View source for Norepinephrine transporter

{{Use dmy dates|date=March 2014}}
{{Infobox gene}}

The '''norepinephrine transporter''' ('''NET'''), also known as '''solute carrier family 6 member 2''' ('''SLC6A2'''), is a [[protein]] that in humans is encoded by the ''SLC6A2'' [[gene]].<ref name="pmid2008212">{{cite journal | vauthors = Pacholczyk T, Blakely RD, Amara SG | title = Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter | journal = Nature | volume = 350 | issue = 6316 | pages = 350–4 | date = Mar 1991 | pmid = 2008212 | doi = 10.1038/350350a0 }}</ref>

NET is a [[monoamine transporter]] and is responsible for the sodium-chloride (Na<sup>+</sup>/Cl<sup>−</sup>)-dependent [[reuptake]] of extracellular [[norepinephrine]] (NE), which is also known as noradrenaline. NET can also reuptake extracellular [[dopamine]] (DA). The reuptake of these two [[neurotransmitter]]s is essential in regulating concentrations in the [[synaptic cleft]]. NETs, along with the other monoamine transporters, are the targets of many antidepressants and recreational drugs. In addition, an overabundance of NET is associated with [[ADHD]].<ref name="Schroeter"/><ref name="pmid14987367">{{cite journal | vauthors = Tellioglu T, Robertson D | title = Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications | journal = Expert Reviews in Molecular Medicine | volume = 2001 | issue = 29 | pages = 1–10 | date = Nov 2001 | pmid = 14987367 | doi = 10.1017/S1462399401003878 }}</ref> There is evidence that [[single-nucleotide polymorphisms]] in the NET gene (''SLC6A2'') may be an underlying factor in some of these disorders.<ref name="pmid14987367"/>

==Gene==
The norepinephrine transporter gene, SLC6A2 is located on human [[chromosome 16]] locus 16q12.2. This gene is encoded by 14 [[exon]]s.<ref name="pmid14987367"/> 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 transporter 1|GABA transporters]].<ref name="pmid14987367"/>

===Single nucleotide polymorphisms===
A [[single-nucleotide polymorphism]] (SNP) is a genetic variation in which a genome sequence is altered by a single nucleotide ([[adenine|A]], [[thymine|T]], [[cytosine|C]] or [[guanine|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<ref name="pmid14987367"/><ref name="pmid17146058">{{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 }}</ref> psychiatric disorders,<ref name="pmid14987367"/> [[Postural orthostatic tachycardia syndrome|postural tachycardia]]<ref name="pmid14987367"/><ref name="pmid10684912">{{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 }}</ref> and [[orthostatic intolerance]].<ref name="pmid14987367"/><ref name="pmid10684912" /> The SNPs rs3785143 and rs11568324 have been related to [[attention-deficit hyperactivity disorder]].<ref name="pmid17876324">{{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 }}</ref> Thus far, however, the only confirmed direct association between a SNP and a clinical condition is that of the SNP, Ala457Pro, and [[#Orthostatic intolerance|orthostatic intolerance]].<ref name="pmid14987367"/> Thirteen NET missense mutations have been discovered so far.<ref name="pmid14987367"/>

{| style="text-align:center; font-size:100%; margin-left:2em; margin:auto;" class="wikitable"
|+ Missense Mutations in the NET Gene<ref name="pmid14987367"/><ref name="Reith2002">{{cite book|author=Maarten E. A. Reith|title=Neurotransmitter transporters: structure, function, and regulation|url=https://books.google.com/books?id=tp8vVbk-2IMC&pg=PA120|accessdate=27 October 2011|year=2002|publisher=Humana Press|isbn=978-0-89603-945-2|page=120}}</ref>
|-
! Location !! Amino Acid Variant !! TMD (if known) !! Related Disease
|-
| Exon 2 || Val69Ile || TMD 1 || None
|-
| Exon 3 || Thr99Ile || TMD 2 || None
|-
| Exon 5 || Val245Ile || TMD 4 || None
|-
| Exon 6 || Asn292Thr || n/a || None
|-
| Exon 8 || Val356Leu || n/a || None
|-
| Exon 8 || Ala369Pro || n/a || None
|-
| Exon 8 || Asn375Ser || n/a || None
|-
| Exon 10 || Val449Ile || TMD 9 || None
|-
| Exon 10 || Ala457Pro || TMD 9 || [[Orthostatic intolerance]]
|-
| Exon 10 || Lys463Arg || n/a || None
|-
| Exon 11|| Gly478Ser || TMD 10 || None
|-
| Exon 12 || Phe528Cys || n/a || None
|-
| Exon 13 || Tyr548His || n/a || None
|}
<div style="text-align: center; font-size:90%">
Abbreviations: TMD, [[transmembrane domain]]; n/a, non-applicable. <br />For the table above, refer to this table of standard [[Amino acid#Table of standard amino acid abbreviations and properties|amino acid abbreviations]]. This notation for <br />missense mutations, take Val69Ile for example, indicates that amino acid Val69 was changed to Ile. </div>

===Genetic variations===
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]].<ref>{{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 }}</ref>

==Structure==
[[File:NET structure picture.png|thumb|Simplified structure of the norepinephrine transporter protein.]]

The norepinephrine transporter is composed of 12 [[transmembrane domain]]s (TMDs). The intracellular portion contains an [[amine|amino]] (-{{chem|NH|2}}) group and [[carboxylic acid|carboxyl]] (-COOH) group. In addition, there is a large extracellular loop located between TMD 3 and 4.<ref name="Stober">{{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 }}</ref><ref name="Schroeter">{{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 }}</ref><ref name="Sager">{{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 }}</ref> The protein is composed of 617 [[amino acid]]s.<ref name=Stober />

==Function==
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<sup>+</sup>/Cl<sup>−</sup>) with the transport of norepinephrine. This occurs at a fixed ratio of 1:1:1.<ref name="Galli">{{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 | pmid = 7500004 | doi =}}</ref> 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.<ref name="Torres">{{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 }}</ref>

[[File:Norepinephrine structure.svg|thumb|Norepinephrine structure]]

Norepinephrine (NE) is released from [[norepinephrine|noradrenergic]] neurons that innervate both the [[Central nervous system|CNS]] and [[Peripheral nervous system|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]].<ref name=Schroeter /><ref name="pmid16871320">{{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 }}</ref> 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.<ref name=Stober />

==Transport mechanisms==
The transport of norepinephrine back into presynaptic cell is made possible by the cotransport with Na<sup>+</sup> and Cl<sup>−</sup>. The sequential binding of the ions results in the eventual reuptake of norepinephrine. The ion gradients of Na<sup>+</sup> and Cl<sup>−</sup> 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.<ref name=Torres /> NETs have conductances similar to those of [[ligand-gated ion channel]]s. The expression of NET results in a leak-channel activity.<ref name=Galli /><ref name=Torres />

==Location in the nervous system==
NETs are restricted to [[norepinephrine|noradrenergic]] neurons and are not present on neurons that release dopamine or epinephrine.<ref name=Schroeter /><ref name=Sager /><ref name=Torres /> The transporters can be found along the cell body, [[axon]]s, and [[dendrite]]s of the neuron.<ref name=Schroeter /> 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.<ref name=Torres /> Norepinephrine transporters are confined to the neurons of the sympathetic system, and those innervating the adrenal medulla, lung, and placenta.<ref name=Torres />

==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]] (PKC).<ref name=Sager /> PKC has been shown to inhibit NET function by sequestration of the transporter from the plasma membrane.<ref name="Gether">{{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 }}</ref> The amino acid sequence of NET has shown multiple sites related to protein kinase phosphorylation.<ref name=Torres /> 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.<ref name=Gether />

==Clinical significance==

===Orthostatic intolerance===
{{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.<ref name="pmid14987367"/> Often, patients have high plasma [[norepinephrine]] (NE) concentrations (at least 600 pg/ml) in relation to sympathetic outflow upon standing, suggesting OI is a hyper[[adrenergic]] condition.<ref name="pmid14987367"/><ref name="pmid10684912"/>
The discovery of identical twin sisters both suffering from OI suggested a genetic basis for the disorder.<ref name="pmid14987367"/><ref name="pmid10684912"/> 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.<ref name="pmid14987367"/> The patients’ defective NET had only 2% of the activity of the [[wild type|wild-type]] version of the gene.<ref name="pmid14987367"/> 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.<ref name="pmid14987367"/> 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.<ref name="pmid11804991">{{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 }}</ref>

==Therapeutic uses==
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]].<ref name="pmid16871320"/>

===Major depressive disorder===
{{Main|Major depressive disorder}}
[[File:Amineptine.gif|thumb|[[Amineptine]], an [[Norepinephrine-dopamine reuptake inhibitor|NDRI]] [[tricyclic antidepressant]]]]
[[File:Fluoxetine-2D-skeletal.svg|thumb|[[Fluoxetine]], a [[selective serotonin reuptake inhibitor]]]]

Certain [[antidepressant]] medications act to raise noradrenaline, such as [[serotonin–norepinephrine reuptake inhibitor|serotonin-norepinephrine reuptake inhibitors]] (SNRIs), [[norepinephrine-dopamine reuptake inhibitor]]s (NDRIs), [[norepinephrine reuptake inhibitor]]s (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,<ref name="pmid11784783">{{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 =}}</ref> 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.<ref name="pmid17881525">{{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 }}</ref> 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).<ref name="pmid16871320"/> 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.<ref name="Preskorn - Applied Clinical Pharmacology">[http://www.preskorn.com/books/ssri_s4.html Clinical Pharmacology of SSRI's: How SSRIs as a Group Differ From TCAs], Preskorn</ref>

===ADHD===
{{Main|ADHD}}
[[File:Atomoxetine structure.svg|thumb|[[Atomoxetine]], 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 transporter]]s (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.<ref name = "NIMH">{{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 | work = | accessdate = }}</ref><ref name="pmid14717619">{{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 }}</ref> 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 who suffer from ADHD.<ref name="urlAtomoxetine - PubMed Health">{{cite web | url = https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000222/ | title = Atomoxetine -| date = | format = | work = PubMed Health | publisher = | pages = | archiveurl = | archivedate = | quote = | accessdate = 2 November 2011 }}</ref>

==Psychostimulants==

===Cocaine===
{{Main|Cocaine}}

[[Cocaine]] is a powerful [[psychostimulant]] and known to be one of the most widely abused substances.<ref name="Macey">{{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 =}}</ref> Cocaine is a nonselective, [[reuptake inhibitor]] of the [[norepinephrine]], [[serotonin]], and [[dopamine]] transporters. This thwarts the absorption of these chemicals into the [[presynaptic terminal]]<ref name="Macey"/> 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 transporter]]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.<ref name="isbn0-7817-0166-X">{{cite book |veditors=Kupfer DJ, Bloom FE | title = Psychopharmacology: the fourth generation of progress | publisher = Raven Press | location = New York | year = 1995 | pages = | isbn = 0-7817-0166-X | chapter = Norepinephrine and Serotonin Transporters |vauthors=Barker EL, Blakely RD | url = http://www.acnp.org/g4/GN401000029/CH029.html | accessdate = 2 November 2011 }}</ref>

===Amphetamines===
{{Main|Amphetamine}}
[[File:MDMA.svg|thumb|The chemical structure of [[MDMA]] or "ecstasy"]]

[[Amphetamines]] have an effect on [[norepinephrine]] levels similar to that of [[cocaine]] in that they both increase NE levels in the brain.<ref name = "Drug Sheet" >{{Cite web
| last = Drug and Human Performance Fact Sheets
| title = Methamphetamine (And Amphetamine)
| url=http://www.nhtsa.gov/people/injury/research/job185drugs/methamphetamine.htm
| accessdate = 1 November 2011
| postscript = <!-- Bot inserted parameter. Either remove it; or change its value to "." for the cite to end in a ".", as necessary. -->{{inconsistent citations}} }}</ref> Amphetamine-like drugs are substrates for [[monoamine transporter]]s, include NET, that cause a reversal in the direction of neurotransmitter transport.<ref name="Torres" /><ref name="pmid7751968">{{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 =}}</ref> Amphetamines cause a large accumulation of extracellular NE.<ref name = "Drug Sheet" /> High levels of NE in the brain account for most of the profound effects of amphetamines, including alertness and anorectic, locomotor and sympathomimetic effects.<ref name = "Drug Sheet" /> However, the effects that amphetamines have on the brain are slower but last longer than the effects cocaine has on the brain.<ref name = "Drug Sheet" /> [[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.<ref name="pmid21677639">{{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 }}</ref>

==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]], [[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.<ref name=Sager /><ref name=Torres />

===Schizophrenia===
{{Main|Schizophrenia}}
[[File:MHPG.png|thumb|Chemical structure of [[3-methoxy-4-hydroxyphenylglycol]] (MHPG), a metabolite of [[Norepinephrine|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.<ref name = "Decaire">{{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
| accessdate = 1 November 2011
| postscript = <!-- Bot inserted parameter. Either remove it; or change its value to "." for the cite to end in a ".", as necessary. -->{{inconsistent citations}}}}</ref><ref name = "Breier">{{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 }}</ref><ref name = "Sternberg">{{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 }}</ref><ref name = "Kammen">{{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 }}</ref> The only relationship that has been understood between researchers is that there is a positive correlation between increased NE levels in the brain and [[Cerebrospinal fluid|spinal fluid]] (CSF) and activity of schizophrenia.<ref name = "Decaire"/><ref name = "Breier"/><ref name = "Sternberg"/><ref name = "Kammen"/> 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 [[3-methoxy-4-hydroxyphenylglycol|MHPG]] (3-methoxy-4-hydroxyphenylglycol), a metabolite of NE, in the normal control group, but not in the group of schizophrenic patients.<ref name = "Sternberg"/> 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.<ref name = "Sternberg"/> In addition to increased NE levels in the brain and CSF, increased levels of MHPG has also been associated with a diagnosis of schizophrenia.<ref name = "Kammen"/> Impaired NE regulation in schizophrenia has been an area of interest for researchers and research on this topic is still ongoing.<ref name = "Sternberg"/><ref name = "Kammen"/>

==Imaging==
Via [[positron emission tomography]] imaging technique, NET has been selectively investigated. [[11C ME@HAPTHI]] and [[18F-MeNER]] are two NET selective [[radio tracer]]s for PET imaging.<ref name="Wadsak">{{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 | 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 = Dec 2015 | pmid = 26061602 | doi = 10.1186/s13550-015-0113-3 | url = http://www.ejnmmires.com/content/5/1/34 | pmc=4467816}}</ref>

==See also==
* [[Neurotransmitter transporter]]
* [[Sodium:neurotransmitter symporter]]
* [[Solute carrier family]]
* [[Norepinephrine]]
* [[Monoamine transporter]]
* [[Orthostatic intolerance]]
* [[Single-nucleotide polymorphisms]]

==References==
{{Reflist|colwidth=35em}}

==External links==
* {{MeshName|Norepinephrine+transporter}}

{{Membrane transport proteins|bg|bg0}}
{{Neurotransmitter transporters}}
{{Monoamine reuptake inhibitors}}
{{Monoamine releasing agents}}
{{Amphetamine}}

{{DEFAULTSORT:Norepinephrine Transporter}}
[[Category:Amphetamine]]
[[Category:Membrane biology]]
[[Category:Neurotransmitter transporters]]
[[Category:Norepinephrine]]
[[Category:Solute carrier family]]