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]