What are the primary functions of norepinephrine in the brain. How does norepinephrine affect cognitive processes and behavior. What is the role of the noradrenergic system in the body’s stress response. How is norepinephrine synthesized and regulated in the nervous system. What are the key components of the noradrenergic synapse.

The Significance of Norepinephrine in Brain Function

Norepinephrine, also known as noradrenaline, is a crucial neurotransmitter and hormone that plays a vital role in various physiological processes. First identified in the 1940s by Swedish physiologist Ulf von Euler, norepinephrine has since been recognized as a key player in regulating arousal, attention, cognitive function, and stress reactions in the brain. Its importance extends beyond the central nervous system, as it also functions as a hormone in the peripheral nervous system, particularly in the body’s “fight or flight” response.

The noradrenergic system, which is responsible for the production and regulation of norepinephrine, has been implicated in the pathogenesis of several significant neuropsychiatric disorders. As a result, it has become an important pharmacologic target in the treatment of various psychiatric, neurologic, and cardiopulmonary disorders. Understanding the physiology of the noradrenergic synapse is crucial for developing effective treatments and interventions for these conditions.

The Cellular Synthesis of Norepinephrine

The production of norepinephrine in the brain is a complex process that involves several steps and enzymes. How is norepinephrine synthesized at the cellular level. The process begins with the amino acid tyrosine, which can cross the blood-brain barrier and enter neurons in the presynaptic terminal. Elevated levels of tyrosine in the central nervous system trigger the production of norepinephrine and other catecholamines.

The synthesis of norepinephrine follows these steps:

1. Tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase, which is the rate-limiting step in this process.
2. DOPA is then decarboxylated by L-amino acid decarboxylase to produce dopamine.
3. Dopamine is transported into vesicles through the vesicular monoamine transporter (VMAT).
4. In neurons containing the enzyme dopamine beta-hydroxylase, dopamine is converted to norepinephrine.
5. Norepinephrine can then be released from the presynaptic terminal into the synaptic cleft via exocytosis.

In some neurons, norepinephrine can be further converted to epinephrine by the enzyme phenylethanolamine-N-methyl transferase. It’s worth noting that phenylalanine, another amino acid, can also be used for catecholamine synthesis after it is converted to tyrosine by phenylalanine hydroxylase.

The Noradrenergic System in the Central Nervous System

The central noradrenergic system is a complex network of neurons that produces and utilizes norepinephrine throughout the brain. What are the main components of the central noradrenergic system. This system is composed of two primary ascending projections that originate from the brainstem:

• The dorsal noradrenergic bundle (DNB)
• The ventral noradrenergic bundle (VNB)

The DNB originates from the A6 locus coeruleus, located in the dorsal pons. This region is composed primarily of noradrenergic neurons and serves as the predominant site of norepinephrine production in the central nervous system. The DNB sends projections to innervate the cerebral cortex, hippocampus, and cerebellum exclusively. It also has projections that overlap with those from the VNB to innervate areas of the amygdala, hypothalamus, and spinal cord.

The VNB, on the other hand, originates from nuclei in the pons and medulla. It sends projections to innervate the amygdala, hypothalamus, and areas of the midbrain and medulla. This extensive network of noradrenergic neurons allows for widespread influence on various brain functions and behaviors.

Norepinephrine’s Role in the Peripheral Nervous System

While the central nervous system is a major site of norepinephrine action, this neurotransmitter also plays a crucial role in the peripheral nervous system. How does norepinephrine function in the peripheral nervous system. The sympathetic nervous system and neuroendocrine chromaffin cells, located in the adrenal medulla, are primarily responsible for the synthesis and exocytosis of norepinephrine and other catecholamines into the blood circulation.

In the peripheral nervous system, chromaffin cells in the adrenal medulla synthesize norepinephrine following the same steps as in the central nervous system. Once synthesized, norepinephrine is stored in chromaffin granules. From there, it can be released into the bloodstream or converted to epinephrine by phenylethanolamine-N-methyl transferase.

The release of these hormones into the bloodstream is stimulated by acetylcholine, which is released from preganglionic splanchnic fibers. Acetylcholine binds to nicotinic receptors located in the adrenal medulla, triggering the release of norepinephrine and epinephrine. Once in the bloodstream, these hormones act on alpha- and beta-adrenergic receptors of smooth muscle cells and adipose tissue located throughout the body, producing a wide range of physiological effects.

The Multifaceted Functions of Norepinephrine in the Body

Norepinephrine’s influence extends across various physiological processes in both the central and peripheral nervous systems. What are the primary functions of norepinephrine in the body. One of its most significant roles is in the body’s “fight or flight” response, which is activated during states of stress or anxiety.

When norepinephrine and epinephrine are released and bind to adrenergic receptors throughout the body, they exert a range of effects, including:

• Dilating pupils and bronchioles
• Increasing heart rate
• Constricting blood vessels
• Increasing renin secretion from the kidneys
• Inhibiting peristalsis

Beyond its role in the stress response, norepinephrine also plays a crucial part in metabolic regulation. It has been shown to stimulate glycogenolysis and gluconeogenesis while reducing glucose clearance. Additionally, norepinephrine induces ketogenesis and lipolysis, further demonstrating its importance in energy metabolism.

Norepinephrine’s Impact on Cognition and Behavior

In the central nervous system, norepinephrine’s functions extend far beyond its classical roles in promoting wakefulness and arousal. How does norepinephrine influence cognitive processes and behavior. Recent studies have revealed that the noradrenergic system may also influence several areas of cognition and behavior, including:

• Attention
• Working memory
• Long-term mnemonic processing
• Behavioral flexibility

Specifically, alpha-1 and alpha-2 receptors have been found to influence cognitive functions such as working memory and attention. This understanding has led to the development of various pharmacological interventions targeting the noradrenergic system for the treatment of cognitive disorders and mental health conditions.

The role of norepinephrine in facilitating sensory signal detection is also crucial. By modulating the sensitivity of sensory neurons, norepinephrine helps the brain filter and prioritize incoming sensory information, allowing for more efficient processing of relevant stimuli.

The Noradrenergic System in Neuropsychiatric Disorders

Given its wide-ranging effects on brain function and behavior, it’s not surprising that the noradrenergic system has been implicated in various neuropsychiatric disorders. How is the noradrenergic system involved in mental health conditions. Dysregulation of norepinephrine signaling has been associated with several conditions, including:

• Depression
• Anxiety disorders
• Attention deficit hyperactivity disorder (ADHD)
• Post-traumatic stress disorder (PTSD)
• Alzheimer’s disease

Understanding the role of norepinephrine in these disorders has led to the development of various pharmacological interventions. For example, norepinephrine reuptake inhibitors (NRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used in the treatment of depression and anxiety disorders. These medications work by increasing the availability of norepinephrine in the synaptic cleft, thereby enhancing its effects on target neurons.

In ADHD, medications that target the noradrenergic system, such as atomoxetine, have shown efficacy in improving attention and reducing hyperactivity symptoms. Similarly, prazosin, an alpha-1 adrenergic receptor antagonist, has been used to treat nightmares and sleep disturbances in PTSD patients.

The Noradrenergic Synapse: A Closer Look

To fully understand the function of norepinephrine in the brain, it’s essential to examine the structure and components of the noradrenergic synapse. What are the key elements of a noradrenergic synapse. The noradrenergic synapse consists of several crucial components:

1. Presynaptic terminal: This is where norepinephrine is synthesized, stored in vesicles, and released into the synaptic cleft.
2. Synaptic cleft: The space between the presynaptic and postsynaptic neurons where norepinephrine diffuses after release.
3. Postsynaptic membrane: Contains adrenergic receptors that bind to norepinephrine and initiate cellular responses.
4. Reuptake transporters: Located on the presynaptic membrane, these proteins remove norepinephrine from the synaptic cleft, terminating its action and recycling it for future use.
5. Enzymes: Various enzymes are involved in the synthesis and degradation of norepinephrine, including monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).

The intricate balance of these components ensures proper noradrenergic signaling and maintains optimal brain function. Disruptions in any of these elements can lead to alterations in norepinephrine levels and signaling, potentially contributing to various neurological and psychiatric disorders.

Regulation of Norepinephrine Release and Signaling

The release and signaling of norepinephrine are tightly regulated processes that involve various mechanisms. How is norepinephrine release controlled in the brain. Some of the key regulatory mechanisms include:

• Autoreceptors: Presynaptic alpha-2 adrenergic receptors that provide negative feedback, inhibiting further norepinephrine release when activated.
• Heteroreceptors: Receptors for other neurotransmitters located on noradrenergic neurons that can modulate norepinephrine release.
• Second messenger systems: Intracellular signaling cascades that mediate the effects of norepinephrine on target cells.
• Enzymatic degradation: Enzymes like MAO and COMT break down norepinephrine, terminating its action and regulating its levels in the synaptic cleft.

These regulatory mechanisms work in concert to ensure that norepinephrine signaling is appropriate for the current physiological state and environmental demands. Understanding these processes is crucial for developing targeted interventions for disorders involving noradrenergic dysfunction.

Norepinephrine and Neuroplasticity

Recent research has shed light on the role of norepinephrine in promoting neuroplasticity, the brain’s ability to form new neural connections and adapt to new experiences. How does norepinephrine contribute to neuroplasticity. Norepinephrine has been shown to influence several aspects of neuroplasticity, including:

• Long-term potentiation (LTP): Norepinephrine can enhance LTP, a process crucial for learning and memory formation.
• Synaptic scaling: The noradrenergic system is involved in regulating the strength of synaptic connections across neural networks.
• Neurogenesis: Norepinephrine has been implicated in promoting the growth and survival of new neurons in the adult brain.
• Structural plasticity: Activation of noradrenergic receptors can influence the growth and remodeling of dendritic spines, affecting synaptic connectivity.

These findings highlight the importance of norepinephrine in maintaining brain health and cognitive function throughout life. They also suggest potential therapeutic avenues for enhancing neuroplasticity in conditions characterized by cognitive decline or impaired learning and memory.

Norepinephrine Interactions with Other Neurotransmitter Systems

The noradrenergic system does not function in isolation but interacts with various other neurotransmitter systems in the brain. How does norepinephrine interact with other neurotransmitters. Some notable interactions include:

• Dopamine: Norepinephrine and dopamine often work in concert, particularly in areas related to attention and reward processing.
• Serotonin: The interaction between norepinephrine and serotonin is crucial for mood regulation and is targeted by many antidepressant medications.
• Acetylcholine: Norepinephrine can modulate cholinergic signaling, influencing attention and arousal states.
• GABA: Noradrenergic neurons can influence GABAergic inhibition, affecting overall brain excitability.

These interactions highlight the complex nature of neurotransmitter systems in the brain and underscore the importance of considering these relationships when developing therapeutic interventions for neurological and psychiatric disorders.

Future Directions in Norepinephrine Research

As our understanding of the noradrenergic system continues to grow, several exciting areas of research are emerging. What are some promising areas of future norepinephrine research. Some potential directions include:

• Developing more targeted medications with fewer side effects for treating norepinephrine-related disorders.
• Exploring the role of norepinephrine in neurodegenerative diseases and potential neuroprotective strategies.
• Investigating the interactions between the noradrenergic system and the immune system in neuroinflammatory conditions.
• Utilizing advanced neuroimaging techniques to map noradrenergic function in the human brain more precisely.
• Exploring the potential of nootropic compounds that modulate norepinephrine signaling to enhance cognitive function in healthy individuals.

These research directions hold promise for advancing our understanding of norepinephrine’s role in brain function and developing novel therapeutic approaches for a wide range of neurological and psychiatric conditions.

Physiology, Noradrenergic Synapse – StatPearls

Introduction

First identified in the 1940s by Swedish physiologist Ulf von Euler, norepinephrine, also known as noradrenaline, is a neurotransmitter of the brain that plays an essential role in the regulation of arousal, attention, cognitive function, and stress reactions. It also functions as a hormone peripherally as part of the sympathetic nervous system in the “fight or flight” response.

The noradrenergic system has been implicated in the pathogenesis of some significant neuropsychiatric disorders and has been an important pharmacologic target in various psychiatric, neurologic, and cardiopulmonary disorders. This article will focus on the physiology of the noradrenergic synapse.[1]

Cellular Level

Tyrosine is an aromatic amino acid that can cross the blood-brain barrier and be transported into neurons in the presynaptic terminal, where it serves as a precursor for catecholamine synthesis. Elevated levels of tyrosine in the central nervous system (CNS) triggers the production of norepinephrine and other catecholamines. The steps for norepinephrine synthesis are as follows:

Tyrosine is first hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (rate-limiting step). DOPA is then decarboxylated by L-amino acid decarboxylase to produce dopamine. Dopamine gets transported into a vesicle through vesicular monoamine transporter (VMAT) where it can be converted to norepinephrine by neurons that contain an additional enzyme, dopamine beta-hydroxylase. Norepinephrine can then be released from the presynaptic terminal to the synaptic cleft via exocytosis or convert to epinephrine in neurons that contain the enzyme phenylethanolamine-N-methyl transferase.

Phenylalanine is another amino acid that can also be used for catecholamine synthesis after it is converted to tyrosine by phenylalanine hydroxylase.[2]

In the peripheral nervous system, chromaffin cells in the adrenal medulla (following the same steps as mentioned above) synthesize norepinephrine. Once synthesized, they get stored in chromaffin granules. Norepinephrine can be released into the bloodstream or be converted to epinephrine by phenylethanolamine-N-methyl transferase. The release of these hormones into the bloodstream is stimulated by acetylcholine (released from preganglionic splanchnic fibers) which binds nicotinic receptors located in the adrenal medulla.[3][4][5]

Organ Systems Involved

Central Nervous System

The central noradrenergic system is composed of two primary ascending projections that originate from the brainstem: The dorsal noradrenergic bundle (DNB), and the ventral noradrenergic bundle (VNB).

The DNB originates from A6 locus coeruleus, located in the dorsal pons, and is composed of primarily noradrenergic neurons. It functions as the predominant site of norepinephrine production in the central nervous system. It sends projections to innervate the cerebral cortex, hippocampus, and cerebellum exclusively and has projections that overlap with projections from the VNB to innervate areas of the amygdala, hypothalamus, and spinal cord.

The VNB originates from nuclei in the pons and medulla and sends projections to innervate the amygdala, hypothalamus, and areas of the midbrain and medulla.[6][7][8]

Peripheral Nervous System

The sympathetic nervous system and neuroendocrine chromaffin cells (located in the adrenal medulla) are primarily responsible for the synthesis and exocytosis of norepinephrine and other catecholamines into the blood circulation. The hormones act on alpha- and beta-adrenergic receptors of smooth muscle cells and adipose tissue located throughout the body.[9]

Function

The noradrenergic system has various functions throughout the central and peripheral nervous systems. One major role it is involved in is the body’s “fight or flight” response. During states of stress or anxiety, norepinephrine and epinephrine are released and bind to adrenergic receptors throughout the body which exert effects such as dilating pupils and bronchioles, increasing heart rate and constricting blood vessels, increasing renin secretion from the kidneys, and inhibiting peristalsis.

Norepinephrine has also shown to play a role in metabolic effects such as stimulating glycogenolysis and gluconeogenesis (while reducing glucose clearance) and inducing ketogenesis and lipolysis.[10][11]

In the CNS, the noradrenergic system classically operates in its roles in promoting wakefulness and arousal and facilitating sensory signal detection. Further studies have shown that it may also influence some areas of cognition and behavior such as attention, working memory, long-term mnemonic processing, and behavioral flexibility. Specifically, alpha-1 and alpha-2 receptors have been found to influence cognitive functions such as working memory, attention, and fear and spatial learning. Beta-1 and beta-2 receptors have been found to function in auditory fear, spatial reference and fear memory, and memory retrieval. Stimulation or inhibition of these functions is dependent on agonism or antagonism of the adrenergic receptors. In general, alpha-1 and beta receptors enhance neurotransmission and plasticity, promoting stimulatory effects on the CNS, while alpha-2 receptors have inhibitory effects in the CNS such as reducing norepinephrine release and decreasing neuronal excitability. [12]

Mechanism

After synthesis in the presynaptic terminal, norepinephrine is released into the synaptic cleft to bind post-synaptic receptors, undergo reuptake by the presynaptic neuron, or undergo degradation.

Receptor Binding

Following an action potential into the presynaptic terminal, voltage-gated calcium channels are stimulated and bring an influx of calcium from the extracellular to intracellular space. This influx causes norepinephrine (stored in vesicles) to bind the cell membrane and get released into the synaptic cleft via exocytosis. Norepinephrine can then go on to bind three main receptors: alpha1 (alpha-1), alpha-2, and beta receptors. These receptors classify as G-protein coupled receptors with either inhibitory or excitatory effects and different binding affinities to norepinephrine.

Alpha-1 receptors further subdivide into alpha-1a, alpha-1b, and alpha-1d receptors. These receptors are located postsynaptically in regions of the brain including the locus coeruleus, olfactory bulb, cerebral cortex, dentate gyrus, amygdala, and thalamus. Alph-1 receptors have intermediate binding affinity to norepinephrine and couple to the Gq protein signaling pathway. In this pathway, phospholipase C (PLC) is activated to convert phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) on the cell membrane. IP3 is released to the cytosol and binds to transmembrane IP3 receptors located on the endoplasmic reticulum (ER) which functions as a calcium channel. When bound, the receptor undergoes a conformational change leading to the release of calcium from the ER to the cytosol. DAG remains in the cell membrane and positively regulates protein kinase C (PKC), which functions to phosphorylate other proteins. These combined effects produce excitatory cellular effects.

Alpha-2 receptors subdivide into alpha-2a, alpha-2b, and alpha-2c receptors. These receptors are located both presynaptically and postsynaptically in regions of the brain including locus coeruleus, amygdala, and hypothalamus. These receptors have the highest binding affinity to norepinephrine and couple to the Gi/o protein signaling pathway. In this pathway, cAMP levels are decreased thereby leading to decreased adenylyl cyclase activity, producing inhibitory cellular effects. Presynaptic noradrenergic terminals contain alpha-2 autoreceptors which prevent further release of norepinephrine.

Beta receptors subdivide into beta-1, beta-2, and beta-3 receptors. These receptors are in various regions of the brain, with beta-1 and beta-2 receptors being most prevalent in the cerebral cortex. These receptors have the lowest binding affinity to norepinephrine and couple to the Gs protein signaling pathway. In this pathway, cAMP levels increase leading to protein kinase A (PKA) activation which goes on to phosphorylate other proteins inside the cell and leads to excitatory cellular effects. Beta-2 receptors also couple to Gi protein signaling pathways. Beta-3 receptors are present in adipose tissue.[13][8][12][10][14]

In the adrenal medulla, acetylcholine stimulates adrenaline and noradrenaline release. Acetylcholine binds to nicotinic receptors located on adrenal chromaffin cells, which generate action potentials sustained by voltage-gated sodium and potassium channels. This action potential triggers calcium influx into the cytosol, leading to norepinephrine vesicles binding to the cell membrane leading to the release of norepinephrine into the blood circulation where travel to bind alpha and beta receptors on smooth muscle and adipose cells.[4] 

Presynaptic Reuptake

Reuptake is the most common route of removal of norepinephrine from the synaptic cleft. Norepinephrine transporter (NET) located on presynaptic terminals, is a sodium-chloride dependent transporter that mediates the reuptake of norepinephrine into the presynaptic terminal where it can either undergo degradation or storage in vesicles.[12][15]

Catabolism

Norepinephrine can be degraded intracellularly or in the synaptic cleft by the enzymes monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT). MAO oxidizes norepinephrine while COMT metabolizes deaminated norepinephrine through O-methylation. MAO and COMT are found in adrenal chromaffin cells, while sympathetic nerves contain MAO only. COMT is found in all organs.[16] The liver is responsible for the complete degradation of norepinephrine to vanillylmandelic acid (VMA).[7][9]

Pathophysiology

Changes in adrenergic receptors may contribute to the pathogenesis of cardiovascular diseases such as heart failure and hypertension. Studies have shown age-associated changes in the autonomic nervous system such as increased cardiac sympathetic tone with decreased parasympathetic input, dampened cardiovagal baroreceptor sensitivity, and reduced clearance of norepinephrine in the plasma. Furthermore, age-related declines in beta-adrenergic receptor function have been found in patients with cardiovascular disorders. These findings include reduced beta-1 receptor sensitivity and responsiveness in the myocardium and reduced beta-2 receptor function in endothelial and vascular smooth muscle cells, leading to impaired vasodilation. [17]  

Changes in the noradrenergic system have also been associated with several neuropsychiatric and neurodegenerative diseases processes:

Alzheimer’s Disease

Alzheimer’s disease is the most frequently encountered form of dementia characterized by progressive loss of memory and cognition. Proposed mechanisms for the development and progression of the disease include:

• Decreases in locus coeruleus volume and tyrosine hydroxylase-positive cells 

• Hyperphosphorylated tau protein assembly into neurofibrillary tangles that accumulate in the locus coeruleus leading to neuronal degeneration and cell death – rostral cortically-projecting neurons have been found to be predominantly affected, which contributes to the impaired cognition and dementia seen in the disease

• Decreased levels of norepinephrine in the CNS, leading to norepinephrine’s anti-inflammatory and neuroprotective effects on the CNS

• Impaired norepinephrine transmission in the hippocampus due to the accumulation of hyperphosphorylated tau and noradrenergic axonal degeneration

Parkinson’s Disease

Parkinson’s disease is a movement disorder that is also associated with being a cause of dementia. Although dopaminergic system dysfunction is the primary cause of the deficits seen in Parkinson disease, there is some evidence of noradrenergic system impairments involved in the cognitive and emotional deficits seen in Parkinson disease:

• Destruction of noradrenergic neurons in the locus coeruleus (with no topological preference)

• Accumulation of alpha-synuclein in the locus coeruleus which leads to decreased norepinephrine levels and nigrostriatal pathway degenerative due to the loss of norepinephrine’s neuroprotective effects. 

• Loss of alpha-2 auto-receptor protective effects on the noradrenergic and dopaminergic systems 

Attention Deficit Hyperactivity Disorder (ADHD)

A disorder characterized by impairments of working memory and behavioral flexibility, inattention, impulsivity, and/or hyperactivity. Proposed mechanisms for the development of the disorder include:

• Imbalances in the dopaminergic and noradrenergic systems, deficiency in phosphoinositide 3-kinase (PI3K-gamma) enzyme leading to imbalances in the norepinephrine/dopamine ratio and dysregulation of synaptic plasticity, and impaired norepinephrine transporter (NET) function

• Hyperactivity and inattention attributed to dysfunctional noradrenergic transmission within the prefrontal cortex

Schizophrenia

A chronic mental illness characterized by a combination of positive and negative symptoms which may include hallucinations, delusions, blunted affect, inattention, and disorganized thoughts. Although still poorly understood, changes in dopaminergic and glutaminergic signaling are thought to be the leading cause of schizophrenic symptoms. There is also some evidence of the involvement of the noradrenergic system in the disorder such as:

• Elevated norepinephrine levels in blood plasma and cerebrospinal fluid in patients who experience paranoia

• Increased markers for norepinephrine in the brains of post-mortem schizophrenic patients

Medications involving the noradrenergic system have also been implicated in treating or worsening schizophrenic symptoms, depending on function. It has been found that drugs such as alpha-methyldopa, clonidine, and propranolol which decrease noradrenergic transmission in the CNS, help reduce positive symptoms of schizophrenia. Furthermore, medications such as methylphenidate, and desipramine which increase norepinephrine levels in the CNS have been found to worsen positive symptoms.[18] 

Depression

A common disorder that affects a person’s mood, cognition, thoughts, and behavior. Research on peripheral biomolecule levels in depressed individuals has been conducted and is ongoing, with norepinephrine being one of several biomolecules included in studies. It has been found that depressed individuals have increased expression of tyrosine hydroxylase enzyme within the locus coeruleus and increased levels of urinary norepinephrine.[19] 

Clinical Significance

Besides its role in the pathogenesis of various neuropsychiatric conditions, the noradrenergic system has also been an important pharmacologic target as therapy for many of these conditions. Depression is perhaps the most well-known condition associated with treatment that targets the norepinephrine system. The monoaminergic hypothesis, which states that depression is likely due to absolute or relative deficiencies in serotonin and norepinephrine, has been the basis of pharmacologic research and treatment of depression. Serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and selective norepinephrine reuptake inhibitors (NRIs) are a few classes of drugs that serve as a treatment of depression, anxiety disorders, and pain syndromes. They exert their effects by increasing the availability of norepinephrine in the synaptic cleft by either inhibiting reuptake of norepinephrine into presynaptic terminals via inhibition of norepinephrine transporters (SNRIs and NRIs) or preventing catabolism of norepinephrine via inhibition of the enzyme monoamine oxidase.[7]

In the periphery, the norepinephrine transporters have also been a target for evaluation and management of neuroendocrine tumors including pheochromocytoma, neuroblastomas, and paragangliomas. Radiolabeled meta-iodobenzylguanidine (MIBG), a synthetic guanethidine norepinephrine analog, has been used in SPECT imaging of neuroendocrine tumors and as a treatment option for advanced and refractory cases. NET-targeting MIBG therapy is still undergoing further evaluation and development in the hopes of improving therapeutic outcomes.[20]

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Disclosure: Laila Hussain declares no relevant financial relationships with ineligible companies.

Disclosure: Vamsi Reddy declares no relevant financial relationships with ineligible companies.

Disclosure: Christopher Maani declares no relevant financial relationships with ineligible companies.

What Is Norepinephrine? How It Affects the Body and How It’s Used in Medication

Common Questions & Answers

What is the role of norepinephrine?

Norepinephrine works as both a hormone and a neurotransmitter. It plays an important role in the fight-or-flight response, the body’s emergency response to danger or perceived danger. It also boosts alertness, arousal, and attention, and affects your sleep-wake cycle, mood, and memory.

How does norepinephrine affect my mood?

Low norepinephrine levels have been associated with low mood. People with depression may be treated with a class of medications called serotonin and norepinephrine reuptake inhibitors (SNRIs).

What triggers norepinephrine release?

Stress triggers the release of norepinephrine, along with adrenaline. This happens as part of the fight-or-flight response, the body’s emergency response to danger or perceived danger. As a result, various changes happen in the body, including increased heartbeat and blood pressure.

What happens when norepinephrine is high?

High levels of norepinephrine can lead to various health conditions, including high blood pressure; rapid or irregular heartbeat; excessive sweating; cold or pale skin; severe headaches; nervousness or jitters; an adrenal gland tumor called pheochromocytoma; and increased risk of heart, blood vessel, and kidney damage.

What happens when you lack norepinephrine?

If your norepinephrine is low, it can lead to various health conditions, including anxiety, depression, ADHD, headaches, memory problems, sleeping problems, low blood pressure, low blood sugar, and changes in blood pressure and heart rate.

How Norepinephrine Affects Your Body

Stress triggers the release of norepinephrine and adrenaline. This is known as the fight-or-flight response, the body’s emergency response to danger or perceived danger, per Cleveland Clinic. This response causes several changes in the body, including:

• Pupils dilate
• Skin turns pale
• Heart pumps faster
• Blood pressure increases
• Muscles receive more blood flow and oxygen
• You get a burst of energy
• Breathing gets deeper and faster

Norepinephrine also plays other roles in the body. These include:

• Increasing alertness, arousal, and attention
• Affecting your sleep-wake cycle (helping you wake up), mood, and memory

Norepinephrine and ADHD

ADHD medications target norepinephrine and dopamine, both of which affect your attention and concentration, according to KidsHealth.

The following common medications for ADHD increase both norepinephrine and dopamine, per Mental Health America:

• Methylphenidate (Ritalin)
• Dextroamphetamine (Dexedrine)
• Amphetamine and dextroamphetamine (Adderall)

Atomoxetine (Strattera), another drug prescribed for ADHD, raises levels of norepinephrine but not dopamine.

The most common side effects of ADHD medications are loss of appetite and trouble sleeping, per KidsHealth. Other ADHD side effects include jitteriness, irritability, moodiness, headache, stomachaches, fast heart rate, and high blood pressure.

RELATED: What Are the Treatments for ADHD?

Norepinephrine and Depression

Low levels of norepinephrine have been associated with low mood.

People with major depressive disorder — a serious medical condition that negatively affects how a person feels, thinks, and acts — may be prescribed a class of drugs called serotonin-norepinephrine reuptake inhibitors (SNRIs), which keep norepinephrine and serotonin from being reabsorbed and stored in nerve endings, per Mental Health America.

According to Mayo Clinic, commonly prescribed SNRIs include:

• Venlafaxine (Effexor XR)
• Duloxetine (Cymbalta)
• Desvenlafaxine (Pristiq)
• Levomilnacipran (Fetzima)

The most common side effects of SNRIs are nausea, dry mouth, dizziness, headache, and excessive sweating, per the Mayo Clinic. Other possible side effects include fatigue, constipation, insomnia, changes in sexual function, and loss of appetite. Sometimes children, teenagers, and young adults under age 25 may experience an increase in suicidal thoughts or behavior when taking antidepressants.

SNRIs may increase your bleeding risk, particularly when you’re taking other medications that also increase the risk of bleeding, such as ibuprofen (Advil, Motrin IB), aspirin, and blood thinners.

In rare cases, certain antidepressants can cause a serious condition called serotonin syndrome. This typically occurs when two medications that raise serotonin are taken at the same time, such as other antidepressants, certain pain or headache medications, or St. John’s wort.

Another group of drugs called tricyclic antidepressants may also be prescribed to increase norepinephrine.

But these older drugs often cause side effects such as dry mouth, constipation, and weight gain, notes Mental Health America.

RELATED: Depression Signs, Symptoms, and Treatment

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Catecholamines (adrenaline, norepinephrine, dopamine) and serotonin in the blood – 4 parameters. HPLC method. – Family Clinic at Home

Description of the study

Preparation for the study

Indications and general information

Interpretation of the result

Catecholamines are a group of similar hormones produced by the adrenal medulla. The main catecholamines are: dopamine, epinephrine (epinephrine) and norepinephrine. They are released into the blood in response to physical or emotional stress and are involved in the transmission of nerve impulses to the brain, promote the release of glucose and fatty acids as energy sources, dilate bronchioles and pupils. Norepinephrine constricts blood vessels, raising blood pressure, while adrenaline increases heart rate and stimulates metabolism. After completing their action, these hormones are broken down into physiologically inactive substances (homovanilic acid, normetanephrine, etc.).

Normally, catecholamines and their breakdown products are present in the body in small amounts. Their content increases significantly for a short time only under stress. However, chromaffin and other neuroendocrine tumors can cause the formation of large amounts of catecholamines, which leads to a significant increase in the levels of these hormones and their breakdown products in the blood and urine. This threatens with long-term or short-term increases in blood pressure and, accordingly, severe headaches. Other symptoms of elevated catecholamines include trembling, increased sweating, nausea, restlessness, and tingling in the extremities. In addition to catecholamines, pheochromocytomas can synthesize serotonin, adrenocorticotropic hormone, vasoactive intestinal peptide, somatostatin, and other hormones. Correspondence between the size of the tumor, the level of catecholamines in the blood and the clinical picture does not exist.

Serotonin is not a catecholamine, but also belongs to the group of biogenic amines with hormonal and neurotransmitter activity. It is synthesized from the amino acid tryptophan and stored in enterochromaffin cells of the gastrointestinal tract (80-95% of the total), various brain structures, mast cells of the skin, platelets and some other endocrine organs. Serotonin lowers the threshold of pain sensitivity, regulates the function of the pituitary gland, affects vascular tone, blood clotting, motility and secretory activity of the gastrointestinal tract.

Approximately 90% of chromaffin tumors are located in the adrenal glands. Most are benign and do not spread beyond the adrenal glands, although they may continue to grow. Without further treatment, as the tumor grows, over time, the manifestations of the disease sometimes become more severe. High blood pressure caused by a chromaffin tumor can lead to kidney and heart damage and even hemorrhage or heart attack.

In most cases, these tumors are removed surgically, after which the catecholamine levels are significantly reduced, and the symptoms and complications associated with the tumor are mitigated or disappear altogether.

A blood test detects the amount of the hormone at the moment of taking the test, while a urine test – for the previous 24 hours.

Avoid bananas, avocados, cheese, coffee, tea, cocoa, beer within 48 hours prior to the study.
Do not eat for 12 hours before the study, you can drink clean still water.
Cancel (in agreement with the doctor) sympathomimetics 14 days before the study.
Exclude (in agreement with the doctor) the use of diuretics within 48 hours before urine collection.
Completely exclude (in agreement with the doctor) taking medications for 24 hours before the study.
Avoid physical and emotional overexertion within 24 hours prior to the study.
Do not smoke for 24 hours prior to the study.

9003 4 Deadline without taking into account the time for delivery to the laboratory, days

Biological material	blood (EDTA)
Test method	HPLC
3-4 calendar days
Result format, units	4

are erroneously positive. For a confident diagnosis, a general examination of the patient is necessary: ​​an assessment of his physical and emotional state, the medications he takes and the food he eats. When factors interfering with the accuracy of the analysis are established and eliminated, the analysis is often repeated to find out if the level of catecholamines will still be high. In addition, a test for metanephrine in the blood and/or urine and magnetic resonance imaging of the tumor may be ordered to confirm the results.

An elevated catecholamine level in a patient who has previously been treated for a chromaffin tumor indicates tumor recurrence or that therapy has not been entirely effective.

If the catecholamine concentration is normal, then the presence of a chromaffin tumor is unlikely. However, these tumors do not always produce catecholamines at a constant rate. If there have been no recent exacerbations of hypertension, then the concentration of catecholamines may be close to normal even with an existing pheochromocytoma.

Possible causes of increased serotonin levels: carcinoid tumors; medullary thyroid cancer; testicular tumors; celiac disease; endocarditis; dumping syndrome; acute intestinal obstruction; cystic fibrosis; acute myocardial infarction; medication (paracetamol, diazepam, naproxen, pindolol). Reasons for lowering the level of serotonin: mastocytosis; phenylketonuria; Down syndrome; carcinoid tumors of the rectum; Hartnup’s disease; medication (ethanol, imipramine, isoniazid, sulfasalazine).

What can influence the result?

Medications taken (acetaminophen, aminophylline, amphetamines, appetite suppressants, caffeine-containing drugs, chloral hydrate, clonidine, dexamethasone, diuretics, epinephrine, ethanol, insulin, imipramine, lithium, methyldopa, nicotine, nitroglycerin, nasal drops, tricyclic antidepressants and vasodilators).
Food consumed (tea, coffee, alcohol).
Stress.


ADRENALINE, NORADRENALINE (2 parameters). HPLC method. – Family clinic at home

Description of the study

Preparation for the study

Indications and general information

Interpretation of the result

Norepinephrine and epinephrine are catecholamine hormones that are produced in the adrenal medulla. The catecholamines also include the neurotransmitter dopamine, a precursor of norepinephrine.

Catecholamines are released into the blood in response to physical or emotional stress. They help transmit nerve impulses to the brain, increase the level of glucose and fatty acids in the blood. Norepinephrine constricts blood vessels, which leads to an increase in blood pressure, adrenaline increases heart rate and speeds up metabolism. Norepinephrine and epinephrine are metabolized to inactive compounds and excreted in the urine.

As a rule, catecholamines and their metabolites are contained in the body in small quantities, fluctuations in hormone levels are possible only during or after a stressful situation.

Some rare neuroendocrine tumors – pheochromocytoma, ganglioneuroma, neuroblastoma – can lead to a significant increase in the level of catecholamines in the urine and blood. An increased amount of dopamine, adrenaline and noradrenaline entails an increase in blood pressure, sweating, headache, tachycardia, convulsions.

In pheochromocytoma, the amount of catecholamines increases tenfold and decreases with effective treatment of the disease. A recurrence of catecholamines after successful treatment of a pheochromocytoma indicates a recurrence of the disease.

The level of dopamine, adrenaline and norepinephrine is increased by some foods – coffee, tea, cocoa, chocolate, vanilla, alcohol, bananas. Many drugs have a dopaminergic (catecholamine-increasing) effect, which can lead to false positive results when testing hormone levels.

The level of catecholamines in the blood changes rapidly, therefore, the study of catecholamines and their metabolites in the urine is preferred.

This test allows you to detect and determine the amount of catecholamines in daily urine. The analysis helps to diagnose pheochromocytoma, ganglioneuroma, ganglioblastoma, neuroblastoma.

Get a preservative from the medical office in advance. Daily urine is collected in a clean glass jar with a preservative. The jar should be protected from direct sunlight (wrapped in dark paper) and stored in the cold;
Attention! All the urine collected during the day, you do not need to bring!
– Empty the bladder in the morning (this portion of urine is poured into the toilet bowl).
Record the time of urination.
All subsequent portions of urine allocated during the day, night and the first
morning portion of the next day (for example, at 8:00) collect in one container.
The last urination should be carried out 24 hours from
the time noted the day before.
After the collection of urine is completed, the contents of the container must be accurately measured,
be sure to mix and immediately pour 30-50 ml into a sterile container with a
lid.
On the container, you must indicate the daily volume of urine (diuresis) in milliliters,
for example, “Diuresis: 1250 ml”, and also write the patient’s height and body weight;
– after the end of the collection of urine, it must be mixed, the total volume of urine collected is measured, and poured into a sterile container of approximately 25 ml. Be sure to inform the administrator of the daily diuresis.”
– Eliminate bananas, avocados, cheese, coffee, tea, cocoa, beer from the diet 48 hours before the study.