|Jmol-3D images||Image 1|
|Molar mass||169.18 g mol−1|
|Density||1.397±0.06 g/cm^3 (20 °C and 760 Torr)|
L: 216.5–218 °C (decomposes)
442.6±40.0 °C (760 Torr)
|Vapor pressure||1.30e-8 Torr|
| (what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Norepinephrine (INN) (abbreviated norepi or NE), noradrenaline (BAN) (abbreviated NA, NAd, or norad), or 4,5-β-trihydroxyphenethylamine is a catecholamine with multiple roles including as a hormone and a neurotransmitter. It is the hormone and neurotransmitter most responsible for vigilant concentration in contrast to its most chemically similar hormone, dopamine, most responsible for cognitive alertness.
Areas of the body that produce or are affected by norepinephrine are described as noradrenergic. The terms noradrenaline (from the Latin) and norepinephrine (from the Greek) are interchangeable, with noradrenaline being the common name in most parts of the world. However the U.S. National Library of Medicine has promoted norepinephrine as the favored nomenclature, and this is the term used throughout this article.
One of the most important functions of norepinephrine is its role as the neurotransmitter released from the sympathetic neurons to affect the heart. An increase in norepinephrine from the sympathetic nervous system increases the rate of contractions in the heart.
As a stress hormone, norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are controlled. Norepinephrine also underlies the fight-or-flight response, along with epinephrine, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. It increases the brain's oxygen supply.[broken citation] Norepinephrine can also suppress neuroinflammation when released diffusely in the brain from the locus coeruleus.
When norepinephrine acts as a drug, it increases blood pressure by increasing vascular tone (tension of vascular smooth muscle) through α-adrenergic receptor activation; a reflex bradycardia homeostatic baroreflex is overcome by a compensatory reflex preventing an otherwise inevitable drop in heart rate to maintain blood pressure.
Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase in the secretory granules of the medullary chromaffin cells. 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 in the locus coeruleus. The actions of norepinephrine are carried out via the binding to adrenergic receptors.
- 1 Chemistry
- 2 Origins
- 3 Mechanism
- 4 Noradrenergic agents
- 4.1 By indication
- 4.2 By site of action
- 5 Nutritional sources
- 6 References
- 7 External links
Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is L-(−)-(R)-norepinephrine. The prefix nor- 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, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix nor- is derived as an abbreviation of the word "normal", used to indicate a demethylated compound.
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 coeruleus. 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.
- Cingulate gyrus
- Spinal cord
- Some Brainstem nuclei
This structure explains some of the clinical uses of norepinephrine, since a modification of the system affects large areas of the brain.
Role in decision making
Cortical norepinephrine (NE) release during attention paradigms (patterns) can increase the alteration detection rate (number of times an alteration was selected) in multiple-cue probability learning during tasks involving giving predictive cues (such as auditory or visual), and thereby enhance subsequent learning. A. J. Yu et al. developed a Bayesian framework to examine NE release in instances of "unexpected uncertainty," where a drastic alteration in sensory information produces a large disparity between top-down expectations and what actually occurs. The model predicts that NE levels spike when the predictive context is switched, then subside. It has also been shown that lesions of the locus coeruleus (LC) impair this attentional shift.
In a similar vein, several studies have implicated the LC-NE system in eliciting the P300, a cortical event-related potential that responds to environmental stimuli that have behaviorally relevant, motivational, or attention grabbing properties. The P300 may reflect updating of prior knowledge regarding stimuli relevant for accurate and efficient decision making. Several studies have searched for a P300 generator in the brain and have ultimately concluded that the potential must have a source that is distributed, synchronous and localized in cortex. This definition is ideally satisfied both functionally and anatomically by the LC neuromodulatory system. Given its broad projection pattern and the correlation between NE release and increased sensory signal transmission, it seems likely that noradrenergic cortical release is the neuronal mechanism of the P300.
Examination of the LC’s tonic firing pattern has led to speculation that it is important for the exploratory behavior essential for learning relations between sensory input, decision processing, motor output, and behavioral feedback. Tonic activation within the range of 0–5 Hz has been shown to correlate with levels of drowsiness, accurate task performance, and when slightly more elevated, distractibility and erratic task performance. Furthermore, phasic activation of the LC is observed in response to both highly salient unconditioned and task-relevant stimuli. The phasic response occurs after stimulation and precedes a behavioral response in a time-locked fashion. As such, phasic activation of the LC-NE system is proposed to enhance signal processing and behavioral responses specifically to task-relevant stimuli. Given the contrasting functional roles of LC tonic and phasic activity, it is plausible that projections from this brain region are important for maintaining a balance between exploratory and goal-directed behaviors that regulate probabilistic environmental learning and corresponding decision making.
The LC-NE system receives convergent input from the orbitofrontal (OFC) and anterior cingulate cortices (ACC). The OFC has been associated with evaluation of reward. For example, Tremblay et al. found that the response magnitude of single-units in this region is varied with the hedonic value of a stimulus. Additionally, neurons in this region are activated by rewarding stimuli but not by identification of the stimulus or corresponding response preparation. Activation of the ACC appears to reflect some evaluation of cost-benefit. Several studies show ACC activation in response to performance error, negative feedback or monetary loss. Additionally, ACC responds to task difficulty. Therefore, ACC activation may serve to integrate evaluations of task difficulty with corresponding outcome information to gauge the benefits of engaging an action in regards to a particular environmental stimulus. Conceivably, the functions of the ACC and OFC are directly related to decision-making, and their projections to LC may modulate the phasic release of NE in order to gain-modulate cortical responses to decision outcomes.
LC-NE may play a significant role in synchronizing cortical activity in response to a decision process. In computational modeling of decision, the most accurate and efficient decision mechanisms are mathematically defined random walk or drift-diffusion processes that utilize single-layer neural networks to calculate the disparity in evidence between two options. NE release gated by the LC-NE system is elicited after neurons processing sensory information have presumably reached a decision threshold. Thus, the phasic burst can alter activation in all cortical processing layers in a temporally dependent manner, essentially collapsing the vast information processing circuit to the outcome of a single decision layer. Brown et al. found that the addition of a phasic LC mechanism was sufficient to yield optimal performance from a single layer decision network.
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.
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 must be released from synaptic vesicles. Many substances modulate this release, some inhibiting it and some stimulating it. An action potential reaches the presynaptic membrane, which changes the membrane polarisation. Calcium ions thus enter, resulting in vesicular fusion, releasing norepinephrine.
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 done either 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.
|Uptake||Transporter||Vmax (n mol/g/min)||KM||Specificity||Location||Other substrates||Inhibitors |
|Uptake 1||Norepinephrine transporter||1.2||0.3||norepinephrine > epinephrine > isoprenaline||presynaptic|
|Uptake 2||100||250||epinephrine > norepinephrine > isoprenaline||cell membrane of non-neuronal cells|
|Vesicular||VMAT||-||~0.2||norepinephrine > epinephrine > isoprenaline||Synaptic vesicle membrane|
In mammals, norepinephrine is rapidly degraded to various metabolites. The principal metabolites are:
- Normetanephrine (via the enzyme catechol-O-methyl transferase, COMT)
- 3,4-Dihydroxymandelic acid (via monoamine oxidase, MAO)
- Vanillylmandelic acid (3-Methoxy-4-hydroxymandelic acid), also referred to as vanilmandelate or VMA (via MAO)
- 3-Methoxy-4-hydroxyphenylethylene glycol, "MHPG" or "MOPEG" (via MAO)
- 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 system) 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, cannot cross the blood–brain barrier, so drugs such as amphetamines are necessary to increase brain levels.
Norepinephrine, like dopamine, has come to be recognized as playing a large role in attention. For people with ADHD, psychostimulant medications such as amphetamines (Adderall, Desoxyn,) are prescribed to increase both levels of norepinephrine and dopamine. Methylphenidate (Ritalin/Concerta), a dopamine reuptake inhibitor, and Atomoxetine (Strattera), a selective norepinephrine reuptake inhibitor, increase both norepinephrine and dopamine in the prefrontal cortex equally but only dopamine and norepinephrine, respectively, elsewhere in other parts of the brain. 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. This is because SNRIs work by inhibiting reuptake, i.e. inhibiting 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 (in particular 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. 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. Data supports the efficacy of novel antipsychotics that deal with agonism of the NMDA glutamate receptors, associated with regulating uptake of norepinephrine, which in turn affects the trafficking of glutamate. 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.
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 used mainly to treat patients in vasodilatory shock states such as septic shock and neurogenic shock, while showing fewer adverse side-effects compared to dopamine treatment.
By site of action
Different medications affecting norepinephrine function have their targets at different points in the mechanism, from synthesis to signal termination.
Vesicular transport modulators
|norepinephrine (itself)/epinephrine||α2 receptor|
|angiotensin II||AT1 receptor|
Receptor binding modulators
Inhibitors of uptake 1 include:
Inhibitors 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 diffuses 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 cells are lost in Alzheimer’s Disease. It has been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines and their phagocytosis of Aβ, suggesting this loss might have a role in causing this disease.
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). However, adult humans readily synthesize tyrosine from phenylalanine, an essential amino acid. Tyrosine is the precursor to dopamine, which in turn is a precursor to epinephrine and norepinephrine.
- Merck Index, 11th Edition, 6612.
- "51-41-2". SciFinder. SciFinder. Retrieved 14 November 2011.
- "Norepinephrine definition". dictionary.reference.com. Retrieved 2008-11-24.
- "RxNorm_full_prescribe_01072013.zip". U.S. National Library of Medicine. Retrieved 22 January 2013.
- Guyton, Arthur; Hall, John (2006). "Chapter 10: Rhythmical Excitation of the Heart". In Gruliow, Rebecca. Textbook of Medical Physiology (BookISBN 0-7216-0240-1.) (11th ed.). Philadelphia, Pennsylvania: Elsevier Inc. p. 122.
- Tanaka2000 Tanaka M, et al. (2000). Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies. doi:10.1016/S0014-2999(00)00569-0
- The Hormone Foundation. "The Endocrine System & Types of Hormones."
- 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. 17:6058–6063 doi:10.1073/pnas.0909586107 PMID 20231476
- "Introduction to Autonomic Pharmacology" (PDF). Elsevier International. Link redirected to commercial site!
- Sharma B, Satish A, Kumar R (1999). Dictionary of Drugs. Anmol Publications. ISBN 81-261-1820-2.
- Gaddum JH (June 1956). "The Prefix 'Nor' in Chemical Nomenclature". Nature 177 (1046): 1046–1046. Bibcode:1956Natur.177.1046G. doi:10.1038/1771046b0.
- Matthiessen A, Foster GC (1868). "Researches into the chemical constitution of narcotine and of its products of decomposition". Journal of the Chemical Society 358.
- Devauges V, Sara SJ, Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav. Brain Res., 1990 Jun 18;39(1):19–28.
- Yu, A. J.; Dayan, P. (2005). "Uncertainty, neuromodulation, and attention". Neuron 46 (4): 681–92. doi:10.1016/j.neuron.2005.04.026. PMID 15944135.
- Johnson, R.; Jr (1993). "On the neural generators of the P300 component of the event-related potential". Psychophysiology 30 (1): 90–97. doi:10.1111/j.1469-8986.1993.tb03208.x. PMID 8416066.
- Pineda, J.A.; Foote, S.L.; Neville, H.J. (1989). "Effects of Locus Coeruleus Lesions on Auditory Event-Related Potentials in Monkey". J. Neurosci 9 (1): 81–93. PMID 2563282.
- Swick, D., Pineda, J. a, Schacher, S., & Foote, S. L. (1994). Locus coeruleus neuronal activity in awake monkeys: relationship to auditory P300-like potentials and spontaneous EEG. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale, 101(1), 86–92.
- Duncan-Johnson, C.C.; Donchin, E. (1977). "On quantifying surprise: The variation of event-related potentials with subjective probability". Psychophysiology 14 (5): 456–467. doi:10.1111/j.1469-8986.1977.tb01312.x. PMID 905483.
- Pineda, J.A., Shafer, K., & Belamonte, M (1993). Noradrinergic modulation of auditory and visual P300 in parietal-temporal cortex. Society for Neuroscience Abstracts, 19, 1607.
- Lutzenberger, W., Elbert, T., Rockstroth, B. (1987). A brief tutorial on the implications of volume conduction for the interpretation of the EEG. Journal of Psychophysiology, 33. S56.
- Berridge, C.W., Waterhouse, B.D. (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Research Reviews, 42. 33–84.
- Usher, M.; Cohen, J. D.; Servan-Schreiber, D.; Rajkowski, J.; Aston-Jones, G. (1999). "The role of locus coeruleus in the regulation of cognitive performance". Science 283 (5401): 549–54. Bibcode:1999Sci...283..549U. doi:10.1126/science.283.5401.549. PMID 9915705.
- Clayton, E. C., Rajkowski, J., Cohen, J. D., & Aston-Jones, G. (2004). Phasic activation of monkey locus ceruleus neurons by simple decisions in a forced-choice task. J.Neurosci. 24(44), 9914–20.
- Tremblay, L., Schultz, W., (1999). Relative reward preference in primate orbitofrontal cortex. Nature, 398. 704–708.
- Eisenberger, N. I.; Lieberman, M. D.; Williams, K. D. (2003). "Does rejection hurt? An FMRI study of social exclusion". Science 302 (5643): 290–2. Bibcode:2003Sci...302..290E. doi:10.1126/science.1089134. PMID 14551436.
- Falkenstein M, Hohnsbein J, Hoorman J, Blanke L. (1991). Effects of crossmodal divided attention on late ERP components: II. Error processing in choice reaction tasks. Electroencephalogr. Clin. Neurophysiol. 78:447–55
- Gehring, WJ; Goss, B; Coles, MGH; Meyer, DE; Donchin, E. (1993). "A neural system for error detection and compensation. Psychol". Sci 4: 385–90.
- Barch, DM; Braver, TS; Nystrom, LE; Forman, SD; Noll, DC; Cohen, JD (1997). "Dissociating working memory from task difficulty in human prefrontal cortex". Neuropsychologia 35 (10): 1373–80. doi:10.1016/S0028-3932(97)00072-9. PMID 9347483.
- Bogacz, R., Cohen, J.D., (2004). Parameterization of connectionist models. Behav. Res. Methods, Instruments, & Computers, 36(4), pp. 732–741.
- Nieuwenhuis, S.; Aston-Jones, G.; Cohen, J. D. (2005). "Decision making, the P3, and the locus coeruleus-norepinephrine system". Psychological Bulletin 131 (4): 510–32. doi:10.1037/0033-2909.131.4.510. PMID 16060800.
- Brown, E. T., Gilzenrat, M. S., & Cohen, J. D. (2004). The locus coeruleus, adaptive gain, and the optimization of simple decision tasks. Technical Report No. 04–02.
- Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167
- 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 167
- 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.
- Figure 11-4 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.
- "Endokrynologia Kliniczna" ISBN 83-200-0815-8, page 502
- Chapter 11 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.
- Agronin, Marc E; Maletta, Gabe J (2005-11-14). Principles and Practice of Geriatric Psychiatry. ISBN 9780781748100.
- De Backer, Daniel; et al. (March 4, 2010). "Comparison of Dopamine and Norepinephrine in the Treatment of Shock". New England Journal of Medicine 362 (9): 11.
- Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 129
- Mental Health: A report of surgeon general. Etiology of Anxiety Disorders