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Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT(1A) Receptor with 5-HT(3) Receptor Inhibition in Rats
Vortioxetine is a novel, multimodal antidepressant with unique targets, including the inhibition of the serotonin transporter (SET), of serotonin 5-HT(3) (5-HT3R), and of 5-HT(7) (5-HT7R) receptors and partial agonism to serotonin 5-HT(1A) (5-HT1AR) receptors in humans. Vortioxetine has a lower affi...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940928/ https://www.ncbi.nlm.nih.gov/pubmed/31835640 http://dx.doi.org/10.3390/ijms20246235 |
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author | Okada, Motohiro Okubo, Ruri Fukuyama, Kouji |
author_facet | Okada, Motohiro Okubo, Ruri Fukuyama, Kouji |
author_sort | Okada, Motohiro |
collection | PubMed |
description | Vortioxetine is a novel, multimodal antidepressant with unique targets, including the inhibition of the serotonin transporter (SET), of serotonin 5-HT(3) (5-HT3R), and of 5-HT(7) (5-HT7R) receptors and partial agonism to serotonin 5-HT(1A) (5-HT1AR) receptors in humans. Vortioxetine has a lower affinity to 5-HT1AR and 5-HT7R in rats compared with humans, but several behavior studies have demonstrated its powerful antidepressant-like actions. In spite of these efforts, detailed effects of the subchronic administration of vortioxetine on serotonergic transmission remain to be clarified. This study examined the mechanisms underlying the clinical effects of vortioxetine by measuring the releases of 5-HT and GABA in the medial prefrontal cortex (mPFC) of freely moving rats compared with the selective SET inhibitor, escitalopram. Inhibition of 5-HT3R in the mPFC enhanced regional 5-HT release via GABAergic disinhibition. Activation of somatodendritic 5-HT1AR in the dorsal raphe nucleus (DRN) and presynaptic 5-HT1AR in the mPFC inhibited 5-HT release in the mPFC. Escitalopram subchronically activated mesocortical serotonergic transmission via desensitization of 5-HT1AR in the mPFC and DRN and of 5-HT3R in the mPFC; however, vortioxetine also subchronically activated mesocortical serotonergic transmission via desensitization of 5-HT1AR in the mPFC and DRN but not of 5-HT3R in the mPFC. These demonstrations, the desensitization of 5-HT1AR with the inhibition of 5-HT3R (without 5-HT3R desensitization), at least partially, contribute to the multimodal antidepressant action of vortioxetine in rats. |
format | Online Article Text |
id | pubmed-6940928 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69409282020-01-09 Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT(1A) Receptor with 5-HT(3) Receptor Inhibition in Rats Okada, Motohiro Okubo, Ruri Fukuyama, Kouji Int J Mol Sci Article Vortioxetine is a novel, multimodal antidepressant with unique targets, including the inhibition of the serotonin transporter (SET), of serotonin 5-HT(3) (5-HT3R), and of 5-HT(7) (5-HT7R) receptors and partial agonism to serotonin 5-HT(1A) (5-HT1AR) receptors in humans. Vortioxetine has a lower affinity to 5-HT1AR and 5-HT7R in rats compared with humans, but several behavior studies have demonstrated its powerful antidepressant-like actions. In spite of these efforts, detailed effects of the subchronic administration of vortioxetine on serotonergic transmission remain to be clarified. This study examined the mechanisms underlying the clinical effects of vortioxetine by measuring the releases of 5-HT and GABA in the medial prefrontal cortex (mPFC) of freely moving rats compared with the selective SET inhibitor, escitalopram. Inhibition of 5-HT3R in the mPFC enhanced regional 5-HT release via GABAergic disinhibition. Activation of somatodendritic 5-HT1AR in the dorsal raphe nucleus (DRN) and presynaptic 5-HT1AR in the mPFC inhibited 5-HT release in the mPFC. Escitalopram subchronically activated mesocortical serotonergic transmission via desensitization of 5-HT1AR in the mPFC and DRN and of 5-HT3R in the mPFC; however, vortioxetine also subchronically activated mesocortical serotonergic transmission via desensitization of 5-HT1AR in the mPFC and DRN but not of 5-HT3R in the mPFC. These demonstrations, the desensitization of 5-HT1AR with the inhibition of 5-HT3R (without 5-HT3R desensitization), at least partially, contribute to the multimodal antidepressant action of vortioxetine in rats. MDPI 2019-12-10 /pmc/articles/PMC6940928/ /pubmed/31835640 http://dx.doi.org/10.3390/ijms20246235 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Okada, Motohiro Okubo, Ruri Fukuyama, Kouji Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT(1A) Receptor with 5-HT(3) Receptor Inhibition in Rats |
title | Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT(1A) Receptor with 5-HT(3) Receptor Inhibition in Rats |
title_full | Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT(1A) Receptor with 5-HT(3) Receptor Inhibition in Rats |
title_fullStr | Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT(1A) Receptor with 5-HT(3) Receptor Inhibition in Rats |
title_full_unstemmed | Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT(1A) Receptor with 5-HT(3) Receptor Inhibition in Rats |
title_short | Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT(1A) Receptor with 5-HT(3) Receptor Inhibition in Rats |
title_sort | vortioxetine subchronically activates serotonergic transmission via desensitization of serotonin 5-ht(1a) receptor with 5-ht(3) receptor inhibition in rats |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940928/ https://www.ncbi.nlm.nih.gov/pubmed/31835640 http://dx.doi.org/10.3390/ijms20246235 |
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