that stop it from being turned into dopamine in the body, such as carbidopa or benserazide. Over time, long-term use of L-DOPA can cause side effects like uncontrollable movements, but it remains the best long-term treatment for most patients.

L-DOPA does not replace the dopamine cells that have been lost, but it helps the remaining cells make more dopamine, which can reduce the effects of the loss. In advanced stages, the treatment becomes less effective because the loss of cells is too severe for the remaining cells to compensate. Other drugs, such as bromocriptine and pergolide, may also be used to treat Parkinson's disease, but L-DOPA is usually the best option for balancing benefits and side effects.

Drugs used to treat Parkinson's disease can sometimes lead to a condition called dopamine dysregulation syndrome, which involves using too much medication and acting on impulses, such as gambling or engaging in sexual activities. These behaviors are similar to those seen in people with behavioral addictions.

Drugs like cocaine, amphetamines (including methamphetamine), Adderall, and methylphenidate (sold as Ritalin or Concerta) work by increasing dopamine levels in the brain. Cocaine and methylphenidate block the reabsorption of dopamine, which raises its levels in the brain. Amphetamines and amphetamine also increase dopamine levels but through different methods.

These drugs can cause faster heartbeats, higher body temperatures, and sweating. They can also improve alertness, attention, and endurance, and make rewarding experiences feel more pleasurable. However, at high doses, they may cause agitation, anxiety, or confusion. These drugs are highly addictive because they activate the brain's reward system. At lower doses, they can help treat ADHD and narcolepsy. A key difference is how quickly they work and how long their effects last. Cocaine acts quickly and lasts for a short time, which increases its risk of addiction. Methylphenidate, when taken as a pill, works more slowly and lasts longer, which can reduce the risk of abuse and make treatment easier to follow.

Many addictive drugs increase dopamine activity in the brain's reward system. Stimulants like nicotine, cocaine, and methamphetamine raise dopamine levels, which are a major reason for addiction. For other drugs, such as heroin, dopamine may play a smaller role in causing addiction. When people who use stimulants stop, they do not experience the physical pain of alcohol or opioid withdrawal. Instead, they feel intense cravings, which are linked to psychological dependence.

The dopamine system is important in how addiction develops. At first, differences in genes that control dopamine receptors can predict whether someone will find stimulants appealing or unpleasant. Using stimulants increases dopamine levels in the brain for minutes to hours. Over time, repeated use of high doses of stimulants causes long-term changes in the brain that lead to the behaviors seen in addiction. Treating stimulant addiction is difficult because even after stopping use, cravings from psychological withdrawal can return when people are exposed to reminders of the drug, such as certain people, places, or situations. The brain's networks are highly connected, making it hard to break these associations.

In the 1950s, psychiatrists discovered that a group of drugs called typical antipsychotics (also known as major tranquilizers) helped reduce the symptoms of schizophrenia.

Comparative biology and evolution

Dopamine has not been found in archaea, but it has been detected in some types of bacteria and in a single-celled organism called Tetrahymena. Some bacteria contain similar versions of the enzymes that animals use to make dopamine. Scientists believe that animals may have inherited their ability to produce dopamine from bacteria through a process called horizontal gene transfer, which may have happened later in evolutionary history, possibly when bacteria were incorporated into eukaryotic cells that led to the development of mitochondria.

Dopamine acts as a neurotransmitter in most multicellular animals. It has been found in sponges, but its function there is unknown. In many radially symmetric animals, such as jellyfish, hydra, and some corals, dopamine is present in their nervous systems. This suggests that dopamine began functioning as a neurotransmitter when nervous systems first appeared over 500 million years ago during the Cambrian Period. Dopamine serves as a neurotransmitter in vertebrates, echinoderms, arthropods, molluscs, and several types of worms.

In every animal studied, dopamine affects movement. In the model organism, the nematode Caenorhabditis elegans, dopamine reduces movement and increases food-seeking behavior. In flatworms, it causes "screw-like" movements. In leeches, it stops swimming and encourages crawling. Across many vertebrates, dopamine helps animals switch between behaviors and choose responses, similar to how it works in mammals.

Dopamine is also involved in reward learning in all animal groups. Like in vertebrates, invertebrates such as roundworms, flatworms, molluscs, and fruit flies can learn to repeat actions if they are followed by increased dopamine levels. In fruit flies, different dopamine neurons handle short- and long-term learning, similar to how the brain works in mammals.

It was once thought that arthropods did not use dopamine for rewards, as octopamine (a neurotransmitter related to norepinephrine) was believed to handle this role. Recent studies, however, show that dopamine does play a role in reward learning in fruit flies. Research also suggests that octopamine’s rewarding effects involve activating specific dopamine neurons. Dopamine is also found in the ink of cephalopods.

Many plants, including food plants, produce dopamine in varying amounts. Bananas have the highest levels, with 40 to 50 parts per million in their pulp. Potatoes, avocados, broccoli, and Brussels sprouts may contain dopamine at 1 part per million or more. Other plants, such as oranges, tomatoes, spinach, beans, and others, have lower levels. Plants make dopamine from the amino acid tyrosine through chemical processes similar to those in animals. Dopamine can be broken down into melanin and alkaloids. While the exact roles of plant catecholamines are unclear, they may help plants respond to stress, promote growth, and affect sugar metabolism. The receptors and internal processes involved in these actions are not yet fully understood.

Dopamine from food cannot reach the brain because it cannot cross the blood–brain barrier. However, some plants contain L-DOPA, a substance the body uses to make dopamine. The highest levels of L-DOPA are found in the leaves and pods of plants in the genus Mucuna, especially Mucuna pruriens (velvet beans), which are used as a source of L-DOPA for medicine. Another plant with significant L-DOPA is Vicia faba, which produces fava beans. L-DOPA levels in fava beans are lower than in other parts of the plant. Seeds from Cassia and Bauhinia trees also contain L-DOPA.

In the marine green algae Ulvaria obscura, a type of algae that forms blooms, dopamine is present in very high amounts—about 4.4% of the algae’s dry weight. Evidence suggests this dopamine helps protect the algae from herbivores like snails and isopods by reducing their consumption.

Melanins are dark-colored substances found in many organisms. Chemically, they are related to dopamine. A type of melanin called dopamine-melanin can be made by oxidizing dopamine with the enzyme tyrosinase. The melanin that darkens human skin is not dopamine-melanin; it is made from L-DOPA instead. However, the dark pigment in the brain’s substantia nigra, called neuromelanin, is partly dopamine-melanin.

Dopamine-derived melanin likely appears in other biological systems as well. Some dopamine in plants may be used to make dopamine-melanin. The complex patterns on butterfly wings and black-and-white stripes on insect larvae are thought to result from organized accumulations of dopamine-melanin.

History and development

Dopamine was first made in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England. It was first found in the human brain in 1957 by Katharine Montagu. The name "dopamine" comes from the fact that it is a type of chemical called a monoamine. The chemical that is used to make dopamine in the Barger-Ewens process is called 3,4-dihydroxyphenylalanine, also known as levodopa or L-DOPA. In 1958, Arvid Carlsson and Nils-Åke Hillarp at Sweden's National Heart Institute's Laboratory for Chemical Pharmacology discovered that dopamine acts as a neurotransmitter. Carlsson received the 2000 Nobel Prize in Physiology or Medicine for proving that dopamine is not only used to make norepinephrine (noradrenaline) and epinephrine (adrenaline) but also functions as a neurotransmitter itself.

Research inspired by sticky proteins found in mussels led to the discovery in 2007 that many materials can form a layer of polymerized dopamine when placed in a slightly basic solution of dopamine. This polymerized dopamine forms through a reaction that happens on its own and is a type of melanin. Dopamine can also form polymers that change the strength of gel-like materials made from peptides. To make polydopamine, dopamine hydrochloride is usually mixed with Tris in water. The exact structure of polydopamine is not yet known.

Polydopamine coatings can form on objects of many sizes, from tiny particles to large surfaces. These coatings have chemical properties that could be very useful. Studies have explored their potential uses, such as protecting materials from light damage or creating capsules for drug delivery. More advanced uses include using their sticky qualities as bases for biosensors or other biological molecules.