Dopamine (DA) is a monoamine and catecholamine neurotransmitter that is found in most multicellular animals. It plays a major role in regulating reward-motivated behaviour. It is also a precursor to the catecholamines norepinephrine and epinephrine. In the central nervous system (CNS) DA is produced by dopaminergic neurons from the amino acid tyrosine. Dopaminergic neurons are found in the substantia nigra, the ventral tegmental area and the hypothalamus, from where 4 major dopamine pathways transmit DA to the striatum, the cortex, the nucleus accumbens and the pituitary gland. In humans DA regulates motor control, decision-making, emotional regulation, reward, salience and the release of certain hormones. After its release, dopamine’s signaling action is terminated by reuptake or enzymatic breakdown. Many groups of drugs target various parts of the dopamine system, from antipsychotics, antiparkinson drugs, ADHD drugs and certain antidepressants to recreational drugs.
Dopamine production and release
Dopamin (DA) is produced in dopaminergic neurons from the non-essential amino acid tyrosine (TYR). Tyrosine is found in many high-protein food products and can be synthesized in the body from the amino acid phenylalanine. Seafood, meat, dairy products, eggs, spirulina, nuts and seeds, soybeans and other legumes, are all examples of food with abundance of tyrosin. After being absorbed by the digestive system, or after being synthesized in the body from phenylalanine, tyrosine is transported by the bloodstream to the brain. Tyrosine crosses the blood-brain-barrier (BBB) and enters the extracellular space by the use of the large neutral amino acid transporter (LAT). A specialized tyrosine transporter (TT) on dopaminergic nerve terminals moves tyrosine across the cell membrane (CM) and into the cell. Inside, DA is produced from tyrosine by a two-step enzymatic process involving the enzymes tyrosine hydroxylase (TYR-OH, rate-limiting step) and DOPA decarboxylase (DDC) with DOPA as an intermediate product. Conversion by tyrosine hydroxylase is the rate-limiting step and requires the cofactor tetrahydrobiopterin, which is also needed for the conversion of phenylalanine to tyrosin. The neurotransmitter is then packed into synaptic vesicles by the vesicular monoamine transporter (VMAT2), and subsequently stored until a neuronal impulse signals its release into the synaptic cleft. It can then bind to various DA receptors (DA-R).
Dopamine termination of action and metabolism
The signalling action of dopamine in the synaptic cleft is terminated by enzymatic destruction or active transport into the presynaptic neuron or by surrounding astrocytic glial cells (astroglia). The transportation is facilitated by the dopamine transporter (DAT), also known as the DA reuptake pump, and the less specific plasma membrane monoamine transporter (PMAT). The norepinephrine transporter (NET) present on astroglia and norepinephric neurons can also transport DA, which is highly relevant in the prefrontal cortex where the presence of dopamine transporters are sparse. Once back inside the neuron, DA can be repacked into synaptic vesicles by vesicular monoamine transporter (VMAT2) and reused for later neurotransmission. Alternatively, it can be broken down by the enzyme monoamine oxidase (MAO) intracellularly or cathechol-O-methyltransferase (COMT) extracellularly, with homovanillic acid (HVA) as the main end-product. HVA is excreted in the urine. The two main pathways for dopamine metabolism involve the enzymes monoamine oxidase (MAO), aldehyde dehydrogenase (ALDH) and cathechol-O-methyltransferase (COMT) acting in sequence. The enzymes act either in the above order with the short-lived 3,4-Dihydrophenylacetaldehyde (DOPAL) and then 3,4-Dihydroxyphenylacetic acid (DOPAC) as intermediate products, or in the order of COMT, MAO and ALDH with 3-Methoxytyramine (3-MT) and the short-lived 3-methoxy-4-hydroxyphenylacetaldehyde (MHPA) as intermediate products.
Dopamine acts on 5 different receptors in the human body, labelled D1 to D5. All are G-protein linked receptors. The D1-receptor is the most numerous DA receptor, but the D2-receptor is the one we know most about as it’s the primary target for antipsychotic drugs and drugs that treat Parkinson’s disease. D3/4/5-receptors are all present in a significantly lower amount. All are postsynaptic heteroreceptors found on other neurons and cells, but the D2-receptor can also be found as a presynaptic somatodendritic or terminal autoreceptor that provide regulatory negative feedback to the dopaminergic neuron itself. The receptors are grouped into the D1-like family (D1/5-receptors) and the D2-like family (D2/3/4-receptors). The D1-like family are Gs-coupled receptors which increase the intracellular amount of the second messenger cAMP once stimulated, while the D2-like family are Gi-coupled receptors who decrease intracellular cAMP. The net effects depend on the postsynaptic neuron or cell in question. The D1-like receptors show low affinity for DA, while the D2-like receptors show higher affinity for DA. Knowledge regarding the function of the individual types of DA receptors is quite limited due to a lack of highly selective drugs. To understand the function of this neurotransmitter it is thus better to look to the function of the different dopamine pathways.
The substantia nigra and ventral tegmental area (VTA) holds the largest cell groups of dopaminergic neurons in the brain. Three of the four major DA projections origin here; the mesocortical, the mesolimbic and the nigrostriatal dopamine pathway. The mesocortical and mesolimbic pathway is sometimes collectively referred to as the mesocorticolimbic pathway. A dopaminergic cell group in the hypothalamus is the origin of the last major dopamine pathway, the tuberoinfundibular pathway. a few lesser dopamine pathways also exist, but little is currently known about them. Dopamine does not pass the blood-brain barrier and the function of DA as a signalling substance outside the CNS is less clear than its function inside the CNS.
Mesocortical dopamine pathway
The mesocortical dopamine pathway transmits dopamine from neurons in the midbrain Ventral Tegmental Area (VTA) to the cortex. Branches from the mesocortical pathway innervate in particular the dorsolateral prefrontal cortex (DLPFC) and the ventromedial prefrontal cortex (VMPFC). The DLPFC is involved in the management of cognitive processes. The VMPFC has a central role in emotional regulation and decision-making. A hypo-functioning mesocortical dopamine circuit can result in reduced executive function, cognitive impairment and affective symptoms. Due to the sparsity of dopamine transporters (DATs) in the prefrontal cortex, DA released here will more frequently escape from the synaptic cleft and affect neighboring neurons.
Mesolimbic dopamine pathway
The mesolimbic dopamine pathway transmits dopamine from neurons in the Ventral Tegmental Area (VTA) to the nucleus accumbens. The nucleus accumbens is one of the limbic areas in the brain, found in the ventral striatum, which is also a component of the basal ganglia. The nucleus accumbens has a significant role in the regulation of motivation, pleasure, reward and reinforcement learning. The nucleus accumbens is often labelled the “reward center” of the brain. It is strongly linked to addiction and addictive behaviors. Over-activation of the mesolimbic circuit can result in mania, delusions and hallusinations, possibly also aggression. A hypo-functioning mesolimbic dopamine circuit can result in amotivation, asociality and anhedonia.
Nigrostriatal dopamine pathway
The nigrostriatal dopamine pathway transmits dopamine from neurons in the substantia nigra to the dorsal striatum. The name substantia nigra reflects its darker appearance due to high level of neuromelanin in the dopaminergic neurons. The nigrostriatal pathway origins from the pars compacta part of the substantia nigra and projects to the caudate nucleus and putamen in the dorsal striatum. The nigrostriatal dopamine pathway is part of the extrapyramidal nervous system which participates in regulating motor functions and movement. Overactivity in the nigrostriatal circuit can lead to hyperkinetic movements such as tics and chorea. A hypo-functioning nigrostriatal dopamine circuit can lead to parkinsonism – a clinical syndrome characterized by tremor, bradykinesia, rigidity and postural instability. Death of the dopaminergic neurons in the substantia nigra is also the cause for the motor symptoms of Parkinson’s disease. Dystonia, dyskinesia and akathisia are also motor symptoms where dysfunction of the nigrostriatal circuit may be the reason.
Tuberoinfundibular dopamine pathway
The tuberoinfundibular dopamine pathway transmits dopamine from neurons in the arcuate nucleus in the hypothalamus to the hypophyseal portal system which supplies the anterior pituitary gland, also called the adenohypophysis. The anterior pituitary gland regulates several physiological processes, including lactation. Dopamine is the primary neuroendocrine inhibitor of the release of the hormone prolactin from lactotrophs in the anterior pituitary gland. The neurons in the arcuate nucleus reduce their inhibitory activity in the postpartum state, to allow for milk production. A pathological hypo-function in tuberoinfundibular pathway can lead to hyperprolactinemia, with galactorrhea, amenorrhea and sexual dysfunction as possible effects.
Several different classes of medical (and recreational) drugs affect the dopamine system in the brain:
All antipsychotic drugs either block or are partial agonists for the D2-receptor. Hyperactivation of the mesolimbic dopamine circuit is thought to be the cause of positive psychotic symptoms like delusions and hallucinations. Reducing the activity in this circuit is also important for the antimanic properties of antipsychotic drugs.
The motor symptoms of Parkinson’s disease is caused by the death of dopaminergic neurons in the substantia nigra. Common antiparkinson drugs include L-DOPA coupled with a DOPA decarboxylase inhibitor to increase the brain biosynthesis of dopamine, MAO-B inhibitor to reduce the metabolism of DA and the DA receptor agonist apomorphine to replace the natural neurotransmitter.
ADHD medications have their therapeutic effect by boosting the mesocorticolimbic dopamine pathway and norepinephrine projections from the locus coeruleus by increasing the stimulation of postsynaptic dopamine and norepinephrine receptors. Methylphenidate and amphetamine-based pharmaceuticals work by NET and DAT inhibition and are the most commonly prescribed drugs for ADHD. These drugs can induce euphoria at high doses and thus has the potential to be recreational drugs. Non-stimulant drugs for ADHD include the NET inhibitor atomoxetine, which in addition to increasing available norepinephrine, can increase DA in the prefrontal cortex (PFC). This is due to the sparsity of DAT in the PFC, which makes NET responsible for a larger portion of the dopamine reuptake here.
Only a few antidepressants directly affect the dopamine system – MAO inhibitors reduce the rate of DA metabolism, while bupropion inhibits both the dopamine and the norepinephrine transporter (DAT and NET). Others can do so indirectly – Antidepressants with strong NET inhibition (f.ex. reboxetine) also increase DA levels in the PFC, and antidepressants that block the 5HT2C-receptor (f.ex. fluoxetine and mirtazapine) or 5HT3 (f.ex. vortioxetine) can disinhibit DA release.
Amphetamines and cocaine are both psychostimulants that work as monoamine reuptake inhibitors and releasing agents. Both have highest affinity for the catecholamines (dopamine and norepinephrine), but cocaine also affect serotonin. All recreational drugs with the potential to cause addiction does at least indirectly affect the mesolimbic dopamine circuit in some way.
Some other useful facts about dopamine:
Phenylalanine and tyrosine is found in nearly every protein. Consequently tyrosine deficiency is rare. Eating protein rich food will not increase the amount of brain catecholamines as tyrosine will have to compete with other amino acids for passage on the large amino acid transporter across the blood-brain barrier. Tyrosine in foodstuff can be metabolized to tyramine during fermentation and decay, which can act as a cathecholamine releasing factor. Tyramine is quickly metabolized by MAO in the body and is unable to pass the blood-brain barrier. People treated for depression with one of the older, irreversible MAO-inhibitors need to stay on a low-tyramine diet to avoid tyramine causing a dangerous hypertensive crisis. Many plants synthesize dopamine, and the highest concentrations are seen in bananas. However, DA consumed in food cannot pass the blood-brain barrier and is quickly inactivated in the body. Some plants also contain DOPA, the precursor to dopamine, and this can increase brain catecholamines. The highest concentrations are found in bean pods and leaves from the Mucuna pruriens and other members of the genus, the pod shells of Vicia faba that produces fava beans, and seeds from Cassia and Bauchinia trees.
Tyrosine deficiency can occur in people with the inherited disease phenylketonuria, which make them unable to process phenylalanine. It is treated with a phenylalanine-restricted diet and supplements, including tyrosine. There is some evidence that eating purified tyrosine might improve mental performance and memory under stressful conditions, and increase alertness in sleep-deprived individuals, but no effect have been seen on ADHD, depression or exercise performance. Available DOPA supplements are usually based on Mucuna pruriens or Vicia faba extracts. Most of it will be metabolized in the body, but some will be transported into the brain and metabolized to catecholamines. Evidence for clinical effect of DOPA supplements is currently insufficient due to limited research. However, the side effects can be serious, especially at higher doses.
Functions outside the CNS
A substantial amount of dopamine sulfate circulates in the bloodstream and is excreted in the urine. It is most likely produced in the mesentery as a way of inactivating dopamine absorbed from the digestive system. A small amount of unconjugated dopamine is found in the circulation. Here it acts as a vasodilator and inhibit norepinephrine release at normal concentrations. Other effects outside the CNS are mostly exocrine or paracrine, with dopamine being produced locally and acting in a limited area. In the immune system, dopamine reduce the activity of lymphocytes. In the kidney, dopamine increase renal blood flow, glomerular filtration rate and excretion of sodium into the urine. Dopamine also play a role in both the exocrine and endocrine part of the pancreas, but its function here is not clearly established.
Phasic and tonic transmission
Dopamine can be released in the brain by two different mechanisms. The first mechanism is by classic synaptic neurotransmission, with a phasic release of DA from the axon in response to an action potential in the presynaptic dopaminergic neuron. The second mechanism is by tonic release, where small amounts of neurotransmitter is released from the axon without a preceding presynaptic action potential. The tonic release would set the “background” stimulation of DA receptors and the responsiveness of the system to a phasic dopamine release.
Author: Sverre Gunnarsson Larne. Last updated: December 28th 2015.