Fight or flight? Remember or forget? Distraction or focus? This important switch helps decide: norepinephrine, a neurotransmitter with a long reach in your brain and body.
What is Norepinephrine?
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is a compound that functions in the human brain and body as a hormone and a neurotransmitter [1].
A neurotransmitter is a chemical that is released from neurons. Norepinephrine is released in almost the entire brain; exceptions include the basal ganglia [2].
More specifically, norepinephrine is one of the catecholamines: a family of compounds that share the same basic structure. The family gets its name from its backbone, catechol. The catecholamines include not only norepinephrine, but also epinephrine and dopamine [3, 4].
What Does Norepinephrine Do?
Norepinephrine is part of the sympathetic nervous system, which manages the body’s response to stress. It is one of the fight or flight hormones, along with its close relative epinephrine [5].
The sympathetic nervous system’s inverse is the parasympathetic nervous system, which modifies most of the same organs into a state more conducive to rest, recovery, and digestion of food [6, 7].
What is the Function of Norepinephrine?
In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances the formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety [8, 4].
In the rest of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, blocks urination, and slows the rate at which food moves through the gut [8, 4, 5].
Together, and alongside epinephrine, these effects create the fight or flight response to stress. Each change helps us make snap decisions and gives us the strength and speed to follow through on them. However, this comes at the cost of increased wear and tear on all of the affected organs [5, 9, 10].
Where Is it Produced?
The sympathetic nervous system triggers norepinephrine release in response to stress. In the brain, the locus coeruleus uses norepinephrine to communicate panic, fear, and motivation to other regions [11, 12].
Broadly, our autonomic or involuntary nervous system is divided into the sympathetic or fight-or-flight system and the parasympathetic or rest-and-digest system [13].
Nerves that split off from the spinal cord to reach various parts of the body belong to either of these. For the most part, sympathetic nerves release norepinephrine and aid adrenergic activity, while the parasympathetic ones release acetylcholine and support cholinergic activity [13, 14].
Outside the brain, norepinephrine is also released by the inner layer of the adrenal glands, two walnut-sized structures that sit on top of your kidneys [15].
The body makes norepinephrine and other catecholamines in a cascade that can start with either of two amino acids, phenylalanine and tyrosine. The assembly line looks like this [16, 10]:
Phenylalanine → Tyrosine → L-dopa → Dopamine → Norepinephrine → Epinephrine
Norepinephrine vs Epinephrine
Epinephrine and norepinephrine are very similar neurotransmitters. As you see from the assembly line above, they are part of the same system and come from the same precursors. They are both catecholamines, and they both activate the fight or flight response. Nevertheless, they are not identical, and they have slightly different roles in the body [17].
Adrenergic Receptors
Epinephrine and norepinephrine bind to the same series of adrenergic receptors, but each receptor has “preferences” for a certain neurotransmitter. These preferences produce the differing effects of the two compounds.
The α1 receptor prefers norepinephrine. It constricts blood vessels, increases blood pressure, contracts the iris muscle in the eye, and reduces activity in the digestive tract. The β1 receptor also prefers norepinephrine. It increases heart rate and contraction force [18].
By contrast, the α2 receptor prefers epinephrine. It relaxes the digestive tract, decreases insulin secretion, and promotes healing by activating the clotting process. The β2 receptor also prefers epinephrine. It opens up the airway and further reduces activity in the digestive tract [18].
Epinephrine and norepinephrine usually work together, but they produce different parts of the fight or flight response. Norepinephrine increases blood pressure and heart rate, while epinephrine increases breathing capacity and blood clotting. They also work together to decrease activity in the digestive system.
Dopamine and Norepinephrine Interplay
Dopamine is the direct precursor to epinephrine and norepinephrine, and so these catecholamines have a close relationship. One enzyme, dopamine beta hydroxylase (DBH), converts dopamine to norepinephrine directly [19].
The activity of this enzyme can change the relative level of dopamine and norepinephrine in the body. High DBH activity means less dopamine and more norepinephrine, whereas low DBH activity means more dopamine and less norepinephrine [19].
DBH must carefully maintain the balance between dopamine and norepinephrine. Imbalances here may lead to high blood pressure, heart failure, Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia, ADHD, and other conditions [19, 20].
Norepinephrine Effects
To sum it up, norepinephrine acts on the alpha 1 (α1), alpha 2 (α2) and beta (β) adrenergic receptors; it has a much stronger affinity for the β1 receptor than β2 or β3 [21, 22].
In the brain, norepinephrine increases wakefulness, vigilance, and attention. It also promotes the formation of memory and helps us make decisions [23].
Outside of the brain, norepinephrine’s “fight or flight” effects include:
- Increased production of tears and pupil dilation in the eyes [24]
- Increased volume of blood pumped through the heart [9]
- Increased fat burning and calories burned to generate body heat [25]
- Narrowing of blood vessels, causing an increase in blood pressure. This constriction of blood vessels (via α-adrenergic receptors) decreases blood flow to the gastrointestinal tract [26, 9].
- A release of renin in the kidneys, which keeps sodium in the bloodstream [27]
- Increased production of glucose in the liver, either by breaking down glucose from a meal or by creating glucose from glycogen [27]
- Increased glucose uptake in the muscles, which gets you ready to run or defend yourself. Depleting norepinephrine caused a reduction in activity in mice [28]
- Decreased digestive activity. Norepinephrine inhibits the intestinal nervous system, causing a decrease in gut flow, blood flow, and secretion of digestive enzymes [29]
Increasing and Decreasing Norepinephrine
This neurotransmitter needs to be carefully balanced and regulated for your brain and body to stay healthy.
In the second part of this series, we’ll discuss what can happen when norepinephrine is too low and what factors may increase it. In the third part, we’ll go over the symptoms of having too much norepinephrine and the factors that keep it in check.
Catecholamine Testing
Doctors can check their patients’ catecholamine (epinephrine, norepinephrine, and dopamine) levels through either a blood or urine test. In catecholamine blood tests, epinephrine and norepinephrine levels are expected to be significantly higher when the patient is standing up than when he or she is lying down [30, 31].
Catecholamine testing is most often done if your doctor suspects that you or your child may have one of a few rare types of tumors. These tumors all produce abnormally high levels of catecholamines, including norepinephrine:
- Pheochromocytoma, a rare tumor of the adrenal glands [30, 32, 31]
- Paraganglioma, a tumor of nervous tissue [33, 34, 31]
- Neuroblastoma, a tumor of immature nervous tissue that only arises in young children [34]
If your catecholamine levels are high, your doctor will run additional tests to determine the exact cause.
Genetics of Norepinephrine
Dopamine beta-hydroxylase (DBH) converts dopamine to norepinephrine. Variations at several SNPs can block the conversion and lower norepinephrine.
- At rs1108580, the A allele is associated with lower levels of DBH.
- At rs1611115, the T allele is associated with lower levels of DBH.
- At rs2519152, the T allele is associated with lower levels of DBH.
- At rs4531, the T allele is associated with higher levels of DBH.
- At rs77905, the A allele is associated with higher levels of DBH [35].
MAOA and COMT are two enzymes that break down norepinephrine and can help determine if you’re a low or high norepinephrine producer. Higher levels of MAOA and COMT will reduce norepinephrine.
Your Norepinephrine Genes
SelfDecode is an app that can help you decipher how your genes can affect your biology and help you understand why some things work for you, while others don’t.
Takeaway
Norepinephrine is a catecholamine neurotransmitter like dopamine and epinephrine. In fact, it is closely related to these other compounds, and they are all part of the same biosynthesis pathway. Norepinephrine is made in the locus coeruleus, a part of the brain stem, and in the adrenal glands.
Like epinephrine, norepinephrine acts on the adrenergic receptors. Different receptors preferentially bind one or the other neurotransmitter to produce different parts of the fight or flight response. Norepinephrine constricts blood vessels, raises blood pressure, increases heart rate, and reduces activity in the digestive system.
