NORADRENALINE: FUNCTIONS AND MECHANISM OF ACTION - NEUROPSYCHOLOGY - 2025

The noradrenaline or norepinephrine is a chemical that creates our body naturally and can act as hormone and neurotransmitter. Along with dopamine and adrenaline, it belongs to the catecholamine family; substances that are generally associated with physical or emotional stress.

Norepinephrine has multiple functions. As a stress hormone, it appears to affect areas of the brain where attention and reactions to stimuli are controlled. Accompanied by adrenaline, it is responsible for the fight or flight response by directly increasing the heart rate.

Norepinephrine molecule

Norepinephrine has traditionally been related to motivation, alertness and wakefulness, level of consciousness, regulation of sleep, appetite, sexual and aggressive behavior, supervision of learning, memory and reward mechanisms. However, these functions are usually carried out with the help of some other neurotransmitter such as dopamine or serotonin.

On the other hand, a decrease in norepinephrine appears to cause low blood pressure, bradycardia (low heart rate), a decrease in body temperature and depression.

Norepinephrine exerts its effects when it binds to so-called "adrenergic receptors" or "noradrenergic receptors." Thus, the parts of the body that produce norepinephrine or where it works are called "noradrenergic".

In addition to being produced in our body, norepinephrine can be injected for therapeutic purposes in people who have extreme hypotension. There are also drugs that alter the natural levels of this substance, such as cocaine and amphetamines.

Differences between norepinephrine and adrenaline

Structure of adrenaline

Adrenaline is a hormone produced by the adrenal medulla, which is the nucleus of the adrenal glands, which are located just above the kidneys (that's where the term comes from). This substance also acts as a neurotransmitter in our brain, but it is not as important as norepinephrine.

Regarding its structure, adrenaline or epinephrine contains a methyl group attached to its nitrogen. On the other hand, in norepinephrine, instead of a methyl group it has a hydrogen atom.

Synthesis of norepinephrine

Norepinephrine is created in the sympathetic nervous system from an amino acid called tyrosine, which can be obtained directly from the diet in foods such as cheese.

However, it can also be derived from phenylalanine. The latter is one of the essential amino acids for humans and is also captured through food. Specifically, it is found in protein-rich foods such as red meat, eggs, fish, milk, asparagus, chickpeas, peanuts, etc.

Tyrosine is catalyzed by the enzyme tyrosine-hydroxylase (TH), which converts it to levodopa (L-DOPA). Instead, the compound AMPT (Alpha-Methyl-p-tyrosine) is an enzyme that does the opposite effect. That is, it inhibits the conversion of tyrosine to L-DOPA; thus blocking the production of both dopamine and norepinephrine.

Then L-DOPA is transformed into dopamine thanks to the activity of the enzyme DOPA decarboxylase.

Many neurotransmitters are synthesized in the cytoplasm of our brain cells. Later they are stored in a kind of tiny bags called "synaptic vesicles". However, for the synthesis of norepinephrine, the last step occurs inside these vesicles.

Originally, the vesicles are full of dopamine. Inside the vesicles there is an enzyme called dopamine-β-hydroxylase, which is responsible for converting dopamine to norepinephrine.

In these vesicles there is also the compound fusaric acid, which inhibits the activity of the enzyme dopamine-β-hydroxylase to control the production of norepinephrine, and which does not affect the amount of dopamine required.

How is norepinephrine broken down?

When there is an excess of norepinephrine in the terminal button of neurons, it is destroyed by monoamine oxidase type A (MAO-A). It is an enzyme that converts norepinephrine into an inactive substance (this resulting substance is called a metabolite).

The objective is that norepinephrine does not continue to work in the body, since having high levels of this neurotransmitter could have dangerous consequences.

It can also be degraded by the enzyme catechol-O-methyl transfered (COMT), or converted to adrenaline by an enzyme in the adrenal medulla called PNMT (Phenylethanolamine N-methyltransferase).

The main metabolites that arise after this degradation are VMA (Vanillylmandelic acid) in the periphery, and MHPG (3-Methoxy-4-hydroxyphenylglycol) in the central nervous system. Both are excreted in the urine, so they can be detected in a test.

Noradrenergic system and parts of the brain involved

Noradrenergic neurons are reduced in our brain and are organized in small nuclei. The most important nucleus is the locus coeruleus that is located in the dorsal protuberance, although it also exists in the medulla oblongata and the thalamus.

However, they project into many other areas of the brain and their effects are very powerful. Virtually all regions of the brain receive input from noradrenergic neurons.

The axons of these neurons act on adrenergic receptors in various parts of the nervous system, such as: the cerebellum, spinal cord, thalamus, hypothalamus, basal ganglia, hippocampus, amygdala, septum, or neocortex. In addition to the cingulate gyrus and the striatum.

The main effect of the activation of these neurons is the increase in vigilance capacity. That is, an increase in attention to detect events in the environment.

Adrenergic nuclei

In 1964 Dahlström and Fuxe defined several important cell nuclei. They named them “A”, which comes from “aminergic”. They described fourteen "A zones": the first seven contain the neurotransmitter norepinephrine, while the next seven contain dopamine.

The A1 noradrenergic group is located near the lateral reticular nucleus and is essential to control body fluid metabolism. On the other hand, group A2 is found in a part of the brain stem called the solitary nucleus. These cells are involved in stress responses and the control of appetite and thirst. Groups 4 and 5 project primarily to the spinal cord.

However, the locus coeruleus is the most important area; y contains group A6. High activity of the nucleus coeruleus is associated with alertness and reaction rate. In contrast, a drug that suppresses the activity of this area produces a strong sedative effect.

Release out of the brain

On the other hand, outside the brain, norepinephrine functions as a neurotransmitter in the sympathetic ganglia located near the abdomen or spinal cord. It is also released directly into the blood from the adrenal glands, structures above the kidneys that regulate stress responses.

Noradrenergic receptors

There are different types of noradrenergic receptors, which are distinguished according to their sensitivity to certain compounds. These receptors are also called adrenergic receptors, because they tend to capture both adrenaline and norepinephrine.

In the central nervous system, neurons contain adrenergic receptors β1 and β2, and α1 and α2. These four types of receptors are also found in various organs other than the brain. A fifth type, called the β3 receptor, is found outside the central nervous system, primarily in adipose (fat) tissue.

All of these receptors have both excitatory and inhibitory effects. For example, the α2 receptor generally has a net effect of lowering released norepinephrine (inhibitory). While the rest of the receptors normally produce observable excitatory effects.

Features

Norepinephrine is associated with a wide variety of functions. But above all it is linked to a state of physical and mental activation, which prepares us to react to events in our environment. That is, it triggers the fight or flight responses.

Thus, it allows the body to respond adequately to stressful situations through increased heart rate, increased blood pressure, dilation of the pupils, and widening of the airways.

In addition, it causes the narrowing of blood vessels in non-essential organs. That is, it reduces blood flow to the gastrointestinal system, blocking gastrointestinal motility, as well as inhibiting the emptying of the bladder. This happens because our body establishes priorities, and assumes that it is more important to dedicate energy to defend ourselves against a danger than to excrete waste.

The effects of this substance can be further detailed according to the part of the nervous system in which it acts.

-Functions in the sympathetic nervous system

It is the main neurotransmitter of the sympathetic nervous system, and consists of a series of ganglia. The ganglia of the sympathetic chain are located next to the spinal cord, in the chest and in the abdomen.

These establish connections with a wide variety of organs such as the eyes, salivary glands, heart, lungs, stomach, kidneys, bladder, reproductive organs… As well as the adrenal glands.

The objective of norepinephrine is to modify the activity of the organs so that they promote as much as possible a rapid reaction of the body to certain events. The nice effects would be:

- Increase in the amount of blood pumped by the heart.

- It acts on the arteries, causing an increase in blood pressure through the constriction of blood vessels.

- Quickly burn calories in adipose tissue to generate body heat. It also promotes lipolysis, a process that turns fat into energy sources for muscles and other tissues.

- Increase in ocular humidity and dilation of the pupils.

- Complex effects on the immune system (some processes seem to be activated while others are deactivated).

- Increased glucose production through its action in the liver. Remember that glucose is the body's main energy source.

- In the pancreas, norepinephrine promotes the release of a hormone called glucagon. This enhances the production of glucose by the liver.

- Facilitates the skeletal muscles capture the glucose necessary to act.

- In the kidneys, it releases renin and retains sodium in the blood.

- Reduces the activity of the gastrointestinal system. Specifically, it decreases blood flow to that area, and inhibits gastrointestinal mobility, as well as the release of digestive substances.

These effects can be counteracted in the parasympathetic nervous system with a substance called acetylcholine. It has the opposite functions: it reduces the heart rate, encourages a state of relaxation, increases intestinal motility promoting digestion, favors urination, pupil contraction, etc.

Functions in the central nervous system

Noradrenergic neurons in the brain primarily promote a state of alert arousal and readiness for action. The main structure that is responsible for the “mobilization” of our central nervous system is the locus coeruleus, which participates in the following effects:

- Increases vigilance, a state in which we are more attentive to our environment and ready to respond to any event.

- Increased attention and concentration.

- Improves the processing of sensory stimuli.

- As a consequence, a greater release of norepinephrine favors memory. Specifically, it increases the ability to store memories and learn; as well as recovering data already stored. It also improves working memory.

- It reduces reaction times, that is, it takes us much less time to process stimuli and emit a response.

- Increases restlessness and anxiety.

Less norepinephrine is released during sleep. The levels remain stable during wakefulness, and rise much higher in unpleasant, stressful or dangerous situations.

For example, pain, bladder distention, heat, cold, or shortness of breath cause norepinephrine increases. Although states of fear or intense pain are linked to very high levels of activity of the locus coeruleus, and, therefore, a higher amount of norepinephrine.

Therapeutic use of norepinephrine

There is a wide variety of drugs whose effects affect the noradrenergic systems throughout our body. They are mainly used for cardiovascular problems and certain psychiatric conditions.

Sympathomimetic drugs

There are sympathomimetic drugs, or also called adrenergic agonists, that mimic or potentiate some of the effects of existing norepinephrine. In contrast, sympatholytic drugs (or adrenergic antagonists) exert the opposite effect.

Norepinephrine itself would be sympathomimetic, and can be administered directly by intravenous injection in severe hypotension.

Norepinephrine inhibitors

On the other hand, norepinephrine inhibitor drugs can focus on blocking beta receptors. They are used to treat high blood pressure, cardiac arrhythmia or heart failure, glaucoma, angina pectoris, or Marfan syndrome.

However, its use is increasingly limited as it has serious side effects, mainly for diabetics.

Alpha receptor blockers

There are also drugs that block alpha receptors, which have a wide variety of uses because their effects are somewhat more complex. They can be used to relax the bladder muscles in certain conditions such as the expulsion of stones in the bladder.

Mainly alpha 1 receptor inhibitors are also useful for disorders such as generalized anxiety, panic disorder and post-traumatic stress disorder.

While those that block alpha 2 receptors have a final norepinephrine-enhancing effect. They have been used extensively to treat depression, as these patients have traditionally been thought to have low levels of norepinephrine.

Drugs that increase the level of norepinephrine

Drugs that increase norepinephrine levels have also been used in patients with attention deficit hyperactivity disorder. Mainly methylphenidate, which also increases the amount of dopamine.

References

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