Fast antidepressant action of ketamine in mouse models requires normal VGLUT1 levels from prefrontal cortex neurons.

Autor: Belloch FB; Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain., Cortés-Erice M; Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain., Herzog E; Université de Bordeaux, Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France., Zhang XM; Université de Bordeaux, Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France., Díaz-Perdigon T; Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain., Puerta E; Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain., Tordera RM; Department of Pharmacology and Toxicology, University of Navarra, 31008 Pamplona, Spain. Electronic address: rtordera@unav.es.
Jazyk: angličtina
Zdroj: Progress in neuro-psychopharmacology & biological psychiatry [Prog Neuropsychopharmacol Biol Psychiatry] 2023 Mar 08; Vol. 121, pp. 110640. Date of Electronic Publication: 2022 Oct 06.
DOI: 10.1016/j.pnpbp.2022.110640
Abstrakt: The NMDA antagonist ketamine demonstrated a fast antidepressant activity in treatment-resistant depression. Pre-clinical studies suggest that de novo synthesis of the brain-derived neurotrophic factor (BDNF) in the PFC might be involved in the rapid antidepressant action of ketamine. Applying a genetic model of impaired glutamate release, this study aims to further identify the molecular mechanisms that could modulate antidepressant action and resistance to treatment. To that end, mice knocked-down for the vesicular glutamate transporter 1 (VGLUT1+/-) were used. We analyzed anhedonia and helpless behavior as well as the expression of the proteins linked to glutamate transmission in the PFC of mice treated with ketamine or the reference antidepressant reboxetine. Moreover, we analyzed the acute effects of ketamine in VGLUT1+/- mice pretreated with chronic reboxetine or those that received a PFC rescue expression of VGLUT1. Chronic reboxetine rescued the depressive-like phenotype of the VGLUT1+/- mice. In addition, it enhanced the expression of the proteins linked to the AMPA signaling pathway as well as the immature form of BDNF (pro-BDNF). Unlike WT mice, ketamine had no effect on anhedonia or pro-BDNF expression in VGLUT1+/- mice; it also failed to decrease phosphorylated eukaryote elongation factor 2 (p-eEF2). Nevertheless, we found that reboxetine administered as pretreatment or PFC overexpression of VGLUT1 did rescue the antidepressant-like activity of acute ketamine in the mice. Our results strongly suggest that not only do PFC VGLUT1 levels modulate the rapid-antidepressant action of ketamine, but also highlight a possible mechanism for antidepressant resistance in some patients.
Competing Interests: Declaration of Competing Interest All the authors declare no biomedical financial interests or potential conflicts of interest.
(Copyright © 2022. Published by Elsevier Inc.)
Databáze: MEDLINE
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