title: Behavioral and neurochemical characterization of TrkB-dependent mechanisms of agomelatine in glucocorticoid receptor-impaired mice.
abstract: Growing evidence indicates that impairment of the stress response, in particular the negative feedback regulation mechanism exerted by the hypothalamo-pituitary-adrenal (HPA) axis, might be responsible for the hippocampal atrophy observed in depressed patients. Antidepressants, possibly through the activation of BDNF signaling, may enhance neuroplasticity and restore normal hippocampal functions. In this context, glucocorticoid receptor-impaired (GR-i) mice-a transgenic mouse model of reduced GR-induced negative feedback regulation of the HPA axis-were used to investigate the role of BDNF/TrkB signaling in the behavioral and neurochemical effects of the new generation antidepressant drug, agomelatine. GR-i mice exhibited marked alterations in depressive-like and anxiety-like behaviors, together with a decreased cell proliferation and altered levels of neuroplastic and epigenetic markers in the hippocampus. GR-i mice and their wild-type littermates were treated for 21 days with vehicle, agomelatine (50mg/kg/day; i.p) or the TrkB inhibitor Ana-12 (0.5mg/kg/day, i.p) alone, or in combination with agomelatine. Chronic treatment with agomelatine resulted in antidepressant-like effects in GR-i mice and reversed the deficit in hippocampal cell proliferation and some of the alterations of mRNA plasticity markers in GR-i mice. Ana-12 blocked the effect of agomelatine on motor activity as well as its ability to restore a normal hippocampal cell proliferation and expression of neurotrophic factors. Altogether, our findings indicate that agomelatine requires TrkB signaling to reverse some of the molecular and behavioral alterations caused by HPA axis impairment.
authors.affiliation: Centre de Psychiatrie et Neurosciences, Inserm UMR 894, Paris, France; Université Paris Descartes, UMR S894, Paris, France; Department of Psychiatry and Neuropsychology, European Graduate School for Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Boulle
authors.affiliation: Centre de Psychiatrie et Neurosciences, Inserm UMR 894, Paris, France; Université Paris Descartes, UMR S894, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Velthuis
authors.affiliation: Department of Psychiatry and Neuropsychology, European Graduate School for Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Koedam
authors.affiliation: Department of Psychiatry and Neuropsychology, European Graduate School for Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: Department of Psychiatry and Neuropsychology, European Graduate School for Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands; Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: D L A
authors.initials: DLA
authors.lastname: van den Hove
authors.affiliation: Department of Psychiatry and Neuropsychology, European Graduate School for Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Kenis
authors.affiliation: Institut de Recherche International Servier, Suresnes, France.
authors.forename: C
authors.initials: C
authors.lastname: Gabriel
authors.affiliation: Institut de Recherche International Servier, Suresnes, France.
authors.forename: E
authors.initials: E
authors.lastname: Mocaer
authors.affiliation: Centre de Psychiatrie et Neurosciences, Inserm UMR 894, Paris, France; Université Paris Descartes, UMR S894, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Franc
authors.affiliation: Laboratoire d'Innovation Thérepeutique, UMR 7200 CNRS, Université de Strasbourg, Illkirch, France.
authors.forename: D
authors.initials: D
authors.lastname: Rognan
authors.affiliation: Centre de Psychiatrie et Neurosciences, Inserm UMR 894, Paris, France; Université Paris Descartes, UMR S894, Paris, France; EA4475, Pharmacology department, University Paris Descartes, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Mongeau
authors.affiliation: Centre de Psychiatrie et Neurosciences, Inserm UMR 894, Paris, France; Université Paris Descartes, UMR S894, Paris, France. Electronic address: laurence.lanfumey@inserm.fr.
authors.forename: L
authors.initials: L
authors.lastname: Lanfumey
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005239:Fear / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D016037:Single-Blind Method; D012919:Social Behavior; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; D011965:Receptors, Glucocorticoid; C559317:ANA 12 compound; C084711:agomelatine; D009281:Naphthalenes
keywords: Antidepressants; Glucocorticoid; Hippocampus; Neuroplasticity; TrkB inhibitor