Dopamine

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.
In popular culture and media, dopamine is often portrayed as the main chemical of pleasure, but the current opinion in pharmacology is that dopamine instead confers motivational salience; in other words, dopamine signals the perceived motivational prominence of an outcome, which in turn propels the organism's behavior toward or away from achieving that outcome.
Outside the central nervous system, dopamine functions primarily as a local paracrine messenger. In 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 is synthesized locally and exerts its effects near the cells that release it.
Several important diseases of the nervous system are associated with dysfunctions of the dopamine system, and some of the key medications used to treat them work by altering the effects of dopamine. Parkinson's disease, a degenerative condition causing tremor and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra. Its metabolic precursor L-DOPA can be manufactured; Levodopa, a pure form of L-DOPA, is the most widely used treatment for Parkinson's. There is evidence that schizophrenia involves altered levels of dopamine activity, and most antipsychotic drugs used to treat this are dopamine antagonists which reduce dopamine activity. Similar dopamine antagonist drugs are also some of the most effective anti-nausea agents. Restless legs syndrome and attention deficit hyperactivity disorder are associated with decreased dopamine activity. Dopaminergic stimulants can be addictive in high doses, but some are used at lower doses to treat ADHD. Dopamine itself is available as a manufactured medication for intravenous injection. It is useful in the treatment of severe heart failure or cardiogenic shock. In newborn babies it may be used for hypotension and septic shock.

Structure

A dopamine molecule consists of a catechol structure with one amine group attached via an ethyl chain. As such, dopamine is the simplest possible catecholamine, a family that also includes the neurotransmitters norepinephrine and epinephrine. The presence of a benzene ring with this amine attachment makes it a substituted phenethylamine, a family that includes numerous psychoactive drugs.
Like most amines, dopamine is an organic base. As a base, it is generally protonated in acidic environments. The protonated form is highly water-soluble and relatively stable, but can become oxidized if exposed to oxygen or other oxidants. In basic environments, dopamine is not protonated. In this free base form, it is less water-soluble and also more highly reactive. Because of the increased stability and water-solubility of the protonated form, dopamine is supplied for chemical or pharmaceutical use as dopamine hydrochloride—that is, the hydrochloride salt that is created when dopamine is combined with hydrochloric acid. In dry form, dopamine hydrochloride is a fine powder which is white to yellow in color.

Biochemistry

Synthesis

Dopamine is synthesized in a restricted set of cell types, mainly neurons and cells in the medulla of the adrenal glands. The primary and minor metabolic pathways respectively are:
The direct precursor of dopamine, L-DOPA, can be synthesized indirectly from the essential amino acid phenylalanine or directly from the non-essential amino acid tyrosine. These amino acids are found in nearly every protein and so are readily available in food, with tyrosine being the most common. Although dopamine is also found in many types of food, it is incapable of crossing the blood–brain barrier that surrounds and protects the brain. It must therefore be synthesized inside the brain to perform its neuronal activity.
L-Phenylalanine is converted into L-tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen and tetrahydrobiopterin as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O₂, and iron as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, with pyridoxal phosphate as the cofactor.
Dopamine itself is used as precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine. Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase, with O₂ and L-ascorbic acid as cofactors. Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as the cofactor.
Some of the cofactors also require their own synthesis. Deficiency in any required amino acid or cofactor can impair the synthesis of dopamine, norepinephrine, and epinephrine.

Degradation

Dopamine is broken down into inactive metabolites by a set of enzymes—monoamine oxidase, catechol-O-methyl transferase, and aldehyde dehydrogenase, acting in sequence. Both isoforms of monoamine oxidase, MAO-A and MAO-B, effectively metabolize dopamine. Different breakdown pathways exist but the main end-product is homovanillic acid, which has no known biological activity. From the bloodstream, homovanillic acid is filtered out by the kidneys and then excreted in the urine. The two primary metabolic routes that convert dopamine into HVA are:

Dopamine → DOPAL → DOPAC → HVA – catalyzed by MAO, ALDH, and COMT respectively
Dopamine → 3-Methoxytyramine → HVA – catalyzed by COMT and MAO+ALDH respectively

In clinical research on schizophrenia, measurements of homovanillic acid in plasma have been used to estimate levels of dopamine activity in the brain. A difficulty in this approach however, is separating the high level of plasma homovanillic acid contributed by the metabolism of norepinephrine.
Although dopamine is normally broken down by an oxidoreductase enzyme, it is also susceptible to oxidation by direct reaction with oxygen, yielding quinones plus various free radicals as products. The rate of oxidation can be increased by the presence of ferric iron or other factors. Quinones and free radicals produced by autoxidation of dopamine can poison cells, and there is evidence that this mechanism may contribute to the cell loss that occurs in Parkinson's disease and other conditions.

Functions

Cellular effects

Family	Receptor	Gene	Type	Mechanism
D₁-like	D₁		G_s-coupled.	Increase intracellular levels of cAMP by activating adenylate cyclase.
D₁-like	D₅		G_s-coupled.	Increase intracellular levels of cAMP by activating adenylate cyclase.
D₂-like	D₂		G_i-coupled.	Decrease intracellular levels of cAMP by inhibiting adenylate cyclase.
D₂-like	D₃		G_i-coupled.	Decrease intracellular levels of cAMP by inhibiting adenylate cyclase.
D₂-like	D₄		G_i-coupled.	Decrease intracellular levels of cAMP by inhibiting adenylate cyclase.
TAAR	TAAR1		G_s-coupled. G_q-coupled.	Increase intracellular levels of cAMP and intracellular calcium concentration.

Dopamine exerts its effects by binding to and activating cell surface receptors. In humans, dopamine has a high binding affinity at dopamine receptors and human trace amine-associated receptor 1. In mammals, five subtypes of dopamine receptors have been identified, labeled from D₁ to D₅. All of them function as metabotropic, G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system. These receptors can be divided into two families, known as D₁-like and D₂-like. For receptors located on neurons in the nervous system, the ultimate effect of D₁-like activation can be excitation or inhibition ; the ultimate effect of D₂-like activation 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 the second messenger cAMP. D₁ receptors are the most numerous dopamine receptors in the human nervous system; D₂ receptors are next; D₃, D₄, and D₅ receptors are present at significantly lower levels.