(l) 51-41-2 (l)
169.18 g mol
D/L: 191 °C (decomp.)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
catecholamine with multiple roles including as a hormone and a neurotransmitter.
As a stress hormone, norepinephrine affects parts of the brain where attention and responding actions are controlled.
triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. Norepinephrine
can also suppress neuroinflammation when released diffusely in the brain from the locus ceruleus.
receptor activation. The resulting increase in vascular resistance triggers a compensatory reflex that overcomes its
direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called
Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase.
into the blood as a hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous
system where it is released from noradrenergic neurons. The actions of norepinephrine are carried out via the binding
to adrenergic receptors.
The term "norepinephrine" is derived from the chemical prefix nor-, which indicates that norepinephrine is the next
lower homolog of epinephrine. The two structures differ only in that epinephrine has a methyl group attached to its
nitrogen, while the methyl group is replaced by a hydrogen atom in norepinephrine.
Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is
referring to the absence of the methyl functional group at the nitrogen atom.
Norepinephrine is released when a host of physiological changes are activated by a stressful event.
In the brain, this is caused in part by activation of an area of the brain stem called the locus ceruleus. This nucleus is
the origin of most norepinephrine pathways in the brain. Noradrenergic neurons project bilaterally (send signals to
both sides of the brain) from the locus ceruleus along distinct pathways to many locations, including the cerebral
cortex, limbic system, and the spinal cord, forming a neurotransmitter system.
Norepinephrine is also released from postganglionic neurons of the sympathetic nervous system, to transmit the
fight-or-flight response in each tissue respectively. The adrenal medulla can also be counted to such postganglionic
nerve cells, although they release norepinephrine into the blood.
The noradrenergic neurons in the brain form a neurotransmitter system, that, when activated, exerts effects on large
areas of the brain. The effects are alertness and arousal, and influences on the reward system.
Anatomically, the noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The
axons of the neurons in the locus coeruleus act on adrenergic receptors in:
• Cingulate gyrus
• Spinal cord
On the other hand, axons of neurons of the lateral tegmental field act on adrenergic receptors in hypothalamus, for
areas of the brain.
Norepinephrine is synthesized from tyrosine as a precursor, and packed into synaptic vesicles. It performs its action
by being released into the synaptic cleft, where it acts on adrenergic receptors, followed by the signal termination,
either by degradation of norepinephrine, or by uptake by surrounding cells.
Norepinephrine is synthesized by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of
the sympathetic nervous system from the amino acid tyrosine:
• The first reaction is the hydroxylation into dihydroxyphenylalanine (L-DOPA) (DOPA =
3,4-DiHydroxy-L-Phenylalanine), catalyzed by tyrosine hydroxylase. This is the rate-limiting step.
• This is followed by decarboxylation into the neurotransmitter dopamine, catalyzed by pyridoxal phosphate &
• Last is the final β-oxidation into norepinephrine by dopamine beta hydroxylase, requiring ascorbate as a cofactor
Between the decarboxylation and the final β-oxidation, norepinephrine is transported into synaptic vesicles. This is
accomplished by vesicular monoamine transporter (VMAT) in the lipid bilayer. This transporter has equal affinity
for norepinephrine, epinephrine and isoprenaline.
To perform its functions, norepinephrine needs to be released from synaptic vesicles. Many substances modulate this
release, some inhibiting it and some stimulating it.
For instance, there are inhibitory α2 adrenergic receptors presynaptically, that gives negative feedback on release by
Norepinephrine performs its actions on the target cell by binding to and activating adrenergic receptors. The target
cell expression of different types of receptors determines the ultimate cellular effect, and thus norepinephrine has
different actions on different cell types.
Signal termination is a result of reuptake and degradation.
Extracellular uptake of norepinephrine into the cytosol is either done presynaptically (uptake 1) or by non-neuronal
cells in the vicinity (uptake 2). Furthermore, there is a vesicular uptake mechanism from the cytosol into synaptic
Comparison of norepinephrine uptake
~0.2 norepinephrine >
Norepinephrine degradation. Enzymes are shown in boxes. 
In mammals, norepinephrine is rapidly
degraded to various metabolites. The
principal metabolites are:
• Normetanephrine (via the enzyme
monoamine oxidase, MAO)
• Vanillylmandelic acid
acid), also referred to as
vanilmandelate or VMA (via MAO)
glycol, "MHPG" or "MOPEG" (via
• Epinephrine (via PNMT)
In the periphery, VMA is the major metabolite of catecholamines, and is excreted unconjugated in the urine. A minor
metabolite (although the major one in the central nervous sytem) is MHPG, which is partly conjugated to sulfate or
glucuronide derivatives and excreted in the urine.
Norepinephrine may be used for the indications attention-deficit/hyperactivity disorder, depression and hypotension.
Norepinephrine, as with other catecholamines, itself cannot cross the blood-brain barrier, so drugs such as
amphetamines are necessary to increase brain levels.
Norepinephrine, along with dopamine, has come to be recognized as playing a large role in attention and focus. For
people with ADHD, psychostimulant medications such as methylphenidate (Ritalin/Concerta), dextroamphetamine
(Dexedrine), and Adderall (a mixture of dextroamphetamine and racemic amphetamine salts) are prescribed to help
increase levels of norepinephrine and dopamine. Atomoxetine (Strattera) is a selective norepinephrine reuptake
inhibitor, and is a unique ADHD medication, as it affects only norepinephrine, rather than dopamine. As a result,
Strattera has a lower abuse potential. However, it may not be as effective as the psychostimulants are with many
people who have ADHD. Consulting with a physician, physician assistant or nurse practitioner is needed to find the
appropriate medication and dosage. (Other SNRIs, currently approved as antidepressants, have also been used
off-label for treatment of ADHD.)
Differences in the norepinephrine system are implicated in depression. Serotonin-norepinephrine reuptake inhibitors
are antidepressants that treat depression by increasing the amount of serotonin and norepinephrine available to
postsynaptic cells in the brain. There is some recent evidence implying that SNRIs may also increase dopamine
norepinephrine transporters from taking their respective neurotransmitters back to their storage vesicles for later use.
If the norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance dopaminergic
transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be
partly or largely due to the concurrent increase in dopamine (particularly in the prefrontal cortex of the brain).
Tricyclic antidepressants (TCAs) increase norepinephrine activity as well. Most of them also increase serotonin
activity, but tend to produce unwanted side effects due to the nonspecific inactivation of histamine, acetylcholine and
alpha-1 adrenergic receptors. Common side effects include sedation, dry mouth, constipation, sinus tachycardia,
memory impairment, orthostatic hypotension, blurred vision and weight gain.
been replaced by newer selective reuptake drugs. These include the SSRIs, e.g. fluoxetine (Prozac), which however
have little or no effect on norepinephrine, and the newer SNRIs described above, such as venlafaxine (Effexor) and
Norepinephrine is also used as a vasopressor medication (for example, brand name Levophed) for patients with
critical hypotension. It is given intravenously and acts on both α
adrenergic receptors to cause
vasoconstriction. Its effects are often limited to the increasing of blood pressure through agonist activity on α
receptors and causing a resultant increase in peripheral vascular resistance. At high doses, and especially when it is
combined with other vasopressors, it can lead to limb ischemia and limb death. Norepinephrine is mainly used to
treat patients in vasodilatory shock states such as septic shock and neurogenic shock and has shown a survival
benefit over dopamine.
By site of action
Different medications affecting norepinephrine function have their targets at different points in the mechanism, from
synthesis to signal termination.
α-methyltyrosine is a substance that intervenes in norepinephrine synthesis by substituting tyrosine for tyrosine
hydroxylase, and blocking this enzyme.
Vesicular transport modulators
This transportation can be inhibited by reserpine and tetrabenazine.
Inhibitors of norepinephrine release
Receptor binding modulators
Examples include alpha blockers for the α-receptors, and beta blockers for the β-receptors.
of uptake 1 include:
• tricyclic antidepressants
of uptake 2 include:
• steroid hormones
Anti-Inflammatory agent role in Alzheimer’s Disease
The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally defuses from
"varicosities". As such it provides an endogenous anti-inflammatory agent in the microenvironment around the
neurons, glial cells, and blood vessels in the neocortex and hippocampus.
Up to 70% of norepinephrine projecting
Aβ-induced production of cytokines and their phagocytosis of Aβ suggesting this loss might have a role in causing
Shown here is the chemical structure of tyrosine.
The biosynthesis of norepinephrine depends upon
the presence of tyrosine, an amino acid building
block of many proteins in meat, nuts and eggs,
The synthesis of norepinephrine depends on the presence of tyrosine,
an amino acid found in proteins such as meat, nuts, and eggs. Dairy
products such as cheese also contain high amounts of tyrosine (the
amino acid is named for "tyros," the Greek word for cheese). Tyrosine
is the precursor to dopamine, which is in itself a precursor of
epinephrine and norepinephrine.
Serotonin, a neurotransmitter that is in many ways the opposite of the
catecholamines, is also directly synthesized from an amino acid
(tryptophan). However, tryptophan has a somewhat different process of
degradation. When serotonin is catabolized in the body, it does not
break down into useful substrates in the way that dopamine is further
degraded into epinephrine and norepinephrine. Instead, it breaks down into 5-hydroxyindoleacetic acid (5-HIA), an
organic acid which may be harmful in high amounts. Tryptophan can further be catabolized into kynurenate,
quinolinate, and picolinate, harmful substances that are generally regarded as markers of bodily inflammation.
Banana peels contain significant amounts of norepinephrine and dopamine.
• Norepinephrine bitartrate
• Catecholaminergic polymorphic ventricular tachycardia
• Mental Health: A report of surgeon general. Etiology of Anxiety Disorders
 Merck Index, 11th Edition, 6612.
Norepinephrine). dictionary.reference.com. . Retrieved 2008-11-24.
 Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F,
Hanisch UK, Kummer MP. (2010). Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through
pdf) Proc Natl Acad Sci U S A. 107:6058–6063
doi:10.1073/pnas.0909586107 PMID 20231476
 "Introduction to Autonomic Pharmacology" (http:/
pdf) (PDF). Elsevier International.
. Link redirected to commercial site!
 TIHKAL on "nor" (http:/
 These values are from rat heart. Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill
Livingstone. ISBN 0-443-07145-4. Page 167
 Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page
 Unless else specified in boxes, then ref is: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's
 "Endokrynologia Kliniczna" ISBN 83-200-0815-8, page 502
Journal of Agricultural and Food Chemistry 2000 48 (3) 844-848.
pdf) (PDF). Journal of Agriculture and Food Chemistry 48:
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