Reuptake inhibitor

{{Disputed section|date=January 2016}}

Image:Tiagabine.svg, a selective GABA reuptake inhibitor used as an anticonvulsant in the treatment of epilepsy and seizures.]]

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.{{cite book |last= Barker |first= Eric L. |author2=Randy D. Blakely |title= Norepinephrine and serotonin transporters: molecular targets of antidepressant drugs. In: Psychopharmacology: the fourth generation of progress. |year= 1995 }}{{cite journal | doi = 10.1046/j.1471-4159.1998.70062545.x |vauthors=Sur C, Betz H, Schloss P | title = Distinct effects of imipramine on 5-hydroxytryptamine uptake mediated by the recombinant rat serotonin transporter SERT1. | journal = Journal of Neurochemistry | volume = 70 | issue = 6 | pages = 2545–2553 | year = 1998 | pmid = 9603221 | doi-access = free }}{{cite journal |vauthors=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 | s2cid = 14035346 }}{{cite journal |vauthors=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 | s2cid = 15873647 }} 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.

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.{{cite journal |vauthors=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 }}{{cite journal | doi = 10.1097/00000542-199803000-00029 |vauthors=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 |s2cid=30159489 | doi-access = free }}{{cite journal | doi = 10.1016/S0014-5793(98)00126-4 |vauthors=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 | doi-access = free |bibcode=1998FEBSL.423..376N }} They appear to exert their reuptake inhibition by binding to vaguely characterized allosteric sites on each of the respective monoamine transporters.{{cite journal |vauthors=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 | s2cid = 24183939 | url = https://zenodo.org/record/1229376 }}{{cite journal |vauthors=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 }}{{cite journal |vauthors=Goodman CB, Thomas DN, Pert A, Emilien B, Cadet JL, Carroll FI, Blough BE, Mascarella SW, Rogawski MA, Subramaniam S, etal | 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 | s2cid = 19829696 | url = https://zenodo.org/record/1229378 }}{{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 | bibcode = 1994NTxT...16..343R | url = https://zenodo.org/record/1258623 }}{{cite journal |vauthors=Rothman RB, Silverthorn ML, Baumann MH, Goodman CB, Cadet JL, Matecka D, Rice KC, Carroll FI, Wang JB, Uhl GR, etal | 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 }} Benztropine, mazindol, and vanoxerine also bind to these sites and have similar properties.{{cite journal |vauthors=Rothman RB, Cadet JL, Akunne HC, Silverthorn ML, Baumann MH, Carroll FI, Rice KC, de Costa BR, Partilla JS, Wang JB, etal | 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 }} 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.

A few of the selective serotonin reuptake inhibitors (SSRIs) such as the dextro-enantiomer of citalopram appear to be allosteric reuptake inhibitors of serotonin.{{cite journal |vauthors=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 | s2cid = 22917322 }}{{cite journal |vauthors=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 | doi-access = free }} 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. 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.

File:Reserpine.svg, 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 inhibitor of the vesicular monoamine transporter 2 (VMAT2), and is a prototypical example of a vesicular reuptake inhibitor.

Image:Hyperforin3D.png, 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.]]Two of the primary active constituents of the medicinal herb Hypericum perforatum (St. John's Wort) are hyperforin and adhyperforin.{{cite journal |vauthors=Müller WE, Singer A, Wonnemann M | title = Hyperforin – antidepressant activity by a novel mechanism of action | journal = Pharmacopsychiatry | year = 2001 | pmid = 11518085 | volume = 34 | issue = Suppl 1 | pages = S98–102 | doi=10.1055/s-2001-15512| s2cid = 21872392 }}{{cite journal |vauthors=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}} Hyperforin and adhyperforin are wide-spectrum inhibitors of the reuptake of serotonin, norepinephrine, dopamine, glutamate, GABA, glycine,{{cite journal |vauthors=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 |date=October 2002 | pmid = 12354583 | doi = 10.1016/S0024-3205(02)02104-5}} and choline,{{cite journal |vauthors=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 |date=May 2002 | pmid = 11961077 | doi = 10.1124/jpet.301.2.714}} and they exert these effects by binding to and activating the transient receptor potential cation channel TRPC6.{{cite journal |vauthors=Leuner K, Kazanski V, Müller M, etal |title=Hyperforin – a key constituent of St. John's wort specifically activates TRPC6 channels |journal=The FASEB Journal |volume=21 |issue=14 |pages=4101–11 |date=December 2007 |pmid=17666455 |doi=10.1096/fj.07-8110com |doi-access=free |s2cid=14097884 }} Activation of TRPC6 induces the entry of calcium (Ca²⁺) and sodium (Na⁺) into the cell, which causes the effect through unknown mechanism.

• Amino acid reuptake inhibitor
• Excitatory amino acid reuptake inhibitor (or glutamate-aspartate reuptake inhibitor)
• GABA reuptake inhibitor
• Glycine reuptake inhibitor
• Monoamine reuptake inhibitor
• Dopamine reuptake inhibitor
• Norepinephrine reuptake inhibitor
• Serotonin reuptake inhibitor
• Serotonin-norepinephrine reuptake inhibitor
• Norepinephrine-dopamine reuptake inhibitor
• Serotonin-dopamine reuptake inhibitor
• Serotonin-norepinephrine-dopamine reuptake inhibitor
• Miscellaneous
• Adenosine reuptake inhibitor
• Endocannabinoid reuptake inhibitor

• TRPC6 activators (wide-spectrum reuptake inhibitors) – hyperforin, adhyperforin

• Choline reuptake inhibitor – hemicholinium-3, triethylcholine

• Vesicular acetylcholine transporter (VAChT) inhibitor – vesamicol
• Vesicular monoamine transporter (VMAT) inhibitor – reserpine, tetrabenazine

• Releasing agent

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{{DEFAULTSORT:Reuptake Inhibitor}}

Category:Neuropharmacology

Category:Pharmacodynamics