title: Beneficial behavioural and neurogenic effects of agomelatine in a model of depression/anxiety.
abstract: Agomelatine (S20098) is a novel antidepressant drug with melatonergic agonist and 5-HT2C receptor antagonist properties, displaying antidepressant/anxiolytic-like properties in animal models and in humans. In a depression/anxiety-like mouse model in which the response of the HPA axis is blunted, we investigated whether agomelatine could reverse behavioural deficits related to depression/anxiety compared to the classical selective serotonin reuptake inhibitor, fluoxetine. Adult mice were treated for 8 wk with either vehicle or corticosterone (35 μg/ml.d) via drinking water. During the final 4 wk, animals were treated with vehicle, agomelatine (10 or 40 mg/kg i.p.) or fluoxetine (18 mg/kg i.p.) and tested in several behavioural paradigms and also evaluated for home-cage activity. Our results showed that the depressive/anxiety-like phenotype induced by corticosterone treatment is reversed by either chronic agomelatine or fluoxetine treatment. Moreover, agomelatine increased the dark/light ratio of home-cage activity in vehicle-treated mice and reversed the alterations in this ratio induced by chronic corticosterone, suggesting a normalization of disturbed circadian rhythms. Finally, we investigated the effects of this new antidepressant on neurogenesis. Agomelatine reversed the decreased cell proliferation in the whole hippocampus in corticosterone-treated mice and increased maturation of newborn neurons in both vehicle- and corticosterone-treated mice. Overall, the present study suggests that agomelatine, with its distinct mechanism of action based on the synergy between the melatonergic agonist and 5-HT2C antagonist properties, provides a distinct antidepressant/anxiolytic spectrum including circadian rhythm normalization.
authors.affiliation: Université Paris-Sud EA3544, Laboratoire Neuropharmacologie, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Rainer
authors.affiliation: Université Paris-Sud EA3544, Laboratoire Neuropharmacologie, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Lin
authors.initials: L
authors.lastname: Xia
authors.affiliation: Université Paris-Sud EA3544, Laboratoire Neuropharmacologie, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Guilloux
authors.affiliation: Institut de Recherches Internationales Servier, Courbevoie, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gabriel
authors.affiliation: Institut de Recherches Internationales Servier, Courbevoie, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mocaër
authors.affiliation: Departments of Neuroscience and Psychiatry, Columbia University, New York, NY, USA.
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.affiliation: Université Paris-Sud EA3544, Laboratoire Neuropharmacologie, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Enhamre
authors.affiliation: Université Paris-Sud EA3544, Laboratoire Neuropharmacologie, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
authors.affiliation: Université Paris-Sud EA3544, Laboratoire Neuropharmacologie, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Denis J
authors.initials: DJ
authors.lastname: David
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D003345:Corticosterone; D005473:Fluoxetine; D058830:Serotonin 5-HT2 Receptor Antagonists; C084711:agomelatine; D009281:Naphthalenes