Dopamine

What is Dopamine?

Dopamine is a neurotransmitter. It is a chemical messenger that helps in the transmission of signals in the brain and other vital areas. Dopamine is found in humans as well as animals, including both vertebrates and invertebrates.

Dopamine history

Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England.

In 1958, Arvid Carlsson and Nils-Åke Hillarp, at the Laboratory for Chemical Pharmacology of the National Heart Institute of Sweden, discovered the function of dopamine as a neurotransmitter. Arvid Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not just a precursor of norepinephrine and epinephrine but a neurotransmitter, as well.

Dopamine production

Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area. It is a neurohormone that is released by the hypothalamus. Its action is as a hormone that is an inhibitor or prolactin release from the anterior lobe of the pituitary.

Neurotransmitters with discrete localization within the brain. A) The chemical structure of the monoamine neurotransmitter dopamine and a schematic drawing of the localization of dopamine-containing neurons in the human and rat brain and the sites where dopamine-containing axons are found. B) The chemical structure of the monoamine neurotransmitter serotonin and similar brain map showing locations of serotonin-containing cells and their axons.

Dopamine receptors

Dopamine acts on receptors that are specific for it. Five subtypes of mammalian dopamine receptors are grouped into two classes.

  • D1-like receptor class – This comprises of D1 and D5 receptor subtypes
  • D2-like receptor class – This comprises of D2, D3, and D4 receptor subtypes

These receptors have similar signalling properties. They however have different signal transduction pathways that determine their subtypes and classes.

All of the dopamine receptors are G protein-coupled receptors (GPCRs), who’s signalling is primarily mediated by interaction with and activation of GTP-binding proteins (G proteins). Members of this superfamily are also called 7-transmembrane receptors because they traverse the cell membrane seven times. They are also called serpentine receptors because of the snake like manner in which they wind back and forth across the membrane.

Actions of dopamine

Dopamine is also used as medication. It acts on the sympathetic nervous system. Application of dopamine leads to increased heart rate and blood pressure.

Dopamine cannot cross the blood-brain barrier, so dopamine given as a drug does not directly affect the central nervous system.

Dopamine is needed in some brain diseases as well. This includes diseases such as Parkinson's disease and dopa-responsive dystonia. For these patients levodopa is used. This is a precursor of dopamine. It can cross the blood-brain barrier.

Dopamine Biochemistry

Dopamine as a cathecholamine

Dopamine’s chemical formula is C6H3(OH)2-CH2-CH2-NH2 and its chemical name is "4-(2-aminoethyl)benzene-1,2-diol" and its abbreviation is "DA."

Biosynthesis of dopamine

Dopamine is a cathecholamine. This means it has a Cathechol nucleus and is a precursor to norepinephrine (noradrenaline) and then epinephrine (adrenaline) in the biosynthetic pathways for these neurotransmitters.

Dopamine is a derivative of the amino acid tyrosine. Tyrosine is modified by tyrosine hydroxylase to form DOPA. This is a very important step in the formation of Dopamine and is called the rate limiting step.

DOPA decarboxylase then removes carbon dioxide from DOPA to for dopamine

Dopamine Therapeutic Use

Dopamine is a vital neurotransmitter in the brain. It plays a role in several functions in the brain including movement, memory, pleasurable reward, behavior and cognition, attention, inhibition of prolactin production, sleep, mood and learning.

Excess and deficiency of this vital chemical is the cause of several disease conditions. Parkinson's disease and drug addiction are some of the examples of problems associated with abnormal dopamine levels.

Uses of dopamine are both in cardiovascular diseases as well as central nervous system diseases.

Dopamine in Parkinson’s disease

Dopamine in blood is unable to cross the blood-brain barrier to reach the brain. In Parkinson’s disease and dopa-responsive dystonia there is a deficiency of dopamine in specific areas of the brain like the basal ganglia.

Levodopa is a dopamine precursor. It enters the brain by crossing the blood-brain barrier. It is typically co-administered with an inhibitor of peripheral decarboxylation (DDC, dopa decarboxylase), such as carbidopa or benserazide. This additional drug prevents breakdown of the levodopa to dopamine in the peripheral blood and ensures that maximum amount reaches the brain.

There are several other dopamine agonists and inhibitors of alternative metabolic route for dopamine by catechol-O-methyl transferase that may be used for these diseases. These include entacapone and tolcapone.

Dopamine in cardiovascular diseases

When administered through an IV line, dopamine does not cross the blood brain. It acts on the heart by raising its contractility and blood pressure. This is useful in heart failure

The effects of intravenous dopamine are dose dependent. The dosages include:

  1. 2-5 μg/kg/min (low dose) - This dose leads to renal and mesentric vasodilation (via D1 receptors). This dilatation of blood vessels of kidney leads to raised glomerular filtration rate and sodium excretion and raises urine output, leads to better tissue perfusion, BP stabilization. This dose is used in Cardiogenic shock as IV infusion.

  2. 5-10 μg/kg/min (moderate dose) - This dose also causes renal and mesentric vasodilation (via D1). This raises the GFR and sodium excretion and raises urine output, better tissue perfusion and BP stabilization. This dose also acts on Beta 1 receptors on heart and makes its contractions and pumping more forceful. This is used in Acute exacerbation of congestive heart failure as IV infusion.

  3. More than 20 μg/kg/min (high dose) - This leads to constriction of blood vessels via Alpha 1 receptors. This leads to decreased renal blood flow and decreased urine output.

Dopamine Functions

Dopamine is a neurotransmitter released by the brain that plays a number of roles in humans and other animals. Some of its notable functions are in:

  • movement
  • memory
  • pleasurable reward
  • behavior and cognition
  • attention
  • inhibition of prolactin production
  • sleep
  • mood
  • learning

Excess and deficiency of this vital chemical is the cause of several disease conditions. Parkinson's disease and drug addiction are some of the examples of problems associated with abnormal dopamine levels.

Where is dopamine produced?

Dopamine is produced in the dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain, the substantia nigra pars compacta, and the arcuate nucleus of the hypothalamus.

Dopamine in movement

A part of the brain called the basal ganglia regulates movement. Basal ganglia in turn depend on a certain amount of dopamine to function at peak efficiency. The action of dopamine occurs via dopamine receptors, D1-5.

Dopamine reduces the influence of the indirect pathway, and increases the actions of the direct pathway within the basal ganglia. When there is a deficiency in dopamine in the brain, movements may become delayed and uncoordinated. On the flip side, if there is an excess of dopamine, the brain causes the body to make unnecessary movements, such as repetitive tics.

Dopamine in pleasure reward seeking behavior

Dopamine is the chemical that mediates pleasure in the brain. It is released during pleasurable situations and stimulates one to seek out the pleasurable activity or occupation. This means food, sex, and several drugs of abuse are also stimulants of dopamine release in the brain, particularly in areas such as the nucleus accumbens and prefrontal cortex.

Dopamine and addiction

Cocaine and amphetamines inhibit the re-uptake of dopamine. Cocaine is a dopamine transporter blocker that competitively inhibits dopamine uptake to increase the presence of dopamine.

Amphetamine increases 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 presynaptic neuron via its dopamine transporters. By entering, amphetamines force dopamine molecules out of their storage vesicles. By increasing presence of dopamine both these lead to increased pleasurable feelings and addiction.

Dopamine in memory

Levels of dopamine in the brain, especially the prefrontal cortex, help in improved working memory. However, this is a delicate balance and as levels increase or decrease to abnormal levels, memory suffers.

Dopamine in attention

Dopamine helps in focus and attention. Vision helps a dopamine response in the brain and this in turn helps one to focus and direct their attention. Dopamine may be responsible for determining what stays in the short term memory based on an imagined response to certain information. Reduced dopamine concentrations in the prefrontal cortex are thought to contribute to attention deficit disorder.

Dopamine in cognition

Dopamine in the frontal lobes of the brain controls the flow of information from other areas of the brain. Disorders of dopamine in this region lead to decline in neurocognitive functions, especially memory, attention, and problem-solving.

D1 receptors and D4 receptors are responsible for the cognitive-enhancing effects of dopamine. Some of the antipsychotic medications used in conditions like schizophrenia act as dopamine antagonists. Older, so-called "typical" antipsychotics most commonly act on D2 receptors, while the atypical drugs also act on D1, D3 and D4 receptors.

Regulating prolactin secretion

Dopamine is the main neuroendocrine inhibitor of the secretion of prolactin from the anterior pituitary gland. Dopamine produced by neurons in the arcuate nucleus of the hypothalamus is released in the hypothalamo-hypophysial blood vessels of the median eminence, which supply the pituitary gland. This acts on the lactotrope cells that produce prolactin. These cells can produce prolactin in absence of dopamine. Dopamine is occasionally called prolactin-inhibiting factor (PIF), prolactin-inhibiting hormone(PIH), or prolactostatin.

Social functioning

Low D2 receptor-binding is found in people with social anxiety or social phobia. Some features of negative schizophrenia (social withdrawal, apathy, anhedonia) are thought to be related to a low dopaminergic state in certain areas of the brain.

On the other hand those with bipolar disorder in manic states become hypersocial, as well as hypersexual. This is credited to an increase in dopamine. Mania can be reduced by dopamine-blocking anti-psychotics.

Dopamine levels and psychosis

Abnormally high dopaminergic transmission has been linked to psychosis and schizophrenia. Both the typical and the atypical antipsychotics work largely by inhibiting dopamine at the receptor level.

Pain processing

Dopamine plays a role in pain processing in multiple levels of the central nervous system. This includes the spinal cord, periaqueductal gray (PAG), thalamus, basal ganglia, insular cortex, and cingulate cortex. Low levels of dopamine are associated with painful symptoms that frequently occur in Parkinson's disease.

Dopamine in nausea and vomiting

Dopamine is one of the neurotransmitters implicated in the control of nausea and vomiting via interactions in the chemoreceptor trigger zone. Metoclopramide is a D2-receptor antagonist and prevents nausea and vomiting.