Norepinephrine

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.

Etymology

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.

Chemistry

Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is L-(−)-(R)-norepinephrine. The prefix nor-, is derived from the German abbreviation for “N ohne Radikal” (N, the symbol for nitrogen, without radical),^[5] referring to the absence of the methyl functional group at the nitrogen atom.

Origins

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.

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.

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:

• Amygdala
• Cingulate gyrus
• Cingulum
• Hippocampus
• Hypothalamus
• Neocortex
• Spinal cord
• Striatum
• Thalamus

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 the system affects large areas of the brain.

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:

• 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 & DOPA decarboxylase.
• Last is the final β-oxidation into norepinephrine by dopamine beta hydroxylase, requiring ascorbate as a cofactor (electron donor).

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.^[6]

Release

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

Main article: Adrenergic receptor

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 both a result of degradation and reuptake.

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)
• 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)^[7]

VMA and MOPEG are the two major urinary metabolites of catecholamine metabolism.

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, 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.)

Depression

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.^[10] 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.^[11] For this reason, they have largely been replaced by newer selective reuptake drugs such as fluoxetine (Prozac).

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 alpha-1 and alpha-2 adrenergic receptors to cause vasoconstriction. Its effects are often limited to the increasing of blood pressure through agonist activity on alpha-1 and alpha-2 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.

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 Latin 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 catacholamines, 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.^[13]