Norepinephrine transporter

The norepinephrine transporter gene, SLC6A2 is located on human chromosome 16 locus 16q12.2. This gene is encoded by 14 exons. 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 and GABA transporters.

A single-nucleotide polymorphism (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) could potentially be associated with various diseases that involve abnormally high or low plasma levels of norepinephrine 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{{cite journal | vauthors = Kim CH, Hahn MK, Joung Y, Anderson SL, Steele AH, Mazei-Robinson MS, Gizer I, Teicher MH, Cohen BM, Robertson D, Waldman ID, Blakely RD, Kim KS | title = A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 50 | pages = 19164–9 | date = Dec 2006 | pmid = 17146058 | pmc = 1748193 | doi = 10.1073/pnas.0510836103 | bibcode = 2006PNAS..10319164K | doi-access = free }} psychiatric disorders, postural tachycardia{{cite journal | vauthors = Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, Robertson D | title = Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency | journal = The New England Journal of Medicine | volume = 342 | issue = 8 | pages = 541–9 | date = Feb 2000 | pmid = 10684912 | doi = 10.1056/NEJM200002243420803 | doi-access = free }} and orthostatic intolerance. The SNPs rs3785143 and rs11568324 have been related to attention-deficit hyperactivity disorder.{{cite journal | vauthors = Kim JW, Biederman J, McGrath CL, Doyle AE, Mick E, Fagerness J, Purcell S, Smoller JW, Sklar P, Faraone SV | title = Further evidence of association between two NET single-nucleotide polymorphisms with ADHD | journal = Molecular Psychiatry | volume = 13 | issue = 6 | pages = 624–30 | date = Jun 2008 | pmid = 17876324 | doi = 10.1038/sj.mp.4002090 | s2cid = 8341997 }} Thus far, however, the only confirmed direct association between a SNP and a clinical condition is that of the SNP, Ala457Pro, and orthostatic intolerance. Thirteen NET missense mutations have been discovered so far.

An epigenetic 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 and panic disorder.{{cite journal | vauthors = Esler M, Alvarenga M, Pier C, Richards J, El-Osta A, Barton D, Haikerwal D, Kaye D, Schlaich M, Guo L, Jennings G, Socratous F, Lambert G | title = The neuronal noradrenaline transporter, anxiety and cardiovascular disease | journal = Journal of Psychopharmacology | volume = 20 | issue = 4 Suppl | pages = 60–6 | date = Jul 2006 | pmid = 16785272 | doi = 10.1177/1359786806066055 | s2cid = 10728780 }}

rs5569 is a variant of SLC6A2.[https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?chooseRs=het&locusId=6530&mrna=NM_001043.2&ctg=NT_010498.15&prot=NP_001034.1&orien=forward&refresh=refresh dbSNP]

File:NET structure picture.png

The norepinephrine transporter is composed of 12 transmembrane domains (TMDs). The intracellular portion contains an amino (-{{chem|NH|2}}) group and carboxyl (-COOH) group. In addition, there is a large extracellular loop located between TMD 3 and 4.{{cite journal | vauthors = Stöber G, Nöthen MM, Pörzgen P, Brüss M, Bönisch H, Knapp M, Beckmann H, Propping P | title = Systematic search for variation in the human norepinephrine transporter gene: identification of five naturally occurring missense mutations and study of association with major psychiatric disorders | journal = American Journal of Medical Genetics | volume = 67 | issue = 6 | pages = 523–32 | date = Nov 1996 | pmid = 8950409 | doi = 10.1002/(SICI)1096-8628(19961122)67:6<523::AID-AJMG3>3.0.CO;2-I }}{{cite journal | vauthors = Schroeter S, Apparsundaram S, Wiley RG, Miner LH, Sesack SR, Blakely RD | title = Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter | journal = The Journal of Comparative Neurology | volume = 420 | issue = 2 | pages = 211–32 | date = May 2000 | pmid = 10753308 | doi = 10.1002/(SICI)1096-9861(20000501)420:2<211::AID-CNE5>3.0.CO;2-3 | s2cid = 24643588 }}{{cite journal | vauthors = Sager JJ, Torres GE | title = Proteins interacting with monoamine transporters: current state and future challenges | journal = Biochemistry | volume = 50 | issue = 34 | pages = 7295–310 | date = Aug 2011 | pmid = 21797260 | doi = 10.1021/bi200405c }} The protein is composed of 617 amino acids.

NET functions to transport synaptically released norepinephrine 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.{{cite journal | vauthors = Galli A, DeFelice LJ, Duke BJ, Moore KR, Blakely RD | title = Sodium-dependent norepinephrine-induced currents in norepinephrine-transporter-transfected HEK-293 cells blocked by cocaine and antidepressants | journal = The Journal of Experimental Biology | volume = 198 | issue = Pt 10 | pages = 2197–212 | date = Oct 1995 | doi = 10.1242/jeb.198.10.2197 | pmid = 7500004 }} Both the NET and the dopamine transporter (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.{{cite journal | vauthors = Torres GE, Gainetdinov RR, Caron MG | title = Plasma membrane monoamine transporters: structure, regulation and function | journal = Nature Reviews. Neuroscience | volume = 4 | issue = 1 | pages = 13–25 | date = Jan 2003 | pmid = 12511858 | doi = 10.1038/nrn1008 | s2cid = 21545649 }}

File:Norepinephrine.svg

Norepinephrine (NE) is released from noradrenergic 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.{{cite journal | vauthors = Zhou J | title = Norepinephrine transporter inhibitors and their therapeutic potential | journal = Drugs of the Future | volume = 29 | issue = 12 | pages = 1235–1244 | date = Dec 2004 | pmid = 16871320 | pmc = 1518795 | doi = 10.1358/dof.2004.029.12.855246 }} 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.

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

NETs are restricted to noradrenergic neurons and are not present on neurons that release dopamine or epinephrine. The transporters can be found along the cell body, axons, and dendrites 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 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 (PKC). PKC has been shown to inhibit NET function by sequestration of the transporter from the plasma membrane.{{cite journal | vauthors = Gether U, Andersen PH, Larsson OM, Schousboe A | title = Neurotransmitter transporters: molecular function of important drug targets | journal = Trends in Pharmacological Sciences | volume = 27 | issue = 7 | pages = 375–83 | date = Jul 2006 | pmid = 16762425 | doi = 10.1016/j.tips.2006.05.003 }} 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.

{{Main|Orthostatic intolerance}}

Orthostatic intolerance (OI) is a disorder of the autonomic nervous system (a subcategory of dysautonomia) characterized by the onset of symptoms upon standing. Symptoms include fatigue, lightheadedness, headache, weakness, increased heart rate/heart palpitations, anxiety, and altered vision. Often, patients have high plasma norepinephrine (NE) concentrations (at least 600 pg/ml) in relation to sympathetic outflow upon standing, suggesting OI is a hyperadrenergic condition.

The discovery of identical twin sisters who both had OI suggested a genetic basis for the disorder. A missense mutation on the NET gene (SLC6A2) was discovered in which an alanine residue was replaced with a proline residue (Ala457Pro) in a highly conserved region of the transporter. The patients’ defective NET had only 2% of the activity of the wild-type 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 reuptake activity and orthostatic intolerance suggests faulty NE uptake mechanisms can contribute to cardiovascular disease.{{cite journal | vauthors = Schroeder C, Tank J, Boschmann M, Diedrich A, Sharma AM, Biaggioni I, Luft FC, Jordan J | title = Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance | journal = Circulation | volume = 105 | issue = 3 | pages = 347–53 | date = Jan 2002 | pmid = 11804991 | doi = 10.1161/hc0302.102597 | doi-access = free }}

Inhibition of the norepinephrine transporter (NET) has potential therapeutic applications in the treatment of attention deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD)) and clinical depression.

{{Main|Major depressive disorder}}

File:Amineptine.svg, an NDRI tricyclic antidepressant]]

File:Fluoxetine-2D-skeletal.svg, a selective serotonin reuptake inhibitor]]

Certain antidepressant medications act to raise noradrenaline, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRIs), norepinephrine reuptake inhibitors (NRIs or NERIs) and the tricyclic antidepressants (TCAs). The mechanism by which these medications work is that the reuptake inhibitors prevent the reuptake of serotonin and norepinephrine by the presynaptic neuron, paralyzing the normal function of the NET. At the same time, higher levels of 5-HT 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,{{cite journal | vauthors = Morón JA, Brockington A, Wise RA, Rocha BA, Hope BT | title = Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines | journal = The Journal of Neuroscience | volume = 22 | issue = 2 | pages = 389–95 | date = Jan 2002 | pmid = 11784783 | doi =10.1523/JNEUROSCI.22-02-00389.2002| pmc = 6758674 }} 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.{{cite journal | vauthors = Yavich L, Forsberg MM, Karayiorgou M, Gogos JA, Männistö PT | title = Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum | journal = The Journal of Neuroscience | volume = 27 | issue = 38 | pages = 10196–209 | date = Sep 2007 | pmid = 17881525 | doi = 10.1523/JNEUROSCI.0665-07.2007 | pmc = 6672678 }} For many years, the number one choice in treating mood disorders like depression was through administration of TCAs, such as desipramine (Norpramin), nortriptyline (Arentyl, Pamelor), protriptyline (Vivactil), and amoxapine (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.[http://www.preskorn.com/books/ssri_s4.html Clinical Pharmacology of SSRI's: How SSRIs as a Group Differ From TCAs], Preskorn

{{Main|ADHD}}

File:Atomoxetine structure.svg, an NET inhibitor marketed as Strattera]]

Many drugs exist in the treatment of ADHD. Dextroamphetamine (Dexedrine, Dextrostat), Adderall, methylphenidate (Ritalin, Metadate, Concerta, Daytrana), and lisdexamfetamine (Vyvanse) block reabsorption of the catecholamines dopamine and norepinephrine through monoamine transporters (including NET), thereby increasing levels of these neurotransmitters in the brain. The strong selective norepinephrine reuptake inhibitor (NRI), atomoxetine (Strattera), has been approved by the U.S. Food and Drug Administration (FDA) to treat ADHD in adults.{{cite web | url = http://www.nimh.nih.gov/health/publications/mental-health-medications/what-medications-are-used-to-treat-adhd.shtml | title =What medications are used to treat ADHD? | publisher = National Institutes of Mental Health }}{{cite journal | vauthors = Simpson D, Plosker GL | title = Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder | journal = Drugs | volume = 64 | issue = 2 | pages = 205–22 | year = 2004 | pmid = 14717619 | doi = 10.2165/00003495-200464020-00005 | s2cid = 195692609 }} 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.{{cite web | url = https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000222/ | title = Atomoxetine -| work = PubMed Health | access-date = 2 November 2011 }}

{{Main|Cocaine}}

Cocaine is a powerful psychostimulant and known to be one of the most widely used substances recreationally.{{cite journal | vauthors = Macey DJ, Smith HR, Nader MA, Porrino LJ | title = Chronic cocaine self-administration upregulates the norepinephrine transporter and alters functional activity in the bed nucleus of the stria terminalis of the rhesus monkey | journal = The Journal of Neuroscience | volume = 23 | issue = 1 | pages = 12–6 | date = Jan 2003 | pmid = 12514195 | doi =10.1523/JNEUROSCI.23-01-00012.2003| pmc = 6742134 }} Cocaine is a nonselective, reuptake inhibitor of the norepinephrine, serotonin, and dopamine transporters. This thwarts the absorption of these chemicals into the presynaptic terminal 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 dopamine transporters 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.{{cite book |veditors=Kupfer DJ, Bloom FE | title = Psychopharmacology: the fourth generation of progress | publisher = Raven Press | location = New York | year = 1995 | isbn = 978-0-7817-0166-2 | chapter = Norepinephrine and Serotonin Transporters |vauthors=Barker EL, Blakely RD | chapter-url = http://www.acnp.org/g4/GN401000029/CH029.html | access-date = 2 November 2011 }}

{{Main|Amphetamine}}

File:MDMA.svg or "ecstasy"]]

Amphetamines have an effect on norepinephrine levels similar to that of cocaine in that they both increase NE levels in the brain.{{Cite web

| last = Drug and Human Performance Fact Sheets

| title = Methamphetamine (And Amphetamine)

| url = http://www.nhtsa.gov/people/injury/research/job185drugs/methamphetamine.htm

| access-date = 1 November 2011

| archive-url = https://web.archive.org/web/20111031071612/http://www.nhtsa.gov/people/injury/research/job185drugs/methamphetamine.htm

| archive-date = 31 October 2011

| url-status = dead

}} Amphetamine-like drugs are substrates for monoamine transporters, include NET, that cause a reversal in the direction of neurotransmitter transport.{{cite journal | vauthors = Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A | title = Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport | journal = The Journal of Neuroscience | volume = 15 | issue = 5 Pt 2 | pages = 4102–8 | date = May 1995 | pmid = 7751968 | doi =10.1523/JNEUROSCI.15-05-04102.1995| pmc = 6578196 }} 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 or "ecstasy") is an amphetamine with wide recreational use. A study reported that the NET inhibitor reboxetine reduced the stimulant effects of MDMA in humans, demonstrating the crucial role NET has in the cardiovascular and stimulant-like effects of MDMA.{{cite journal | vauthors = Hysek CM, Simmler LD, Ineichen M, Grouzmann E, Hoener MC, Brenneisen R, Huwyler J, Liechti ME | title = The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA ("ecstasy") in humans | journal = Clinical Pharmacology and Therapeutics | volume = 90 | issue = 2 | pages = 246–55 | date = Aug 2011 | pmid = 21677639 | doi = 10.1038/clpt.2011.78 | s2cid = 29087593 }}

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, affective disorder, 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.

{{Main|Schizophrenia}}

File:MHPG.png (MHPG), a metabolite of NE. Abnormally high levels of MHPG are also indicative of impaired NE regulation.]]

The role of NE in schizophrenia has not been fully understood, but has stimulated research into this topic.{{Cite web

| last = Decaire

| first = Michael

| title = The neurophysiology of schizophrenia: Etiology and Psychopharmacological treatment

| url = http://www.uplink.com.au/lawlibrary/Documents/Docs/Doc25.html

| access-date = 1 November 2011

| archive-url = https://web.archive.org/web/20120217001612/http://www.uplink.com.au/lawlibrary/Documents/Docs/Doc25.html

| archive-date = 17 February 2012

| url-status = dead

}}{{cite journal | vauthors = Breier A, Wolkowitz OM, Roy A, Potter WZ, Pickar D | title = Plasma norepinephrine in chronic schizophrenia | journal = The American Journal of Psychiatry | volume = 147 | issue = 11 | pages = 1467–70 | date = Nov 1990 | pmid = 2221157 | doi = 10.1176/ajp.147.11.1467 }}{{cite journal | vauthors = Sternberg DE, Charney DS, Heninger GR, Leckman JF, Hafstad KM, Landis DH | title = Impaired presynaptic regulation of norepinephrine in schizophrenia. Effects of clonidine in schizophrenic patients and normal controls | journal = Archives of General Psychiatry | volume = 39 | issue = 3 | pages = 285–9 | date = Mar 1982 | pmid = 6279049 | doi = 10.1001/archpsyc.1982.04290030025004 }}{{cite journal | vauthors = van Kammen DP, Antelman S | title = Impaired noradrenergic transmission in schizophrenia? | journal = Life Sciences | volume = 34 | issue = 15 | pages = 1403–13 | date = Apr 1984 | pmid = 6323903 | doi = 10.1016/0024-3205(84)90054-7 }} 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 (CSF) and activity of schizophrenia. In one study, clonidine, a drug used to treat medical conditions such as ADHD and high blood pressure, was shown to produce a significant decrease in plasma level MHPG (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, 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.

Via positron emission tomography imaging technique, NET has been selectively investigated. 11C ME@HAPTHI and 18F-MeNER are two NET selective radio tracers for PET imaging.{{cite journal | vauthors = Rami-Mark C, Berroterán-Infante N, Philippe C, Foltin S, Vraka C, Hoepping A, Lanzenberger R, Hacker M, Mitterhauser M, Wadsak W | display-authors = 6 | title = Radiosynthesis and first preclinical evaluation of the novel norepinephrine transporter pet-ligand [(11)C]ME@HAPTHI | journal = EJNMMI Research | volume = 5 | issue = 1 | pages = 113 | date = December 2015 | pmid = 26061602 | pmc = 4467816 | doi = 10.1186/s13550-015-0113-3 | doi-access = free }} Fluorescent substrates for the transporter can also be used to monitor the transporter rate in isolated organs or tissues,{{cite journal | vauthors = Cao LL, Holmes AP, Marshall JM, Fabritz L, Brain KL | title = Dynamic monitoring of single-terminal norepinephrine transporter rate in the rodent cardiovascular system: A novel fluorescence imaging method | journal = Autonomic Neuroscience | volume = 223 | pages = 102611 | date = January 2020 | pmid = 31901784 | doi = 10.1016/j.autneu.2019.102611 | pmc = 6977090 }}{{cite journal | vauthors = Parker LK, Shanks JA, Kennard JA, Brain KL | title = Dynamic monitoring of NET activity in mature murine sympathetic terminals using a fluorescent substrate | journal = British Journal of Pharmacology | volume = 159 | issue = 4 | pages = 797–807 | date = February 2010 | pmid = 20136837 | doi = 10.1111/j.1476-5381.2009.00574.x | pmc = 2829205 }} although these are not suitable for clinical imaging.

• Norepinephrine
• Substrate-type norepinephrine releasing agents (e.g., ephedrine, amphetamine)
• Catecholaminergic activity enhancers (e.g., selegiline, PPAP, BPAP)
• Certain noradrenergic neurotoxins (e.g., DSP-4, xylamine)

{{Main|Norepinephrine reuptake inhibitor}}

• Ampreloxetine
• Atomoxetine
• Nisoxetine
• Reboxetine
• Viloxazine

{{Main|Norepinephrine–dopamine reuptake inhibitor}}

• Amineptine
• Bupropion
• Desoxypipradrol
• Levophacetoperane
• Methylenedioxypyrovalerone (MDPV)
• Methylphenidate
• Nomifensine
• Pipradrol
• Serdexmethylphenidate
• Solriamfetol

{{Main|Serotonin–norepinephrine reuptake inhibitor}}

• Desvenlafaxine
• Duloxetine
• Levomilnacipran
• Milnacipran
• Sibutramine
• Venlafaxine

{{See also|Tricyclic antidepressant|Tetracyclic antidepressant}}

• Amitriptyline
• Amoxapine
• Clomipramine
• Cocaine
• Desipramine
• Imipramine
• Indeloxazine
• Maprotiline
• Mazindol
• Mianserin
• Nortriptyline
• Protriptyline
• Setiptiline
• Tapentadol
• Teniloxazine
• Tramadol

{{Main|Norepinephrine releasing agent|Norepinephrine–dopamine releasing agent}}

• Aminorex
• Amphetamine
• Benzylpiperazine
• Cathinone
• Ephedrine
• Lisdexamfetamine
• Mephedrone
• Methamphetamine
• Methylenedioxymethamphetamine (MDMA)
• Methylone
• Octopamine
• Phenethylamine
• Phenmetrazine
• Phentermine
• Phenylpropanolamine
• Pseudoephedrine
• Tyramine

• Neurotransmitter transporter
• Sodium:neurotransmitter symporter
• Solute carrier family
• Norepinephrine
• Monoamine transporter
• Orthostatic intolerance
• Single-nucleotide polymorphisms

{{Reflist|colwidth=35em}}

• {{MeshName|Norepinephrine+transporter}}

{{Membrane transport proteins|bg|bg0}}

{{Neurotransmitter transporters}}

{{Monoamine reuptake inhibitors}}

{{Monoamine releasing agents}}

{{Amphetamine}}

{{DEFAULTSORT:Norepinephrine Transporter}}

Category:Amphetamine

Category:Membrane proteins

Category:Neurotransmitter transporters

Category:Norepinephrine

Category:Solute carrier family