Cargando…

The 5-HT(1A) receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models

OBJECTIVES: NLX-101 and NLX-204 are highly selective serotonin 5-HT(1A) ‘biased’ agonists, displaying potent and efficacious antidepressant-like activity upon acute administration in models such as the forced swim test. METHODS: we compared the effects of repeated administration of NLX-101, NLX-204...

Descripción completa

Detalles Bibliográficos
Autores principales: Papp, Mariusz, Gruca, Piotr, Lason, Magdalena, Litwa, Ewa, Newman-Tancredi, Adrian, Depoortère, Ronan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10593613/
https://www.ncbi.nlm.nih.gov/pubmed/37310446
http://dx.doi.org/10.1007/s00213-023-06389-5
_version_ 1785124479927582720
author Papp, Mariusz
Gruca, Piotr
Lason, Magdalena
Litwa, Ewa
Newman-Tancredi, Adrian
Depoortère, Ronan
author_facet Papp, Mariusz
Gruca, Piotr
Lason, Magdalena
Litwa, Ewa
Newman-Tancredi, Adrian
Depoortère, Ronan
author_sort Papp, Mariusz
collection PubMed
description OBJECTIVES: NLX-101 and NLX-204 are highly selective serotonin 5-HT(1A) ‘biased’ agonists, displaying potent and efficacious antidepressant-like activity upon acute administration in models such as the forced swim test. METHODS: we compared the effects of repeated administration of NLX-101, NLX-204 and ketamine in the chronic mild stress (CMS) model of depression, considered to have high translational potential, on sucrose consumption (anhedonia measure), novel object recognition (NOR; working memory measure) and elevated plus maze (EPM; anxiety measure) in male Wistar and Wistar-Kyoto rats (the latter being resistant to classical antidepressants). RESULTS: in Wistar rats, NLX-204 and NLX-101 (0.08–0.16 mg/kg i.p.), like ketamine (10 mg/kg i.p.) dose-dependently reversed CMS-induced sucrose intake deficit from treatment Day 1, with nearly full reversal observed at the higher dose at Days 8 and 15. These effects persisted for 3 weeks following treatment cessation. In the NOR test, both doses of NLX-101/NLX-204, and ketamine, rescued the deficit in discrimination index caused by CMS on Days 3 and 17; all three compounds increased time spent in open arms (EPM) but only NLX-204 achieved statistical significance on Days 2 and 16. In Wistar-Kyoto rats, all 3 compounds were also active in the sucrose test and, to a lesser extent, in the NOR and EPM. In non-stressed rats (both strains), the three compounds produced no significant effects in all tests. CONCLUSIONS: these observations further strengthen the hypothesis that biased agonism at 5-HT(1A) receptors constitutes a promising strategy to achieve rapid-acting/sustained antidepressant effects combined with activity against TRD, in addition to providing beneficial effects against memory deficit and anxiety in depressed patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00213-023-06389-5.
format Online
Article
Text
id pubmed-10593613
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-105936132023-10-25 The 5-HT(1A) receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models Papp, Mariusz Gruca, Piotr Lason, Magdalena Litwa, Ewa Newman-Tancredi, Adrian Depoortère, Ronan Psychopharmacology (Berl) Original Investigation OBJECTIVES: NLX-101 and NLX-204 are highly selective serotonin 5-HT(1A) ‘biased’ agonists, displaying potent and efficacious antidepressant-like activity upon acute administration in models such as the forced swim test. METHODS: we compared the effects of repeated administration of NLX-101, NLX-204 and ketamine in the chronic mild stress (CMS) model of depression, considered to have high translational potential, on sucrose consumption (anhedonia measure), novel object recognition (NOR; working memory measure) and elevated plus maze (EPM; anxiety measure) in male Wistar and Wistar-Kyoto rats (the latter being resistant to classical antidepressants). RESULTS: in Wistar rats, NLX-204 and NLX-101 (0.08–0.16 mg/kg i.p.), like ketamine (10 mg/kg i.p.) dose-dependently reversed CMS-induced sucrose intake deficit from treatment Day 1, with nearly full reversal observed at the higher dose at Days 8 and 15. These effects persisted for 3 weeks following treatment cessation. In the NOR test, both doses of NLX-101/NLX-204, and ketamine, rescued the deficit in discrimination index caused by CMS on Days 3 and 17; all three compounds increased time spent in open arms (EPM) but only NLX-204 achieved statistical significance on Days 2 and 16. In Wistar-Kyoto rats, all 3 compounds were also active in the sucrose test and, to a lesser extent, in the NOR and EPM. In non-stressed rats (both strains), the three compounds produced no significant effects in all tests. CONCLUSIONS: these observations further strengthen the hypothesis that biased agonism at 5-HT(1A) receptors constitutes a promising strategy to achieve rapid-acting/sustained antidepressant effects combined with activity against TRD, in addition to providing beneficial effects against memory deficit and anxiety in depressed patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00213-023-06389-5. Springer Berlin Heidelberg 2023-06-13 2023 /pmc/articles/PMC10593613/ /pubmed/37310446 http://dx.doi.org/10.1007/s00213-023-06389-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Investigation
Papp, Mariusz
Gruca, Piotr
Lason, Magdalena
Litwa, Ewa
Newman-Tancredi, Adrian
Depoortère, Ronan
The 5-HT(1A) receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models
title The 5-HT(1A) receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models
title_full The 5-HT(1A) receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models
title_fullStr The 5-HT(1A) receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models
title_full_unstemmed The 5-HT(1A) receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models
title_short The 5-HT(1A) receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models
title_sort 5-ht(1a) receptor biased agonists, nlx-204 and nlx-101, display ketamine-like raad and anti-trd activities in rat cms models
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10593613/
https://www.ncbi.nlm.nih.gov/pubmed/37310446
http://dx.doi.org/10.1007/s00213-023-06389-5
work_keys_str_mv AT pappmariusz the5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT grucapiotr the5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT lasonmagdalena the5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT litwaewa the5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT newmantancrediadrian the5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT depoortereronan the5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT pappmariusz 5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT grucapiotr 5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT lasonmagdalena 5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT litwaewa 5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT newmantancrediadrian 5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels
AT depoortereronan 5ht1areceptorbiasedagonistsnlx204andnlx101displayketaminelikeraadandantitrdactivitiesinratcmsmodels