The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2)

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. NET is a

monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

and is responsible for the sodium-chloride (Na⁺/Cl⁻)-dependent

reuptake Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmi ...

of extracellular

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

(NE), which is also known as noradrenaline. NET can also reuptake extracellular

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

(DA). The reuptake of these two

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

s is essential in regulating concentrations in the

synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in neuromuscular junction, muscles or glands. Chemical synapses allow neurons to form biological neural ...

. NETs, along with the other monoamine transporters, are the targets of many antidepressants and recreational drugs. In addition, altered NET availability is associated with

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple ...

. There is evidence that

single-nucleotide polymorphisms In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

in the NET gene (''SLC6A2'') may be an underlying factor in some of these disorders.

Gene

The norepinephrine transporter gene, SLC6A2 is located on human

chromosome 16 Chromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs (the building material of DNA) and represents just under 3% of the total DNA in cel ...

locus 16q12.2. This gene is encoded by 14

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s. Based on the nucleotide and amino acid sequence, the NET transporter consists of 617 amino acids with 12 membrane-spanning domains. The structural organization of NET is highly homologous to other members of a sodium/chloride-dependent family of neurotransmitter transporters, including dopamine, epinephrine,

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and GABA transporters.

Single-nucleotide polymorphisms

single-nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a ...

(SNP) is a genetic variation in which a genome sequence is altered by a single nucleotide ( A, T, C or G). NET proteins with an altered amino acid sequence (more specifically, a

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...

) could potentially be associated with various diseases that involve abnormally high or low plasma levels of

due to altered NET function. NET SNPs and possible associations with various diseases are an area of focus for many research projects. There is evidence suggesting a relationship between NET SNPs and various disorders such as ADHD psychiatric disorders, postural tachycardia and

orthostatic intolerance Orthostatic intolerance (OI) is the development of symptoms when standing upright that are relieved when reclining. There are many types of orthostatic intolerance. OI can be a subcategory of dysautonomia, a disorder of the autonomic nervous ...

. The SNPs rs3785143 and rs11568324 have been related to

attention-deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

. Thus far, however, the only confirmed direct association between a SNP and a clinical condition is that of the SNP, Ala457Pro, and

. Thirteen NET missense mutations have been discovered so far.

Abbreviations: TMD,

transmembrane domain A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...

; n/a, non-applicable.
For the table above, refer to this table of standard

amino acid abbreviations Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

. This notation for
missense mutations, take Val69Ile for example, indicates that amino acid Val69 was changed to Ile.

Genetic variations

epigenetic In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...

mechanism (hypermethylation of CpG islands in the NET gene promoter region) that results in reduced expression of the noradrenaline (norepinephrine) transporter and consequently a phenotype of impaired neuronal reuptake of norepinephrine has been implicated in both

postural orthostatic tachycardia syndrome Postural orthostatic tachycardia syndrome (POTS) is a condition characterized by an abnormally large increase in heart rate upon sitting up or standing. POTS is a disorder of the autonomic nervous system that can lead to a variety of symptoms, ...

and

panic disorder Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...

rs5569 In genetics, rs5569 (A1287G or G1287A) is a genetic variant. It is a single nucleotide polymorphism (SNP) in the '' SLC6A2'' gene in exon 9. This gene codes the norepinephrine transporter. The SNP is a silent substitution and the nucleotides of bo ...

is a variant of SLC6A2.

Structure

The norepinephrine transporter is composed of 12

s (TMDs). The intracellular portion contains an

amino In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

(-) group and

carboxyl In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl group (e.g. ...

(-COOH) group. In addition, there is a large extracellular loop located between TMD 3 and 4. The protein is composed of 617

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

Function

NET functions to transport synaptically released

back into the presynaptic neuron. As much as 90% of the norepinephrine released will be taken back up in the cell by NET. NET functions by coupling the influx of sodium and chloride (Na⁺/Cl⁻) with the transport of norepinephrine. This occurs at a fixed ratio of 1:1:1. Both the NET and the

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT) can transport norepinephrine and dopamine. The reuptake of norepinephrine and dopamine is essential in regulating the concentration of monoamine neurotransmitters in the synaptic cleft. The transporter also helps maintain homeostatic balances of the presynaptic neuron.

Norepinephrine (NE) is released from

noradrenergic Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "noradrenaline" (from L ...

neurons that innervate both the CNS and PNS. NE, also known as noradrenaline (NA), has an important role in controlling mood, arousal, memory, learning, and pain perception. NE is a part of the

sympathetic nervous system The sympathetic nervous system (SNS or SANS, sympathetic autonomic nervous system, to differentiate it from the somatic nervous system) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous sy ...

. Dysregulation of the removal of norepinephrine by NET is associated with many neuropsychiatric diseases, discussed below. In addition, many antidepressants and recreational drugs compete for the binding of NET with NE.

Transport mechanisms

The transport of norepinephrine back into presynaptic cell is made possible by the cotransport with Na⁺ and Cl⁻. The sequential binding of the ions results in the eventual reuptake of norepinephrine. The ion gradients of Na⁺ and Cl⁻ make this reuptake energetically favorable. The gradient is generated by the Na+/K+-ATPase which transports three sodium ions out and two potassium ions into the cell. NETs have conductances similar to those of

ligand-gated ion channel Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as sodium, Na+, potassium, K+, calcium, Ca2+, and/or chloride, Cl− to ...

s. The expression of NET results in a leak-channel activity.

Location in the nervous system

NETs are restricted to

neurons and are not present on neurons that release dopamine or epinephrine. The transporters can be found along the cell body,

axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...

s, and

dendrite A dendrite (from Ancient Greek language, Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that extends from a nerve cell that propagates the neurotransmission, electrochemical stimulation received from oth ...

s of the neuron. NETs are located away from the synapse, where norepinephrine is released. They are found closer to the plasma membrane of the cell. This requires norepinephrine to diffuse from the site it is released to the transporter for reuptake. Norepinephrine transporters are confined to the neurons of the sympathetic system, and those innervating the adrenal medulla, lung, and placenta.

Regulation

Regulation of NET function is complex and a focus of current research. NETs are regulated at both the cellular and molecular level post-translation. The most understood mechanisms include phosphorylation by the second messenger

protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

(PKC). PKC has been shown to inhibit NET function by sequestration of the transporter from the plasma membrane. The amino acid sequence of NET has shown multiple sites related to protein kinase phosphorylation. Post-translational modifications can have a wide range of effects on the function of the NET, including the rate of fusion of NET-containing vesicles with the plasma membrane, and transporter turnover.

Clinical significance

Orthostatic intolerance

Orthostatic intolerance (OI) is a disorder of the

autonomic nervous system The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates viscera, internal organs, smooth muscle and glands. The autonomic nervo ...

(a subcategory of

dysautonomia Dysautonomia, autonomic failure, or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly. This condition may affect the functioning of the heart, bladder, intestines, sweat glands, pupils, and ...

) characterized by the onset of symptoms upon standing. Symptoms include fatigue, lightheadedness, headache, weakness, increased heart rate/

heart palpitations Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...

, anxiety, and altered vision. Often, patients have high plasma

(NE) concentrations (at least 600 pg/ml) in relation to sympathetic outflow upon standing, suggesting OI is a hyper

adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...

condition. The discovery of identical twin sisters who both had OI suggested a genetic basis for the disorder. A

on the NET gene (SLC6A2) was discovered in which an

alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group sid ...

residue was replaced with a

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

residue (Ala457Pro) in a highly conserved region of the transporter. The patients’ defective NET had only 2% of the activity of the

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...

version of the gene. The genetic defect in the NET protein results in decreased NET activity that could account for abnormally high NE plasma levels in OI. However, 40 other OI patients did not have the same missense mutation, indicating other factors contributed to the phenotype in the identical twins. This discovery of the linkage with NET mutations that results in decreased norepinephrine

activity and orthostatic intolerance suggests faulty NE uptake mechanisms can contribute to cardiovascular disease.

Therapeutic uses

Inhibition of the norepinephrine transporter (NET) has potential therapeutic applications in the treatment of

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD),

substance abuse Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definition ...

, neurodegenerative disorders (e.g.,

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

(AD) and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

(PD)) and

clinical depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

Major depressive disorder

Certain

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

medications act to raise noradrenaline, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs),

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...

s (NRIs or NERIs) and the

tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

(TCAs). The mechanism by which these medications work is that the reuptake inhibitors prevent the reuptake of serotonin and norepinephrine by the

presynaptic neuron Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

, paralyzing the normal function of the NET. At the same time, higher levels of

5-HT Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

are maintained in the synapse increasing the concentrations of the latter neurotransmitters. Since the noradrenaline transporter is responsible for most of the dopamine clearance in the prefrontal cortex, SNRIs block reuptake of dopamine too, accumulating the dopamine in the synapse. However, DAT, the primary way dopamine is transported out of the cell, can work to decrease dopamine concentration in the synapse when the NET is blocked. For many years, the number one choice in treating mood disorders like depression was through administration of TCAs, such as

desipramine Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...

(Norpramin),

nortriptyline Nortriptyline, sold under the brand name Aventyl, among others, is a tricyclic antidepressant. This medicine is also sometimes used for neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. Its use f ...

(Arentyl, Pamelor), protriptyline (Vivactil), and

amoxapine Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCA). It is the N-demethylation, demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1980, approximat ...

(Asendin). SSRIs, which mainly regulate serotonin, subsequently replaced tricyclics as the primary treatment option for depression because of their better tolerability and lower incidence of adverse effects.Clinical Pharmacology of SSRI's: How SSRIs as a Group Differ From TCAs
Preskorn

ADHD

Many drugs exist in the treatment of ADHD.

Dextroamphetamine Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...

(Dexedrine, Dextrostat),

Adderall Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and l ...

methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

(Ritalin, Metadate, Concerta, Daytrana), and

lisdexamfetamine Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used as a treatment for attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge ...

(Vyvanse) block reabsorption of the

catecholamines A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. ...

dopamine and norepinephrine through

s (including NET), thereby increasing levels of these

neurotransmitters A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotransmitters are rele ...

in the brain. The strong

selective norepinephrine reuptake inhibitor Selective norepinephrine reuptake inhibitors (sNRIs) are a class of drugs that have been marketed as antidepressants and are used for various mental disorders, mainly depression and attention deficit hyperactivity disorder (ADHD). The norepine ...

(NRI),

atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...

(Strattera), has been approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) to treat ADHD in adults. The role of the NET in ADHD is similar to how it works to ease the symptoms of depression. The NET is blockaded by atomoxetine and increases NE levels in the brain. It can work to increase one's ability to focus, decrease any impulsiveness, and lessen hyperactivity in both children and adults with ADHD.

Psychostimulants

Cocaine

Cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

is a powerful

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

and known to be one of the most widely used substances recreationally. Cocaine is a nonselective,

reuptake inhibitor Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracel ...

of the

, and

transporters. This thwarts the absorption of these chemicals into the

presynaptic terminal Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

and allows a large concentration of dopamine, serotonin and norepinephrine to build up in the synaptic cleft. The potential for cocaine addiction is thought to be a result of its effects on

s in the CNS, while it has been suggested that the life-threatening cardiovascular effects of cocaine may involve the inhibition of NETs at sympathetic and CNS autonomic synapses.

Amphetamines

Amphetamines Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...

have an effect on

levels similar to that of

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

in that they both increase NE levels in the brain. Amphetamine-like drugs are substrates for

s, include NET, that cause a reversal in the direction of neurotransmitter transport. Amphetamines cause a large accumulation of extracellular NE. High levels of NE in the brain account for most of the profound effects of amphetamines, including alertness and anorectic, locomotor and sympathomimetic effects. However, the effects that amphetamines have on the brain are slower but last longer than the effects cocaine has on the brain.

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

(3,4-Methylenedioxymethamphetamine or "ecstasy") is an amphetamine with wide recreational use. A study reported that the NET inhibitor

reboxetine Reboxetine, sold under the brand name Edronax among others, is a selective norepinephrine reuptake inhibitor (sNRI) medication marketed as an antidepressant by Pfizer for use in the treatment of major depressive disorder, although it has also be ...

reduced the stimulant effects of MDMA in humans, demonstrating the crucial role NET has in the cardiovascular and stimulant-like effects of MDMA.

Further research

The role of the NET in many brain disorders underlies the importance of understanding the (dys)regulation of the transporter. A complete model of the proteins that associate with the transporter will be useful in designing drug therapies for diseases such as

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

affective disorder Affect, in psychology, is the underlying experience of feeling, emotion, attachment, or mood. It encompasses a wide range of emotional states and can be positive (e.g., happiness, joy, excitement) or negative (e.g., sadness, anger, fear, di ...

, and autonomic disorders. Recently discovered mechanisms of the NET, including the ability to act reversibly and as an ion channel, provide other areas of research.

Schizophrenia

The role of NE in

has not been fully understood, but has stimulated research into this topic. The only relationship that has been understood between researchers is that there is a positive correlation between increased NE levels in the brain and

spinal fluid Cerebrospinal fluid (CSF) is a clear, colorless transcellular body fluid found within the meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricles of the brain. CSF is mostly produced by specialized ependym ...

(CSF) and activity of schizophrenia. In one study,

clonidine Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic receptor agonist medication used to treat high blood pressure, attention deficit hyperactivity disorder (ADHD), drug withdrawal (e.g., alcohol, opioids, or nic ...

, a drug used to treat medical conditions such as

and high blood pressure, was shown to produce a significant decrease in plasma level

MHPG 3-Methoxy-4-hydroxyphenylglycol (MHPG, MOPEG) is a metabolite of norepinephrine degradation. In the brain, it is the principal norepinephrine metabolite. It is released into the blood and cerebrospinal fluid, and a blood sample of it may therefo ...

(3-methoxy-4-hydroxyphenylglycol), a metabolite of NE, in the normal control group, but not in the group of schizophrenic patients. This suggests that in schizophrenia, the

alpha-2 adrenergic receptor The alpha-2 (α2) adrenergic receptor (or adrenoceptor) is a G protein-coupled receptor (GPCR) associated with the Gi alpha subunit, Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-adrenergic, α2A-, ...

, a presynaptic inhibitory receptor, may be less sensitive compared to normally functioning alpha-2 receptors and thus relate to elevated NE levels in the disorder. In addition to increased NE levels in the brain and CSF, increased levels of MHPG has also been associated with a diagnosis of schizophrenia. Impaired NE regulation in schizophrenia has been an area of interest for researchers and research on this topic is still ongoing.

Imaging

Via

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

imaging technique, NET has been selectively investigated. 11C ME@HAPTHI and 18F-MeNER are two NET selective radio tracers for PET imaging. Fluorescent substrates for the transporter can also be used to monitor the transporter rate in isolated organs or tissues, although these are not suitable for clinical imaging.

Ligands and modulators

Substrates

Norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

* Substrate-type

norepinephrine releasing agent A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into ...

s (e.g.,

ephedrine Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent hypotension, low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred ...

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

) *

Catecholaminergic activity enhancer Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of drugs that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs ar ...

s (e.g.,

selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

, PPAP, BPAP) * Certain

noradrenergic neurotoxin A monoamine neurotoxin, or monoaminergic neurotoxin, is a drug that selectively damages or destroys monoaminergic neurons. Monoaminergic neurons are neurons that signal via stimulation by monoamine neurotransmitters including serotonin, dopamine ...

s (e.g., DSP-4, xylamine)

Norepinephrine reuptake inhibitors (NRIs)

Selective norepinephrine reuptake inhibitors

Ampreloxetine Ampreloxetine (, ; developmental code name TD-9855) is a binding selectivity, selective norepinephrine reuptake inhibitor (NRI) which is under development for the treatment of symptomatic neurogenic orthostatic hypotension (NOH). It shows high ...

Atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...

Nisoxetine Nisoxetine (developmental code name LY-94939), originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently ...

Reboxetine Reboxetine, sold under the brand name Edronax among others, is a selective norepinephrine reuptake inhibitor (sNRI) medication marketed as an antidepressant by Pfizer for use in the treatment of major depressive disorder, although it has also be ...

* Viloxazine

Norepinephrine–dopamine reuptake inhibitors (NDRIs)

Amineptine Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a le ...

Bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

Desoxypipradrol Desoxypipradrol, also known as 2-⁠diphenylmethylpiperidine (2-DPMP), is a drug developed by Ciba in the 1950s which acts as a norepinephrine-dopamine reuptake inhibitor (NDRI). Chemistry Desoxypipradrol is closely related on a structural lev ...

* Levophacetoperane *

Methylenedioxypyrovalerone Methylenedioxypyrovalerone (abbreviated MDPV, and also called monkey dust) is a stimulant of the cathinone class that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It was first developed in the 1960s by a team at Boehringer In ...

(MDPV) *

Methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

Nomifensine Nomifensine, formerly sold under the brand names Merital and Alival, is a norepinephrine–dopamine reuptake inhibitor (NDRI) drug that was developed in the 1960s by Hoechst AG (now Sanofi-Aventis), who then test marketed it in the United States ...

Pipradrol Pipradrol, also known by its brand name Meratran, is a mild central nervous system stimulant that acts as a norepinephrine-dopamine reuptake inhibitor. Developed in the United States in the 1940s and patented in 1953, pipradrol was initially m ...

Serdexmethylphenidate Serdexmethylphenidate is a prodrug of dexmethylphenidate created by the pharmaceutical company Zevra Therapeutics. The compound was first approved by the FDA as one of the active ingredients in Azstarys for the treatment of attention deficit h ...

Solriamfetol Solriamfetol, sold under the brand name Sunosi, is a wakefulness-promoting medication used in the treatment of excessive sleepiness related to narcolepsy and sleep apnea. It is taken by mouth. Common side effects of solriamfetol include hea ...

Serotonin–norepinephrine reuptake inhibitors (SNRIs)

* Desvenlafaxine *

Duloxetine Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive–compulsive disorder, fibromyalgia, neuropathic pain, central sensitization, and ...

Levomilnacipran Levomilnacipran, sold under the brand name Fetzima, is an antidepressant, used for the treatment of major depressive disorder in adults. It is the levorotatory enantiomer of milnacipran, and has similar effects and pharmacology, acting as a ser ...

Milnacipran Milnacipran (trade names Ixel, Savella, Dalcipran, Toledomin) is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia, Major depressive disorder, and Neuropathic pain. In the US, it is solely appr ...

Sibutramine Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. It works as a serotonin–norepinephrine reuptake inhibitor (SNRI) similar to certain antidepressant ...

Venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...

Non-selective norepinephrine reuptake inhibitors

Amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, and a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headac ...

Amoxapine Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCA). It is the N-demethylation, demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1980, approximat ...

Clomipramine Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyper ...

Desipramine Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...

Imipramine Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth. Common s ...

* Indeloxazine *

Maprotiline Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression (mood), depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specific ...

Mazindol Mazindol, sold under the brand names Mazanor and Sanorex, is a central nervous system (CNS) stimulant which is used as an appetite suppressant. It was developed by Sandoz Laboratories, Sandoz-Wander in the 1960s. The US Food and Drug Administrat ...

Mianserin Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant that is used primarily in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant (TeCA). Mianserin is closel ...

Nortriptyline Nortriptyline, sold under the brand name Aventyl, among others, is a tricyclic antidepressant. This medicine is also sometimes used for neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. Its use f ...

Protriptyline Protriptyline, sold under the brand name Vivactil among others, is a tricyclic antidepressant (TCA), specifically a secondary amine. Uniquely among most of the TCAs, protriptyline tends to be energizing instead of sedating, and is sometimes use ...

Setiptiline Setiptiline (brand name Tecipul), also known as teciptiline, is a tetracyclic antidepressant (TeCA) that acts as a noradrenergic and specific serotonergic antidepressant (NaSSA). It was launched in 1989 for the treatment of depression in Japan ...

Tapentadol Tapentadol, sold under the brand names Nucynta and Palexia among others, is a synthetic opioid analgesic with a dual mode of action as a highly selective full agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI). T ...

* Teniloxazine *

Tramadol Tramadol, sold under the brand name Tramal among others, is an opioid analgesic, pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release form ...

Norepinephrine releasing agents (NRAs)

Aminorex Aminorex, sold under the brand names Menocil and Apiquel among others, is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension (PPH). In the United States, aminorex is a ...

Amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

Benzylpiperazine Benzylpiperazine (BZP) is a substance often used as a recreational drug and is known to have euphoriant and stimulant properties. Several studies conducted between 2000 and 2011 found that the effects of BZP are similar to amphetamine, although ...

Cathinone Cathinone (; also known as β-ketoamphetamine) is a monoamine alkaloid found in the shrub ''Catha edulis'' (khat) and is chemically similar to ephedrine, cathine, methcathinone and other amphetamines. It is probably the main contributor to t ...

Ephedrine Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent hypotension, low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred ...

Lisdexamfetamine Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used as a treatment for attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge ...

Mephedrone Mephedrone, also known as , , and , is a synthetic stimulant drug belonging to the amphetamine and cathinone classes. It is commonly referred to by slang names such as drone, , white magic, meow meow, and bubble. Chemically, it is similar to ...

Methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

Methylenedioxymethamphetamine 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor psychedelic properties. In studies, it has been used alongside psych ...

(MDMA) *

Methylone Methylone, also known as 3,4-methylenedioxy-''N''-methylcathinone (MDMC), is an entactogen and stimulant drug of the amphetamine, cathinone, and benzodioxole families related to 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"). It is th ...

Octopamine Octopamine (OA), also known as ''para''-octopamine and norsynephrine among synonyms, is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is often considered the major "fig ...

Phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

Phenmetrazine Phenmetrazine, sold under the brand name Preludin among others, is a stimulant drug first chemical synthesis, synthesized in 1952 and originally used as an appetite suppressant, but withdrawn drug, withdrawn from the market in the 1980s due to ...

Phentermine Phentermine, sold under the brand name Adipex-P among others, is a medication used together with diet and exercise to treat obesity. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken by mouth. Com ...

Phenylpropanolamine Phenylpropanolamine (PPA), sold under many brand names, is a sympathomimetic agent used as a decongestant and appetite suppressant. It was once common in prescription and over-the-counter cough and cold preparations. The medication is taken ...

Pseudoephedrine Pseudoephedrine, sold under the brand name Sudafed among others, is a sympathomimetic medication which is used as a decongestant to treat nasal congestion. It has also been used off-label for certain other indications, like treatment of lo ...

Tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the bl ...

References

External links

* {{DEFAULTSORT:Norepinephrine Transporter Amphetamine Membrane proteins Neurotransmitter transporters Norepinephrine Solute carrier family