Blockage of 5HT2C Serotonin Receptors by Fluoxetine (Prozac)
Fluoxetine (Prozac) inhibited the membrane currents elicited by serotonin (5-hydroxytryptamine; 5HT) in Xenopus oocytes expressing either cloned 5HT2C receptors or 5HT receptors encoded by rat cortex mRNA. Responses of 5HT2C receptors, elicited by nM concentrations of 5HT, were rapidly and reversibl...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1997-03, Vol.94 (5), p.2036-2040 |
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| creator | Ni, Y. G. Miledi, R. |
| description | Fluoxetine (Prozac) inhibited the membrane currents elicited by serotonin (5-hydroxytryptamine; 5HT) in Xenopus oocytes expressing either cloned 5HT2C receptors or 5HT receptors encoded by rat cortex mRNA. Responses of 5HT2C receptors, elicited by nM concentrations of 5HT, were rapidly and reversibly blocked by micromolar concentrations of fluoxetine. For responses elicited by 1 μ M 5HT, the IC50 of fluoxetine inhibition was ≈ 20 μ M. In accord with the electrophysiological results, fluoxetine inhibited the binding of [3H]5HT to 5HT2C receptors expressed in HeLa cells (Ki≈ 65-97 nM), and the binding to 5HT receptors in rat cortex membranes was also inhibited but less efficiently (Ki≈ 56 μ M). Our results show that fluoxetine is a competitive and reversible antagonist of 5HT2C receptors and suggest that some therapeutic effects of fluoxetine may involve blockage of 5HT receptors, in addition to its known blockage of 5HT transporters. Similar work may help to design more selective compounds for use in the treatment of brain disorders. |
| doi_str_mv | 10.1073/pnas.94.5.2036 |
| format | Article |
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G. ; Miledi, R.</creator><creatorcontrib>Ni, Y. G. ; Miledi, R.</creatorcontrib><description>Fluoxetine (Prozac) inhibited the membrane currents elicited by serotonin (5-hydroxytryptamine; 5HT) in Xenopus oocytes expressing either cloned 5HT2C receptors or 5HT receptors encoded by rat cortex mRNA. Responses of 5HT2C receptors, elicited by nM concentrations of 5HT, were rapidly and reversibly blocked by micromolar concentrations of fluoxetine. For responses elicited by 1 μ M 5HT, the IC50 of fluoxetine inhibition was ≈ 20 μ M. In accord with the electrophysiological results, fluoxetine inhibited the binding of [3H]5HT to 5HT2C receptors expressed in HeLa cells (Ki≈ 65-97 nM), and the binding to 5HT receptors in rat cortex membranes was also inhibited but less efficiently (Ki≈ 56 μ M). Our results show that fluoxetine is a competitive and reversible antagonist of 5HT2C receptors and suggest that some therapeutic effects of fluoxetine may involve blockage of 5HT receptors, in addition to its known blockage of 5HT transporters. Similar work may help to design more selective compounds for use in the treatment of brain disorders.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.94.5.2036</identifier><identifier>PMID: 9050900</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Angiotensin III - pharmacology ; Animals ; Binding, Competitive ; Biological Sciences ; Brain - metabolism ; Carrier Proteins - drug effects ; Carrier Proteins - metabolism ; Cell membranes ; Dose-Response Relationship, Drug ; Drug therapy ; Fluoxetine - pharmacology ; Gene Expression ; HeLa Cells ; Humans ; Inhibitory concentration 50 ; Medical treatment ; Membrane Glycoproteins - drug effects ; Membrane Glycoproteins - metabolism ; Membrane Transport Proteins ; Mental disorders ; Messenger RNA ; Nerve Tissue Proteins ; Neurological disorders ; Oocytes ; Patch-Clamp Techniques ; Pharmacology ; Phosphatidylinositols ; Protein Binding - drug effects ; Rats ; Receptor, Serotonin, 5-HT2C ; Receptors ; Receptors, Serotonin - drug effects ; Receptors, Serotonin - metabolism ; RNA ; RNA, Messenger - metabolism ; Serotonin - metabolism ; Serotonin Plasma Membrane Transport Proteins ; Serotonin Uptake Inhibitors - pharmacology ; Transfection - genetics ; Xenopus</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1997-03, Vol.94 (5), p.2036-2040</ispartof><rights>Copyright 1997 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Mar 4, 1997</rights><rights>Copyright © 1997, The National Academy of Sciences of the USA 1997</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/94/5.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41581$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41581$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53770,53772,57996,58229</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9050900$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ni, Y. G.</creatorcontrib><creatorcontrib>Miledi, R.</creatorcontrib><title>Blockage of 5HT2C Serotonin Receptors by Fluoxetine (Prozac)</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Fluoxetine (Prozac) inhibited the membrane currents elicited by serotonin (5-hydroxytryptamine; 5HT) in Xenopus oocytes expressing either cloned 5HT2C receptors or 5HT receptors encoded by rat cortex mRNA. Responses of 5HT2C receptors, elicited by nM concentrations of 5HT, were rapidly and reversibly blocked by micromolar concentrations of fluoxetine. For responses elicited by 1 μ M 5HT, the IC50 of fluoxetine inhibition was ≈ 20 μ M. In accord with the electrophysiological results, fluoxetine inhibited the binding of [3H]5HT to 5HT2C receptors expressed in HeLa cells (Ki≈ 65-97 nM), and the binding to 5HT receptors in rat cortex membranes was also inhibited but less efficiently (Ki≈ 56 μ M). Our results show that fluoxetine is a competitive and reversible antagonist of 5HT2C receptors and suggest that some therapeutic effects of fluoxetine may involve blockage of 5HT receptors, in addition to its known blockage of 5HT transporters. 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| source | MEDLINE; Jstor Complete Legacy; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Angiotensin III - pharmacology Animals Binding, Competitive Biological Sciences Brain - metabolism Carrier Proteins - drug effects Carrier Proteins - metabolism Cell membranes Dose-Response Relationship, Drug Drug therapy Fluoxetine - pharmacology Gene Expression HeLa Cells Humans Inhibitory concentration 50 Medical treatment Membrane Glycoproteins - drug effects Membrane Glycoproteins - metabolism Membrane Transport Proteins Mental disorders Messenger RNA Nerve Tissue Proteins Neurological disorders Oocytes Patch-Clamp Techniques Pharmacology Phosphatidylinositols Protein Binding - drug effects Rats Receptor, Serotonin, 5-HT2C Receptors Receptors, Serotonin - drug effects Receptors, Serotonin - metabolism RNA RNA, Messenger - metabolism Serotonin - metabolism Serotonin Plasma Membrane Transport Proteins Serotonin Uptake Inhibitors - pharmacology Transfection - genetics Xenopus |
| title | Blockage of 5HT2C Serotonin Receptors by Fluoxetine (Prozac) |
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