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Molar mass 169.18 g/mol
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As a stress hormone, norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, 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.[3]

When norepinephrine acts as a drug it increases blood pressure by increasing vascular tone through α-adrenergic 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 reflex bradycardia.

Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase.[4] It is released from the adrenal medulla 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.


Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is L-(−)-(R)-norepinephrine. 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. The prefix nor- is likely derived as an abbreviation of the word "normal", used to indicate a demethylated compound.[5][6][7]




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.

Norepinephrine system

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.



This structure explains some of the clinical uses of norepinephrine, since a modification of the system affects large areas of the brain.





Vesicular transport



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 homotropic modulation.

Receptor binding



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 vesicles.

Comparison of norepinephrine uptake
Uptake Transporter Vmax (nmol/g/min)[9] KM[9] Specificity[10] Location Other substrates[10] Inhibitors [11]
Uptake 1 Norepinephrine transporter[11] 1.2 0.3 norepinephrine > epinephrine > isoprenaline presynaptic
Uptake 2 100 250 epinephrine > norepinephrine > isoprenaline cell membrane of non-neuronal cells[8]
Vesicular VMAT[11] -[11] ~0.2[11] norepinephrine > epinephrine > isoprenaline[11] Synaptic vesicle membrane[11]


File:Noradrenaline breakdown.svg
Norepinephrine degradation. Enzymes are shown in boxes.[12]


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.[14]

Noradrenergic agents

By indication

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.

Attention-deficit/hyperactivity disorder

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 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 transmission.[15] This is because SNRIs work by inhibiting reuptake, i.e. preventing the serotonin and 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.[16] For this reason, they have largely 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 duloxetine (Cymbalta).


A commonly-known side effect associated with schizo-affective patients known as akathisia (commonly mistaken for schizophrenic symptoms) was found to be associated with increased levels of norepinephrine.[17] Data supports the efficacy of novel antipsychotics which deal with agonism of the NMDA glutamate receptors,[18] associated with regulating uptake of norepinephrine,[19] which in turn affects the trafficking of glutamate.[20] This suggests that schizophrenia may in fact have a greater association with abnormal norepinephrine-reuptake kinetics and less with dopamine, which may actually be responsible for a large part of the mechanism of glutamate release.[20]


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 α1 and α2 adrenergic receptors to cause vasoconstriction. Its effects are often limited to the increasing of blood pressure through agonist activity on α1 and α2 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


Synthesis modulators

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.[8]

Release modulators

Inhibitors of norepinephrine release
Substance[21] Receptor[21]
acetylcholine muscarinic receptor
norepinephrine (itself)/epinephrine α2 receptor
5-HT 5-HT receptor
adenosine P1 receptor
PGE EP receptor
histamine H2 receptor
enkephalin δ receptor
dopamine D2 receptor
ATP P2 receptor
Stimulators of norepinephrine release
Substance[21] Receptor[21]
adrenaline β2 receptor
angiotensin II AT1 receptor

Receptor binding modulators


Termination modulators

Uptake modulators

Inhibitors[8] of uptake 1 include:

Inhibitors[8] of uptake 2 include:

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.[3] Up to 70% of norepinephrine projecting cells are lost in Alzheimer’s Disease. It has been shown that norepinephrine stimulates mouse microglia to suppress -induced production of cytokines and their phagocytosis of Aβ suggesting this loss might have a role in causing this disease.[3]

Nutritional sources

File:L-Tyrosin - L-Tyrosine.svg
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, for example.



Banana peels contain significant amounts of norepinephrine and dopamine.[22]

See also

External links


  1. Merck Index, 11th Edition, 6612.
  2. "Norepinephrine definition". Retrieved 2008-11-24. Text " " ignored (help)
  3. 3.0 3.1 3.2 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 norepinephrine. Proc Natl Acad Sci U S A. 107:6058–6063 doi:10.1073/pnas.0909586107 PMID 20231476
  4. "Introduction to Autonomic Pharmacology" (PDF). Elsevier International. Link redirected to commercial site!
  5. Sharma B, Satish A, Kumar R (1999). Dictionary of Drugs. Anmol Publications. ISBN 8126118202.
  6. Gaddum JH (1956). "The Prefix 'Nor' in Chemical Nomenclature". Nature. 177 (1046): 1046. doi:10.1038/1771046b0. Unknown parameter |month= ignored (help)
  7. Matthiessen A, Foster GC (1868). "Researches into the chemical constitution of narcotine and of its products of decomposition". Journal of the Chemical Society. 358.
  8. 8.0 8.1 8.2 8.3 8.4 Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167
  11. 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 Unless else specified in boxes, then ref is: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.
  13. "Endokrynologia Kliniczna" ISBN 83-200-0815-8, page 502
  20. 20.0 20.1
  22. Kanazawa, Kazuki (2000). "High content of Dopamine, a strong antioxidant, in Cavendish banana" (PDF). Journal of Agriculture and Food Chemistry. 48: 844–848. doi:10.1021/jf9909860. Retrieved 8 November 2007. Unknown parameter |coauthors= ignored (help)