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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...

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Detalles Bibliográficos
Autores principales: Okada, Motohiro, Okubo, Ruri, Fukuyama, Kouji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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.
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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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