Rapid reorganization of serotonin projections and antidepressant response to 5-HT1A-biased agonist NLX-101 in fluoxetine-resistant cF1ko mice.

Autor: Vahid-Ansari F; OHRI Neuroscience, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, Ontario, K1H-8M5, Canada., Newman-Tancredi A; Neurolixis, SAS, Castres, France., Fuentes-Alvarenga AF; OHRI Neuroscience, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, Ontario, K1H-8M5, Canada., Daigle M; OHRI Neuroscience, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, Ontario, K1H-8M5, Canada., Albert PR; OHRI Neuroscience, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, Ontario, K1H-8M5, Canada. Electronic address: palbert@uottawa.ca.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2024 Dec 15; Vol. 261, pp. 110132. Date of Electronic Publication: 2024 Aug 27.
DOI: 10.1016/j.neuropharm.2024.110132
Abstrakt: Selective serotonin (5-HT) reuptake inhibitors (SSRIs) like fluoxetine remain a first-line treatment for major depression, but are effective in less than half of patients and can take 4-8 weeks to show results. In this study, we examined cF1ko mice with genetically induced upregulation of 5-HT1A autoreceptors that reduces 5-HT neuronal activity. These mice display anxiety- and depression-related behaviors that did not respond to chronic fluoxetine treatment. We examined treatment with NLX-101, a biased agonist that preferentially targets 5-HT1A heteroreceptors. By testing different doses of NLX-101, we found that a dose of 0.2 mg/kg was effective in reducing depression-related behavior in cF1ko mice without causing hypothermia, a 5-HT1A autoreceptor-mediated response. After 1 h, this dose activated dorsal raphe 5-HT neurons and cells in the medial prefrontal cortex (mPFC), increasing nuclear c-fos labelling in cF1ko mice. In cF1ko mice but not wild-type littermates, 0.2 mg/kg NLX-101 administered 1 h prior to each behavioral test for two weeks reduced depressive behavior in the forced swim test, but increased anxiety-related behaviors in the open field, elevated plus maze, and novelty suppressed feeding tests. During this treatment, NLX-101 induced widespread increases in the density of 5-HT axons, varicosities, and especially synaptic and triadic structures, particularly in depression-related brain regions including mPFC, hippocampal CA1 and CA2/3, amygdala and nucleus accumbens of cF1ko mice. Overall, NLX-101 was rapid and effective in reducing depressive behavior in SSRI-resistant mice, but also induced anxiety-related behaviors. The increase in serotonin innervation induced by intermittent NLX-101 may contribute to its behavioral actions.
Competing Interests: Declaration of competing interest The authors FV-A, AFF-A, MD and PRA declare no conflict of interest. The author A.N.-T. is an employee and stockholder of Neurolixis, M.P.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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