title: Rapid anxiolytic effects of a 5-HT₄ receptor agonist are mediated by a neurogenesis-independent mechanism.
abstract: Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT₄ receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT₄ receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression, and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT₄ receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety- and depression-related behaviors, as well as on hippocampal neurogenesis in comparison with chronic fluoxetine treatment (18 mg/kg/day). Then, using our anxiety/depression model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7 days) or chronic (28 days) RS67333 treatment. We also assessed whether a 5-HT₄ receptor antagonist (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis, specifically facilitating maturation of newborn neurons. However, unlike fluoxetine, anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT₄ receptor activation is necessary for these effects of SSRIs. 5-HT₄ receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.
authors.affiliation: Univ Paris Sud, EA3544, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Indira
authors.initials: I
authors.lastname: Mendez-David
authors.affiliation: Univ Paris Sud, EA3544, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Denis J
authors.initials: DJ
authors.lastname: David
authors.affiliation: Univ Paris Sud, EA3544, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Flavie
authors.initials: F
authors.lastname: Darcet
authors.affiliation: 1] Departments of Neuroscience and Psychiatry, Columbia University, New York, NY, USA [2] Department of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Melody V
authors.initials: MV
authors.lastname: Wu
authors.affiliation: Univ Paris Sud, INSERM UMR 996, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Saadia
authors.initials: S
authors.lastname: Kerdine-Römer
authors.affiliation: Univ Paris Sud, EA3544, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
authors.affiliation: 1] Departments of Neuroscience and Psychiatry, Columbia University, New York, NY, USA [2] Department of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: René
authors.initials: R
authors.lastname: Hen
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D015897:Comorbidity; D003345:Corticosterone; D003866:Depressive Disorder / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology*; D058832:Serotonin 5-HT4 Receptor Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000814:Aniline Compounds; D014151:Anti-Anxiety Agents; D018687:Antidepressive Agents, Second-Generation; D007211:Indoles; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D013449:Sulfonamides; D005473:Fluoxetine; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333; D003345:Corticosterone; C082871:GR 113808