Psychopharmacology, 2011, Vol.217(3), pp.301-313
Byline: Sara Morley-Fletcher (1), Jerome Mairesse (1), Amelie Soumier (2), Mounira Banasr (2), Francesca Fagioli (3), Cecilia Gabriel (4), Elisabeth Mocaer (4), Annie Daszuta (2), Bruce McEwen (5), Ferdinando Nicoletti (1,6,7), Stefania Maccari (1) Keywords: Agomelatine; Prenatal stress; Adult neurogenesis; Ventral hippocampus; Fluoxetine; Phospho-CREB; Metabotropic glutamate receptors Abstract: Rationale and objectives The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 melatonin receptor agonist/5-HT.sub.2c serotonin receptor antagonist. Results Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40--50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a "disease-dependent" drug. Conclusions These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders. Author Affiliation: (1) Neuroplasticity Team, UMR 8576 CNRS Structural and Functional Glycobiology Unit, University Lille North of France (USTL), 59655, Villeneuve d'Ascq, France (2) IC2N, IBDLM, UMR6216, CNRS, Marseille, France (3) Azienda Sanitaria Locale, RM.E. Unita Operativa Complessa Adolescent, Rome, Italy (4) Institut de Recherches Internationales Servier, Courbevoie, France (5) Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, USA (6) Department of Human Physiology and Pharmacology, Sapienza University, Rome, Italy (7) I.N.M. Neuromed, Pozzilli, Italy Article History: Registration Date: 24/03/2011 Received Date: 10/01/2011 Accepted Date: 23/03/2011 Online Date: 19/04/2011 Article note: S. Morley-Fletcher and J. Mairesse contributed equally to this work.
Agomelatine ; Prenatal stress ; Adult neurogenesis ; Ventral hippocampus ; Fluoxetine ; Phospho-CREB ; Metabotropic glutamate receptors
View full text in Springer (Subscribers only)