Rapid Anxiolytic Effects of a 5-HT sub(4) Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 39; no. 6; pp. 1366 - 1378
• Main Authors: Mendez-David, Indira, David, Denis J, Darcet, Flavie, Wu, Melody V, Kerdine-Romer, Saadia, Gardier, Alain M, Hen, Rene
• Format: Journal Article
• Language: English
• Published: 01.05.2014
• ISSN: 0893-133X
• DOI: 10.1038/npp.2013.332

Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT sub(4) receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT sub(4) 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-HT sub(4) 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-HT sub(4) 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-HT sub(4) receptor activation is necessary for these effects of SSRIs. 5-HT sub(4) receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.