Fast antidepressant action of ketamine in mouse models requires normal VGLUT1 levels from prefrontal cortex neurons
Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2022-10-01; : 110640
Lire sur PubMed
de Borja Belloch F(1), Cortés-Erice M(1), Herzog E(2), Zhang XM(2), Díaz-Perdigon T(1), Puerta E(1), Tordera RM(3).
(1)Department of Pharmacology and Toxicology, University of Navarra, 31008
(2)Université de Bordeaux, Univ. Bordeaux, CNRS, Interdisciplinary Institute for
Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France.
(3)Department of Pharmacology and Toxicology, University of Navarra, 31008
Pamplona, Spain. Electronic address: .
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.
Copyright © 2022. Published by Elsevier Inc.
Conflict of interest statement: Declaration of Competing Interest All the authors
declare no biomedical financial interests or potential conflicts of interest.