Norepinephrine (NE) is a monoamine and catecholamine neurotransmitter present in many animals. It plays a major role in arousal and vigilance, both in the CNS and in the sympathetic division of the autonomous nervous system. It is also a precursor to the catecholamine epinephrine. Inside the central nervous system norepinephrine is produced by noradrenergic neurons from the amino acid tyrosine, with dopamine as an intermediate product. Noradrenergic neurons are found in several cell groups in the brain, with the locus coeruleus in the pons as the most important one, projecting to all major brain structures and the spinal cord. Noradrenergic neurons in the paravertebral ganglia and the adrenal medulla is responsible for the peripheral production of norepinephrine for the sympathetic nervous system. After its release, norepinephrine’s signaling action is terminated by reuptake or enzymatic breakdown. Several groups of drugs target various parts of the norepinephrine system; from ADHD drugs, antidepressants, antihypertension drugs and bronchodilators to recreational drugs.
Norepinephrine production and release
Norepinephrine (NE) is produced in noradrenergic neurons from the non-essential amino acid tyrosine (TYR). Tyrosine can be synthesized in the body from the amino acid phenylalanine and both are found in most high-protein food products. Tyrosine is transported across the blood-brain barrier (BBB) by the large neutral amino acid transporter (LAT) into brain extracellular space. It is then transported across the cell membrane (CM) of the adrenergic neuron and into the cytosol by a specialized tyrosine transporter (TT). Tyrosine is firstly metabolized by the enzyme tyrosine hydroxylase (TYR-OH) to DOPA, and secondly by the enzyme DOPA decarboxylase (DDC) into dopamine, another monoamine and cathecholamine neurotransmitter. Conversion by tyrosine hydroxylase is the rate-limiting step and requires the cofactor tetrahydrobiopterin, a cofactor also needed for the conversion of phenylalanine to tyrosin. The last metabolic step is conversion of dopamine to norepinephrine by the enzyme dopamine β-hydroxylase (DBH). Norepinephrine is then packed into synaptic vesicles by the vesicular monoamine transporter (VMAT2), where it is stored until a neuronal impulse signals its release into the synaptic cleft. It can then bind to various alpha- or beta-adrenergic receptors (α/β-R).
Norepinephrine termination of action and metabolism
Norepinephrine’s signaling action in the synaptic cleft is terminated by enzymatic destruction or active transport into the presynaptic neuron or surrounding astrocytic glial cells (astroglia). The transport is facilitated by the norepinephrine transporter (NET), also known as the norepinephrine reuptake pump, and the less specific plasma membrane monoamine transporter (PMAT). Once back inside the neuron, NE can be repacked into synaptic vesicles by vesicular monoamine transporter (VMAT2) and reused during later neurotransmission. Alternatively, it can be broken down by the enzyme monoamine oxidase (MAO) intracellularly or cathechol-O-methyltransferase (COMT) extracellularly, with 3-Methoxy-4-hydroxyphenylglycol (MHPG) as the principal common norepinephrine metabolite in the brain. The two main pathways for enzymatic norepinephrine detruction involve the enzymes monoamine oxidase, aldehyde reductase (ALR) and cathechol-O-methyltransferase acting in sequence. The enzymes act either in the above order with short lived 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and then 3,4-dihydroxyphenylglycol (DHPG) as intermediate products before MHPG is produced, or in the order of COMT, MAO and ALR with normetanephrine (NME) and then the short-lived 3-methoxy-4-hydroxyphenylglycolaldehyde (MOPEGAL) as intermediate products before MHPG is produced. MHPG is then converted to vanillymandelic acid (VMA) in the liver by the enzymes alcohol dehydrogenase (ALCDH) and aldehyde dehydrogenase (ALDH) acting in sequence, with the short-lived MOPEGAL as an intemediate product. VMA is the end-stage metabolite and is excreted in the urine.
Adrenergic receptors are all G-protein coupled receptors. They are divided into alpha (α) and beta (β) family of receptors. There are two types α-receptors; α1 and α2, with three sub-types for each, and three types β-receptors; β1, β2 and β3. α1- and β-receptors usually have activating effects, while α2-receptors usually are inhibitory autoreceptors providing negative feedback to the neuron. Adrenergic receptors bind both norepinephrine and epinephrine, but with varying affinity depending on the receptor. Norepinephrine have important properties as a neurotransmitter in the central nervous system, but also as the major end-neurotransmitter and hormone in the sympathetic division of the autonomic nervous system.
Alpha-1 adrenergic receptor (α1-receptor)
Stimulation of α1-receptors cause vasoconstriction in the skin, mucosa, kidney, GI-tract and abdominal viscera, which resulting increased blood flow to the skeletal muscles. It also induces contraction of the iris dilator muscle (causing pupillary dilation), contraction of arrector pili (leading to goose bumps), secretion from sweat glands and increased sodium reabsorption from the urine. Glucogenolysis and gluconeogenesis is activated to increase available blood glucose. α1-receptor activation is also responsible for contraction of the vas deferense and seminal tract during ejaculation. In the brain, stimulation of α1-receptors activates serotonergic neurons and stimulates cortical arousal. α1-receptor activation can also produce anorexia. α1-receptor blocking properties are found in most atypical antipsychotic drugs, where potent α1 antagonism may reduce the incidence of extrapyramidal side effects, but also cause sedation and orthostatic hypotension. α1-receptor blockers can used to treat hypertension and anxiety disorders. Three subtypes of the α1-receptor exist: α1A, α1B and α1D.
Alpha-2 adrenergic receptor (α2-receptor)
α2-receptors can be presynaptic somatodendritic or terminal autoreceptors that provide negative feedback to the noradrenergic neuron, inhibiting further release of norepinephrine, which causes sedation. Activation of α2-receptors on serotonergic axon terminals inhibits the release of serotonin. Activation of α2-receptors in the spinal cord can produce analgesia. Activation of the α2-receptor in the periphery inhibits lipolysis, inhibits insulin release and induces glucagon release from the pancreas. The NaSSA or tetracyclic group of antidepressants (mirtazapine and mianserin) are antagonists for the α2-receptor, which disinhibits both norepinephrine and serotonin release. Three subtypes of the α2-receptor exist: α2A, α2B and α2C.
Beta-1 adrenergic receptor (β1-receptor)
β1-receptor stimulation have positive chronotropic, dromotropic and inotropic efffects – that is; increasing heart rate, conduction velocity and stroke volume, which increases the cardiac output. Activating this receptor also stimulate amylase secretion, lipolysis and renin-release. β1-selective beta blockers (and unselective beta-blockers) are used to treat coronary heart disease, heart failure, arrhythmias and hypertension.
Beta-2 adrenergic receptor (β2-receptor)
β2-receptor stimulation causes smooth muscle relaxation in the bronchi leading to bronchodilation, in the GI tract leading to reduced motility, in the detrusor urinae muscle relaxing the bladder wall and in skeletal muscle blood vessels leading to vasodilation (which increases the blood from to the skeletal muscles). It also promotes lipolysis, glucogenolysis, gluconeogenesis and insulin secretion. β2-receptor agonists are used as bronchial spasmolytics to treat asthma and COPD.
Beta-3 adrenergic receptor (β3-receptor)
β3-receptor stimulation enhances lipolysis in adipose tissue and thermogenesis in skeletal muscle and brown fat. The usefulness of this as a possible weight-loss mechanism is limited by the tremor it produces. β3-receptor stimulation also relaxes the detrusor urinae muscle of the bladder.
Norepinephrine is produced by noradrenergic neurons in the CNS and in the sympathetic division of the autonomic nervous system. Noradrenergic neurons in the brain are found in several small cell bodies. The small nucleus locus coeruleus in the pons is the most important one and activity here corresponds to to the level of vigilance. It projects to every major part of the brain and also to the spinal cord. The sympathetic nervous system have 24 pairs of paravertebral ganglia, also called ganglia of the sympathetic trunk, located next to the spinal cord. These ganglia supply numerous organs, including the eyes, salivary glands, lungs, heart, skin, stomach, intestines, liver, gall bladder, kidneys, adrenal glands, urinary bladder and reproductive organs. Sympathetic activation of the adrenal glands leads to norepinephrine release from the adrenal medulla into the bloodstream, where norepinephrine act as a hormone and reach even more tissues, including blood vessels, the immune system, adipose tissue and skeletal muscle. The sympathetic nervous system have many opposite action to the parasympathetic nervous system, the other division of the autonomic nervous system. The sympathetic nervous system is often labelled the “fight-flight-freeze” system and puts the body in a state conductive to active movement and increased energy use. The parasympathetic nervous system on the other hand is often called the “rest and digest” system and puts the body in a state more conductive for recovery, digestion and conservation of energy. Most psychiatric drugs that affect the noradrenergic system in the brain will also affect the tone of the autonomic nervous system.
Several different classes of medical (and recreational) drugs affect the epinephrine system in the body:
Medication for ADHD work by boosting both norepinephrine projections from the locus coeruleus and the mesocorticolimbic dopamine pathway. Methylphenidate and amphetamine-based pharmaceuticals work by NET and DAT inhibition and are the most commonly prescribed drugs for ADHD. Non-stimulant drugs for ADHD include the NET inhibitor atomoxetine, which boost norepinephrine and also increase dopamine in the prefrontal cortex (PFC), as NET due to the sparsity of DAT in the PFC is responsible for a larger portion of the dopamine reuptake here.
Many antidepressants affect the norepinephrine system. Serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs) and norepinephrine-dopamine reuptake inhibitors (NDRIs) all inhibit the norepinephrine transporter (NET) which increase the concentration of extracellular NE. Monoamineoxidase (MAO) inhibitors reduce the enzymatic degradation of norepinephrine. α2-receptor antagonists disinhibits both norepinephrine and serotonin release, while 5HT2C or 5HT3 antagonists can do the same for norepinephrine and dopamine.
Many antipsychotic medications have α1-receptor and/or α2-receptor blocking properties. While blocking the α1-receptor might reduce the incidence of extrapyramidal side effect, it is also causes side effects like sedation and orthostatic hypotension. α2-receptor blocking properties might contribute to possible antidepressive effects of the drug.
Betablockers are commonly used antihypertensive drugs that are of particular benefit to those who already have had a heart attack. α1-receptor blockers or α2-receptor agonists can also result in lowered blood pressure, but are rarely used for this indication.
Short- and longacting β2-receptor stimulating drugs are commonly used to threat bronchospasms in asthma and COPD, usually delivered as an inhalation drug.
The psychostimulants amphetamines and cocaine are monoamine reuptake inhibitors and releasing agents. Both have highest affinity for the catecholamines (dopamine and norepinephrine), but cocaine also affect serotonin.
Some other useful facts about norepinephrine:
Norepinephrine is the precursor of epinephrine, also called adrenalin. Epinephrine is also a monoamine and catecholamine neurotransmitter and hormone. It is primarily produced in the adrenal medulla of the adrenal gland as part of the sympathetic nervous system and the “fight-flight-freeze” reaction, but is also produced by a few adrenergic neurons in the CNS involved with the regulation of autonomic activities. Norepinephrine is converted to epinephrine by the enzyme phenylethanolamine-N-methyltransferase (PNMT) using S-adenosylmethionine (SAMe) as a methyl donor. Epinephrine is commonly used to treat anaphylaxis and cardiac arrest.
Food and supplements
Phenylalanine, tyrosine, DOPA and dopamine are all precursors of norepinephrine that can be found in food and in supplements. The effect on brain catecholamines of ingesting these precursors in food or supplements is detailed in the dopamine article. Norepinephrine is found as a neurotransmitter in many animals and in most vertebrates. It has also been detected in some plants like bananas, but norepinephrine consumed in food is unlikely to have any physiological significance.
Author: Sverre Gunnarsson Larne. Last updated: December 28th 2015.