title: Hippocampal and behavioral dysfunctions in a mouse model of environmental stress: normalization by agomelatine.
abstract: Stress-induced alterations in neuronal plasticity and in hippocampal functions have been suggested to be involved in the development of mood disorders. In this context, we investigated in the hippocampus the activation of intracellular signaling cascades, the expression of epigenetic markers and plasticity-related genes in a mouse model of stress-induced hyperactivity and of mixed affective disorders. We also determined whether the antidepressant drug agomelatine, a MT1/MT2 melatonergic receptor agonist/5-HT2C receptor antagonist, could prevent some neurobiological and behavioral alterations produced by stress. C57BL/6J mice, exposed for 3 weeks to daily unpredictable socio-environmental stressors of mild intensity, were treated during the whole procedure with agomelatine (50 mg kg(-1) per day, intraperitoneal). Stressed mice displayed robust increases in emotional arousal, vigilance and motor activity, together with a reward deficit and a reduction in anxiety-like behavior. Neurobiological investigations showed an increased phosphorylation of intracellular signaling proteins, including Atf1, Creb and p38, in the hippocampus of stressed mice. Decreased hippocampal level of the repressive epigenetic marks HDAC2 and H3K9me2, as well as increased level of the permissive mark H3K9/14ac suggested that chronic mild stress was associated with increased gene transcription, and clear-cut evidence was further indicated by changes in neuroplasticity-related genes, including Arc, Bcl2, Bdnf, Gdnf, Igf1 and Neurod1. Together with other findings, the present data suggest that chronic ultra-mild stress can model the hyperactivity or psychomotor agitation, as well as the mixed affective behaviors often observed during the manic state of bipolar disorder patients. Interestingly, agomelatine could normalize both the behavioral and the molecular alterations induced by stress, providing further insights into the mechanism of action of this new generation antidepressant drug.
authors.affiliation: 1] Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris, France [2] Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands [3] European Graduate School for Neuroscience (EURON), Maastricht, The Netherlands [4] Université Paris Descartes Paris 5, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Boulle
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Massart
authors.affiliation: 1] Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris, France [2] UPMC, Université Paris 6, UMR S677, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Stragier
authors.affiliation: 1] Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris, France [2] UPMC, Université Paris 6, UMR S677, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Païzanis
authors.affiliation: 1] Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris, France [2] UPMC, Université Paris 6, UMR S677, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Zaidan
authors.affiliation: 1] Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris, France [2] UPMC, Université Paris 6, UMR S677, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Marday
authors.affiliation: IRIS, Suresnes, France.
authors.forename: C
authors.initials: C
authors.lastname: Gabriel
authors.affiliation: IRIS, Suresnes, France.
authors.forename: E
authors.initials: E
authors.lastname: Mocaer
authors.affiliation: 1] Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris, France [2] Université Paris Descartes Paris 5, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Mongeau
authors.affiliation: 1] Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris, France [2] UPMC, Université Paris 6, UMR S677, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Lanfumey
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology*; D000342:Affective Symptoms / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D011595:Psychomotor Agitation / Q000188:drug therapy / Q000209:etiology; D044094:Receptors, Melatonin / Q000819:agonists; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D044094:Receptors, Melatonin; D058830:Serotonin 5-HT2 Receptor Antagonists; C084711:agomelatine; D009281:Naphthalenes