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(New page: {{BioPsy}} A '''neurotransmitter uptake inhibitor''' is a drug which inhibits the reuptake of the neurotransmitter, thus extending the duration of its effect. Examples include: * ...)
 
 
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{{BioPsy}}
 
{{BioPsy}}
A '''neurotransmitter uptake inhibitor''' is a drug which inhibits the [[reuptake]] of the [[neurotransmitter]], thus extending the duration of its effect.
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[[Image:Escitalopram structure.svg|thumb|right|160px|[[Escitalopram]], a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant.]]
   
Examples include:
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A '''reuptake inhibitor''' ('''RI'''), also known as a '''transporter blocker''', is a [[drug]] that inhibits the [[plasmalemma]]l [[transporter]]-mediated [[reuptake]] of a [[neurotransmitter]] from the [[synapse]] into the [[Synapse|pre-synaptic neuron]], leading to an increase in the [[extracellular]] [[concentration]]s of the [[neurotransmitter]] and therefore an increase in [[neurotransmission]]. Various [[drug]]s utilize reuptake inhibition to exert their [[psychological]] and [[physiological]] effects, including many [[antidepressants]] and [[psychostimulant]]s.<ref name="pmid16402124">{{cite journal | author = Iversen L. | title = Neurotransmitter transporters and their impact on the development of psychopharmacology. | journal = Br J Pharmacol. | volume = 147 | issue = 1 | pages = S82–88 | year = 2006 | pmid = 16402124 | doi = 10.1038/sj.bjp.0706428 | pmc = 1760736 }}</ref>
* [[Adrenergic uptake inhibitor]]/[[Norepinephrine reuptake inhibitor]]
 
* [[Dopamine reuptake inhibitor]]
 
* [[Serotonin reuptake inhibitor]]
 
   
* [[Serotonin-norepinephrine reuptake inhibitor]]
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Most known reuptake inhibitors affect the [[monoamine neurotransmitter]]s [[serotonin]], [[norepinephrine]] (and [[epinephrine]]), and [[dopamine]].<ref name="pmid16402124" /> However there are also a number of [[pharmaceutical drug|pharmaceutical]]s and [[research chemical]]s that act as reuptake inhibitors for other [[neurotransmitter]]s such as [[glutamate]],<ref name="pmid9259454">{{cite journal | doi = 10.1016/S0304-3940(97)00465-5 | author = West AR, Galloway MP | title = Inhibition of glutamate reuptake potentiates endogenous nitric oxide-facilitated dopamine efflux in the rat striatum: an in vivo microdialysis study | journal = Neurosci Lett. | volume = 230 | issue = 1 | pages = 21–4 | year = 1997 | pmid = 9259454 }}</ref> [[γ-aminobutyric acid]] (GABA),<ref name="pmid16420077">{{cite journal | doi = 10.4088/JCP.v66n1109 | author = Pollack MH, Roy-Byrne PP, Van Ameringen M, Snyder H, Brown C, Ondrasik J, Rickels K | title = The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study | journal = J Clin Psychiatry. | volume = 66 | issue = 11 | pages = 1401–8 | year = 2005 | pmid = 16420077 }}</ref> [[glycine]],<ref name="pmid22138164">{{cite journal | author = Alberati D, Moreau JL, Lengyel J, ''et al.'' | title = Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia | journal = Neuropharmacology | volume = 62 | issue = 2 | pages = 1152–61 | year = 2012 | month = February | pmid = 22138164 | doi = 10.1016/j.neuropharm.2011.11.008 | url = http://linkinghub.elsevier.com/retrieve/pii/S0028-3908(11)00487-4}}</ref> [[adenosine]],<ref name="pmid8383814">{{cite journal | doi = 10.1016/0028-3908(93)90095-K | author = Boissard CG, Gribkoff VK | title = The effects of the adenosine reuptake inhibitor soluflazine on synaptic potentials and population hypoxic depolarizations in area CA1 of rat hippocampus in vitro | journal = Neuropharmacology. | volume = 32 | issue = 2 | pages = 149–55 | year = 1993 | pmid = 8383814 }}</ref> [[choline]] (the [[precursor (chemistry)|precursor]] of [[acetylcholine]]),<ref name="pmid12432531">{{cite journal | author = Barkhimer TV, Kirchhoff JR, Hudson RA, Messer WS | title = Evaluation of the inhibition of choline uptake in synaptosomes by capillary electrophoresis with electrochemical detection | journal = Electrophoresis | volume = 23 | issue = 21 | pages = 3699–704 | year = 2002 | month = November | pmid = 12432531 | doi = 10.1002/1522-2683(200211)23:21<3699::AID-ELPS3699>3.0.CO;2-E | url = http://dx.doi.org/10.1002/1522-2683(200211)23:21<3699::AID-ELPS3699>3.0.CO;2-E}}</ref> and the [[endocannabinoid]]s,<ref name="pmid16770320">{{cite journal | author = Costa B, Siniscalco D, Trovato AE, Comelli F, Sotgiu ML, Colleoni M, Maione S, Rossi F, Giagnoni G | title = AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain | journal = Br J Pharmacol. | volume = 148 | issue = 7 | pages = 1022–32 | year = 2006 | pmid = 16770320 | doi = 10.1038/sj.bjp.0706798 | pmc = 1751928 }}</ref> among others.<ref name="pmid16402124" />
* [[Norepinephrine-dopamine reuptake inhibitor]]
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* [[Serotonin-noradrenaline-dopamine reuptake inhibitor]]
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==Mechanism of action==
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===Active site transporter substrates===
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[[Image:Tiagabine.svg|thumb|right|160px|[[Tiagabine]], a selective GABA reuptake inhibitor used as an anticonvulsant in the treatment of epilepsy and seizures.]]
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Standard reuptake inhibitors are believed to act simply as [[competitive inhibition|competitive]] [[substrate (biochemistry)|substrate]]s that work by [[binding (molecular)|binding]] directly to the [[plasmalemma]] [[membrane transport protein|transporter]] of the [[neurotransmitter]] in question.<ref name="Norepinephrine and serotonin transporters: molecular targets of antidepressant drugs">{{cite book |last= Barker |first= Eric L. |coauthors= Randy D. Blakely |title= Norepinephrine and serotonin transporters: molecular targets of antidepressant drugs. In: Psychopharmacology: the fourth generation of progress. |year= 1995 }}</ref><ref name="pmid9603221">{{cite journal | doi = 10.1046/j.1471-4159.1998.70062545.x | author = Sur C, Betz H, Schloss P. | title = Distinct effects of imipramine on 5-hydroxytryptamine uptake mediated by the recombinant rat serotonin transporter SERT1. | journal = J Neurochem. | volume = 70 | issue = 6 | pages = 2545–2553 | year = 1998 | pmid = 9603221 }}</ref><ref name="pmid12944499">{{cite journal | author = Ravna AW, Sylte I, Dahl SG. | title = Molecular mechanism of citalopram and cocaine interactions with neurotransmitter transporters. | journal = J Pharmacol Exp Ther. | volume = 307 | issue = 1 | pages = 34–41 | year = 2003 | pmid = 12944499 | doi = 10.1124/jpet.103.054593 }}</ref><ref name="pmid18801947">{{cite journal | author = Apparsundaram S, Stockdale DJ, Henningsen RA, Milla ME, Martin RS. | title = Antidepressants targeting the serotonin reuptake transporter act via a competitive mechanism. | journal = J Pharmacol Exp Ther. | volume = 327 | issue = 3 | pages = 982–990 | year = 2008 | pmid = 18801947 | doi = 10.1124/jpet.108.142315 }}</ref> They [[receptor theory|occupy]] the [[transporter protein|transporter]] in place of the respective [[neurotransmitter]] and [[competitive inhibition|competitively]] [[receptor antagonist|block]] it from being [[active transport|transported]] from the [[nerve terminal]] or [[synapse]] into the [[synapse|pre-synaptic]] [[neuron]]. With high enough doses, [[receptor theory|occupation]] becomes as much as 80-90%. At this level of inhibition, the [[transporter protein|transporter]] will be considerably less efficient at removing excess [[neurotransmitter]] from the [[synapse]] and this causes a substantial increase in the [[extracellular]] [[concentration]]s of the [[neurotransmitter]] and therefore an increase in overall [[neurotransmission]].
  +
  +
===Allosteric site transporter substrates===
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[[Image:Hyperforin3D.png|thumb|right|160px|[[Hyperforin]], the primary active constituent responsible for the therapeutic benefits of extracts of the herb ''Hypericum perforatum'' (St. John's Wort), which is used as an antidepressant.]]
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Alternatively, some reuptake inhibitors [[binding (molecular)|bind]] to [[allosteric|allosteric sites]] and inhibit [[reuptake]] indirectly and [[non-competitive inhibition|noncompetitively]].
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  +
[[Phencyclidine]] and related [[drug]]s such as [[benocyclidine]], [[tenocyclidine]], [[ketamine]], and [[dizocilpine]] (MK-801), have been shown to inhibit the reuptake of the [[monoamine neurotransmitter]]s.<ref name="pmid16288927">{{cite journal | author = Pechnick RN, Bresee CJ, Poland RE | title = The role of antagonism of NMDA receptor-mediated neurotransmission and inhibition of the dopamine reuptake in the neuroendocrine effects of phencyclidine | journal = Life Sci. | volume = 78 | issue = 17 | year = 2006 | pmid = 16288927 | pages = 2006–11 | doi = 10.1016/j.lfs.2005.09.018 }}</ref><ref name="pmid9523822">{{cite journal | doi = 10.1097/00000542-199803000-00029 | author = Nishimura M, Sato K, Okada T, Yoshiya I, Schloss P, Shimada S, Tohyama M | title = Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells | journal = Anesthesiology | volume = 88 | issue = 3 | pages = 768–74 | year = 1998 | pmid = 9523822 }}</ref><ref name="pmid9515743">{{cite journal | doi = 10.1016/S0014-5793(98)00126-4 | author = Nishimura M, Sato K, Okada T, Schloss P, Shimada S, Tohyama M. | title = MK-801 blocks monoamine transporters expressed in HEK cells. | journal = FEBS Lett. | volume = 423 | issue = 3 | pages = 376–380 | year = 1998 | pmid = 9515743 }}</ref> They appear to exert their reuptake inhibition by binding to vaguely characterized allosteric sites on each of the respective [[monoamine transporter]]s.<ref name="pmid1833849">{{cite journal | author = Akunne HC, Reid AA, Thurkauf A, Jacobson AE, de Costa BR, Rice KC, Heyes MP, Rothman RB. | title = [3H]1-[2-(2-thienyl)cyclohexyl]piperidine labels two high-affinity binding sites in human cortex: further evidence for phencyclidine binding sites associated with the biogenic amine reuptake complex. | journal = Synapse. | volume = 8 | issue = 4 | pages = 289–300 | year = 1991 | pmid = 1833849 | doi = 10.1002/syn.890080407 }}</ref><ref name="pmid2557536">{{cite journal | author = Rothman RB, Reid AA, Monn JA, Jacobson AE, Rice KC. | title = The psychotomimetic drug phencyclidine labels two high affinity binding sites in guinea pig brain: evidence for N-methyl-D-aspartate-coupled and dopamine reuptake carrier-associated phencyclidine binding sites. | journal = Mol Pharmacol. | volume = 36 | issue = 6 | pages = 887–896 | year = 1989 | pmid = 2557536 }}</ref><ref name="pmid8134901">{{cite journal | author = Goodman CB, Thomas DN, Pert A, Emilien B, Cadet JL, Carroll FI, Blough BE, Mascarella SW, Rogawski MA, Subramaniam S, et al. | title = RTI-4793-14, a new ligand with high affinity and selectivity for the (+)-MK801-insensitive [3H]1-]1-(2-thienyl)cyclohexyl]piperidine binding site (PCP site 2) of guinea pig brain. | journal = Synapse. | volume = 16 | issue = 1 | pages = 59–65 | year = 1994 | pmid = 8134901 | doi = 10.1002/syn.890160107 }}</ref><ref name="pmid7968938">{{cite journal | doi = 10.1016/0892-0362(94)90022-1 | author = Rothman RB. | title = PCP site 2: a high affinity MK-801-insensitive phencyclidine binding site. | journal = Neurotoxicol Teratol. | volume = 16 | issue = 4 | pages = 343–353 | year = 1994 | pmid = 7968938 }}</ref><ref name="pmid7616423">{{cite journal | author = Rothman RB, Silverthorn ML, Baumann MH, Goodman CB, Cadet JL, Matecka D, Rice KC, Carroll FI, Wang JB, Uhl GR, et al. | title = Studies of the biogenic amine transporters. VI. Characterization of a novel cocaine binding site, identified with [125I]RTI-55, in membranes prepared from whole rat brain minus caudate. | journal = J Pharmacol Exp Ther. | volume = 274 | issue = 1 | pages = 385–395 | year = 1995 | pmid = 7616423 }}</ref> [[Benztropine]], [[fluoxetine]], [[mazindol]], and [[vanoxerine]] also bind to these sites and have similar properties.<ref name="pmid1833849"/><ref name="pmid7616423"/><ref name="pmid8035327">{{cite journal | author = Rothman RB, Cadet JL, Akunne HC, Silverthorn ML, Baumann MH, Carroll FI, Rice KC, de Costa BR, Partilla JS, Wang JB, et al. | title = Studies of the biogenic amine transporters. IV. Demonstration of a multiplicity of binding sites in rat caudate membranes for the cocaine analog [125I]RTI-55. | journal = J Pharmacol Exp Ther. | volume = 270 | issue = 1 | pages = 296–309 | year = 1994 | pmid = 8035327 }}</ref> In addition to their high [[Affinity (pharmacology)|affinity]] for the [[active site|main site]] of the monoamine transporters, several [[competitive inhibition|competitive]] [[transporter protein|transporter]] [[Substrate (biochemistry)|substrate]]s such as [[cocaine]] and [[indatraline]] have lower affinity for these allosteric sites as well.<ref name="pmid8134901"/><ref name="pmid7616423"/><ref name="pmid8035327"/>
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A few of the [[selective serotonin reuptake inhibitor]]s (SSRIs) such as [[fluoxetine]] and the dextro-[[enantiomer]] of [[citalopram]] appear to be allosteric reuptake inhibitors of serotonin.<ref name="pmid15695064">{{cite journal | author = Chen F, Larsen MB, Sánchez C, Wiborg O. | title = The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. | journal = Eur Neuropsychopharmacol. | volume = 15 | issue = 2 | pages = 193–198 | year = 2005 | pmid = 15695064 | doi = 10.1016/j.euroneuro.2004.08.008 }}</ref><ref name="pmid16448580">{{cite journal | author = Mansari ME, Wiborg O, Mnie-Filali O, Benturquia N, Sánchez C, Haddjeri N. | title = Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies. | journal = Int J Neuropsychopharmacol. | volume = 10 | issue = 1 | pages = 31–40 | year = 2007 | pmid = 16448580 | doi = 10.1017/S1461145705006462 }}</ref> Instead of binding to the active site on the [[serotonin transporter]], they bind to an allosteric site, which exerts its effects by causing [[conformational change]]s in the [[transporter protein]] and thereby modulating the affinity of substrates for the active site.<ref name="pmid15695064" /> As a result, [[escitalopram]] has been [[marketing|marketed]] as an ''[[allosteric serotonin reuptake inhibitor]]''. Notably, this allosteric site may be directly related to the above-mentioned [[phencyclidine|PCP]] [[binding site]]s.<ref name="pmid1833849"/><ref name="pmid8035327"/>
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Two of the primary [[active constituent]]s of the [[medicinal herb]] ''[[Hypericum perforatum]]'' (St. John's Wort) are [[hyperforin]] and [[adhyperforin]].<ref name="pmid11518085">{{cite journal | author = Müller WE, Singer A, Wonnemann M | title = Hyperforin--antidepressant activity by a novel mechanism of action | journal = Pharmacopsychiatry. | year = 2001 | pmid = 11518085 | volume = 34 Suppl 1 | pages = S98–102 }}</ref><ref name="pmid9718074">{{cite journal |author=Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE |title=Hyperforin as a possible antidepressant component of hypericum extracts |journal=Life Sci. |volume=63 |issue=6 |pages=499–510 |year=1998 |pmid=9718074 |doi=10.1016/S0024-3205(98)00299-9}}</ref> Hyperforin and adhyperforin are wide-spectrum inhibitors of the reuptake of serotonin, norepinephrine, dopamine, glutamate, GABA, glycine,<ref name="pmid12354583">{{cite journal | author = Marsh WL, Davies JA | title = The involvement of sodium and calcium ions in the release of amino acid neurotransmitters from mouse cortical slices elicited by hyperforin | journal = Life Sciences | volume = 71 | issue = 22 | pages = 2645–55 | year = 2002 | month = October | pmid = 12354583 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/S0024320502021045}}</ref> and choline,<ref name="pmid11961077">{{cite journal | author = Buchholzer ML, Dvorak C, Chatterjee SS, Klein J | title = Dual modulation of striatal acetylcholine release by hyperforin, a constituent of St. John's wort | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 301 | issue = 2 | pages = 714–9 | year = 2002 | month = May | pmid = 11961077 | doi = | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11961077}}</ref> and they exert these effects [[allosteric inhibition|allosterically]] by binding to and [[receptor theory|activating]] the [[transient receptor potential]] [[cation channel]] [[TRPC6]].<ref name="pmid9718074"/><ref name="pmid17666455">{{cite journal |author=Leuner K, Kazanski V, Müller M, ''et al'' |title=Hyperforin--a key constituent of St. John's wort specifically activates TRPC6 channels |journal=The FASEB journal : official publication of the Federation of American Societies for Experimental Biology |volume=21 |issue=14 |pages=4101–11 |year=2007 |month=December |pmid=17666455 |doi=10.1096/fj.07-8110com |url=}}</ref> Activation of TRPC6 induces the entry of [[calcium]] (Ca<sup>2+</sup>) and [[sodium]] (Na<sup>+</sup>) into the [[Cell (biology)|cell]], which causes the effect.<ref name="pmid17666455"/>
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===Vesicular transporter substrates===
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[[Image:Reserpine.png|thumb|right|160px|[[Reserpine]], a vesicular reuptake inhibitor that was used in the past to deplete serotonin, norepinephrine, and dopamine stores as an antipsychotic and antihypertensive. It was notorious for causing anxiety and depression, and as a result, was replaced by newer, more modern drugs instead.]]
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A second type of reuptake inhibition affects [[Vesicle (biology and chemistry)|vesicular]] [[active transport|transport]], and [[receptor antagonist|block]]s the [[intracellular]] [[active transport|repackaging]] of [[neurotransmitter]]s into [[cytoplasmic]] vesicles. In contrast to [[plasmalemmal]] reuptake inhibitors, vesicular reuptake inhibitors do not increase the [[Synapse|synaptic]] [[concentration]]s of a [[neurotransmitter]], only the [[cytoplasmic]] [[concentration]]s; unless, that is, they also act as [[plasmalemmal]] [[transporter protein|transporter]] [[transporter reversal|reverser]]s via [[phosphorylation]] of the [[transporter protein]], also known as a [[releasing agent]]. Pure vesicular reuptake inhibitors tend to actually lower [[Synapse|synaptic]] [[neurotransmitter]] [[concentration]]s, as [[receptor antagonist|blocking]] the [[active transport|repackaging]] of, and [[Synaptic vesicle|storage]] of the [[neurotransmitter]] in question leaves them vulnerable to [[metabolism|degradation]] via [[enzyme]]s such as [[monoamine oxidase]] (MAO) that exist in the [[cytoplasm]]. With vesicular [[active transport|transport]] [[receptor antagonist|blocked]], [[neurotransmitter]] stores quickly become depleted.
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[[Reserpine]] (Serpasil) is an [[irreversibility|irreversible]] and [[competitive inhibition|competitive]] inhibitor of the [[vesicular monoamine transporter 2]] (VMAT2), and is a classic example of a vesicular reuptake inhibitor.
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==Classes and examples==
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===Selective reuptake inhibitors===
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* [[Adenosine reuptake inhibitor]]
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** [[Dilazep]], [[dipyridamole]], [[hexobendine]], [[pentoxifylline]]
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* [[Dopamine reuptake inhibitor]] (DRI, DARI)
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** [[Amfonelic acid]], [[benocyclidine]], [[RTI-121]], [[RTI-229]], [[troparil]], [[vanoxerine]]
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* [[Endocannabinoid reuptake inhibitor]]
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** [[AM-404]], [[LY-2183240]], [[O-2093]], [[OMDM-2]], [[UCM-707]], [[VDM-11]]
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* [[Glutamate reuptake inhibitor]] (or excitatory amino acid reuptake inhibitor)
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** [[Dihydrokainic acid]], [[L-trans-Pyrrolidine-2,4-dicarboxylic acid|PDC]], [[WAY-213,613]]
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* [[GABA reuptake inhibitor]]
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** [[Deramciclane]], [[nipecotic acid]], [[tiagabine]]
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* [[Glycine reuptake inhibitor]]
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** [[ACPPB]], [[ALX-5407]], [[glycyldodecylamide]], [[Org 24589]], [[Org 25935]], [[sarcosine]], [[SSR-103,800]], [[SSR-504,734]]
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* [[Norepinephrine reuptake inhibitor]] (NRI, NARI, NERI)
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** [[Atomoxetine]], [[nisoxetine]], [[reboxetine]], [[viloxazine]]
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* [[Serotonin reuptake inhibitor]] (SRI)
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** [[Escitalopram]], [[fluoxetine]], [[sertraline]]
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===Non-selective reuptake inhibitors===
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* [[Serotonin-norepinephrine reuptake inhibitor]] (SNRI, SNARI)
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** [[Duloxetine]], [[milnacipran]], [[venlafaxine]]
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* [[Norepinephrine-dopamine reuptake inhibitor]] (NDRI)
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** [[Amineptine]], [[bupropion]], [[methylenedioxypyrovalerone|MDPV]], [[methylphenidate]]), [[pipradrol]]
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* [[Serotonin-dopamine reuptake inhibitor]] (SDRI)
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** [[RTI-83]], [[UWA-101]]
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* [[Serotonin-norepinephrine-dopamine reuptake inhibitor]] (SNDRI; or triple reuptake inhibitor (TRI))
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** [[Cocaine]], [[indatraline]], [[nefopam]], [[tesofensine]]
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* ''Wide-spectrum reuptake inhibitor''
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** [[Adhyperforin]], [[hyperforin]]
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===Antagonistic reuptake inhibitors===
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* [[Choline reuptake inhibitor]]
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** [[Hemicholinium-3]], [[triethylcholine]]
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* [[Vesicular reuptake inhibitor]]
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** [[Vesicular acetylcholine transporter]] (VAChT) inhibitor
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*** [[Vesamicol]]
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** [[Vesicular monoamine transporter]] (VMAT) inhibitor
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*** [[Ibogaine]], [[reserpine]], [[tetrabenazine]]
   
 
==See also==
 
==See also==
* [[monoamine transporter]]
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* [[Releasing agent]]
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* [[Monoamine reuptake inhibitor]]
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==References==
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{{Reflist|2}}
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{{Neuromodulation}}
   
==External links==
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{{DEFAULTSORT:Reuptake Inhibitor}}
* {{MeshName|Neurotransmitter+uptake+inhibitors}}
 
   
   
{{Receptor agonists and antagonists}}
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[[Category:Neurochemistry]]
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[[Category:Neurotransmitter uptake inhibitors]]
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[[Category:Pharmacology]]
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[[Category:Synapse]]
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{{enWP|Reuptake inhibitor}}

Latest revision as of 12:17, July 22, 2013

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File:Escitalopram structure.svg

A reuptake inhibitor (RI), also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an increase in neurotransmission. Various drugs utilize reuptake inhibition to exert their psychological and physiological effects, including many antidepressants and psychostimulants.[1]

Most known reuptake inhibitors affect the monoamine neurotransmitters serotonin, norepinephrine (and epinephrine), and dopamine.[1] However there are also a number of pharmaceuticals and research chemicals that act as reuptake inhibitors for other neurotransmitters such as glutamate,[2] γ-aminobutyric acid (GABA),[3] glycine,[4] adenosine,[5] choline (the precursor of acetylcholine),[6] and the endocannabinoids,[7] among others.[1]

Mechanism of actionEdit

Active site transporter substratesEdit

File:Tiagabine.svg

Standard reuptake inhibitors are believed to act simply as competitive substrates that work by binding directly to the plasmalemma transporter of the neurotransmitter in question.[8][9][10][11] They occupy the transporter in place of the respective neurotransmitter and competitively block it from being transported from the nerve terminal or synapse into the pre-synaptic neuron. With high enough doses, occupation becomes as much as 80-90%. At this level of inhibition, the transporter will be considerably less efficient at removing excess neurotransmitter from the synapse and this causes a substantial increase in the extracellular concentrations of the neurotransmitter and therefore an increase in overall neurotransmission.

Allosteric site transporter substratesEdit

File:Hyperforin3D.png

Alternatively, some reuptake inhibitors bind to allosteric sites and inhibit reuptake indirectly and noncompetitively.

Phencyclidine and related drugs such as benocyclidine, tenocyclidine, ketamine, and dizocilpine (MK-801), have been shown to inhibit the reuptake of the monoamine neurotransmitters.[12][13][14] They appear to exert their reuptake inhibition by binding to vaguely characterized allosteric sites on each of the respective monoamine transporters.[15][16][17][18][19] Benztropine, fluoxetine, mazindol, and vanoxerine also bind to these sites and have similar properties.[15][19][20] In addition to their high affinity for the main site of the monoamine transporters, several competitive transporter substrates such as cocaine and indatraline have lower affinity for these allosteric sites as well.[17][19][20]

A few of the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and the dextro-enantiomer of citalopram appear to be allosteric reuptake inhibitors of serotonin.[21][22] Instead of binding to the active site on the serotonin transporter, they bind to an allosteric site, which exerts its effects by causing conformational changes in the transporter protein and thereby modulating the affinity of substrates for the active site.[21] As a result, escitalopram has been marketed as an allosteric serotonin reuptake inhibitor. Notably, this allosteric site may be directly related to the above-mentioned PCP binding sites.[15][20]

Two of the primary active constituents of the medicinal herb Hypericum perforatum (St. John's Wort) are hyperforin and adhyperforin.[23][24] Hyperforin and adhyperforin are wide-spectrum inhibitors of the reuptake of serotonin, norepinephrine, dopamine, glutamate, GABA, glycine,[25] and choline,[26] and they exert these effects allosterically by binding to and activating the transient receptor potential cation channel TRPC6.[24][27] Activation of TRPC6 induces the entry of calcium (Ca2+) and sodium (Na+) into the cell, which causes the effect.[27]

Vesicular transporter substratesEdit

Reserpine

Reserpine, a vesicular reuptake inhibitor that was used in the past to deplete serotonin, norepinephrine, and dopamine stores as an antipsychotic and antihypertensive. It was notorious for causing anxiety and depression, and as a result, was replaced by newer, more modern drugs instead.

A second type of reuptake inhibition affects vesicular transport, and blocks the intracellular repackaging of neurotransmitters into cytoplasmic vesicles. In contrast to plasmalemmal reuptake inhibitors, vesicular reuptake inhibitors do not increase the synaptic concentrations of a neurotransmitter, only the cytoplasmic concentrations; unless, that is, they also act as plasmalemmal transporter reversers via phosphorylation of the transporter protein, also known as a releasing agent. Pure vesicular reuptake inhibitors tend to actually lower synaptic neurotransmitter concentrations, as blocking the repackaging of, and storage of the neurotransmitter in question leaves them vulnerable to degradation via enzymes such as monoamine oxidase (MAO) that exist in the cytoplasm. With vesicular transport blocked, neurotransmitter stores quickly become depleted.

Reserpine (Serpasil) is an irreversible and competitive inhibitor of the vesicular monoamine transporter 2 (VMAT2), and is a classic example of a vesicular reuptake inhibitor.

Classes and examplesEdit

Selective reuptake inhibitorsEdit

Non-selective reuptake inhibitorsEdit

Antagonistic reuptake inhibitorsEdit

See alsoEdit

ReferencesEdit

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