Norepinephrine Norepinephrine , also called noradrenaline
, or 4,5-β-trihydroxy phenethylamine is a catecholamine with multiple roles including
those 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, which is most responsible for cognitive alertness.
Medically it is used in those with severe hypotension. It does this by increasing vascular
tone (tension of vascular smooth muscle) through α-adrenergic receptor activation.
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 name.
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. 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. Medical uses
Norepinephrine is used for hypotension. Hypotension
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.
Physiological effects 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 (LC). 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 coeruleus 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 contribute to such post-ganglionic 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 manifested in alertness, arousal,
and influences on the reward system. 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: Amygdala
Cingulate gyrus Cingulum
Hippocampus Hypothalamus
Neocortex Spinal cord
Striatum Thalamus
Some Brainstem nuclei Cerebellum
On the other hand, axons of neurons of the lateral tegmental field act on adrenergic
receptors in hypothalamus, for example. This structure explains some of the clinical
uses of norepinephrine, since a modification of this system affects large areas of the
brain. Role in cognition
Cortical norepinephrine (NE) release during attention paradigms (patterns) can increase
the alteration detection rate (frequency at which 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", wherein 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 impair this
attentional shift. Similarly, several studies have implicated
the LC-NE system in eliciting the P300, a cortical event-related potential that responds
to environmental stimuli with 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
within 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 nor 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 taking 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. Fasting
A study has shown that fasting leads to increased levels of norepinephrine (NE) in the blood
for up to 4 days of fasting. Macronutrient intake
Glucose intake was found to significantly increase plasma NE levels. In contrast, protein
and fat intake was found to have no effect. Schizophrenia
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 the 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
than with dopamine, which may actually be responsible for a large part of the mechanism
of glutamate release. Drug interactions
Different medications affecting norepinephrine function have their targets at different points
in the mechanism, from synthesis to signal termination.
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.
Receptor binding modulators Examples include alpha blockers for the α-receptors,
and beta blockers for the β-receptors. Termination modulators
Uptake modulators Inhibitors of uptake 1 include:
cocaine tricyclic antidepressants
desipramine desipramine
phenoxybenzamine amphetamine
reboxetine Inhibitors of uptake 2 include:
normetanephrine steroid hormones
phenoxybenzamine 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. Chemistry
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. Mechanism
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. Biosynthesis
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.
Vesicular transport 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.
Release 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. For instance, there are inhibitory α2 adrenergic
receptors presynaptically that give negative feedback on release by homotropic modulation.
Receptor binding 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. Termination
Signal termination is a result of reuptake and degradation.
Uptake 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. Degradation
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.
Nutritional sources 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.
See also Catecholaminergic polymorphic ventricular
tachycardia History of catecholamine research