Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

• Published in: Neuropsychopharmacology Vol. 34; no. 11; pp. 2390 - 2403
• Main Authors: SOUMIER, Amélie, BANASR, Mounira, LORTET, Sylviane, MASMEJEAN, Frédérique, BERNARD, Nathalie, KERKERIAN-LE-GOFF, Lydia, GABRIEL, Cecilia, MILLAN, Mark J, MOCAER, Elisabeth, DASZUTA, Annie
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.10.2009
• Subjects: Acetamides - pharmacology; Animals; Antidepressants; Antidepressive Agents - pharmacology; Biological and medical sciences; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - physiology; Cellular Biology; Hippocampus - drug effects; Hippocampus - physiology; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Investigative techniques, diagnostic techniques (general aspects); Kinases; Life Sciences; Male; Medical sciences; Nervous system; Neurogenesis - drug effects; Neurogenesis - physiology; Neurons - drug effects; Neurons - physiology; Neuropharmacology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Wistar; Receptors, Melatonin - antagonists & inhibitors; Receptors, Melatonin - metabolism; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction - drug effects; Vascular Endothelial Growth Factor A - metabolism; France; Immunohistochemistry; Melatonin; Rat; Psychotropic; Central nervous system; Neurogenesis; Encephalon; Signal transduction; Immunoblotting assay; Antidepressant agent; Mechanism of action; 5-HT2C serotonin receptor; Pineal hormone; trophic factors; Rodentia; Trophic factor; antidepressant; Exploration; Experimental study; In vitro; Vertebrata; Mammalia; receptor; Analog; Adult animal; cell signaling; Agomelatine; 5-HT; ELISA assay; Hippocampus
• ISSN: 0893-133X; 1740-634X; 0007-0920
• DOI: 10.1038/npp.2009.72

Agomelatine is a novel antidepressant acting as a melatonergic receptor agonist and serotonergic (5-HT(2C)) receptor antagonist. In adult rats, chronic agomelatine treatment enhanced cell proliferation and neurogenesis in the ventral hippocampus (VH), a region pertinent to mood disorders. This study compared the effects of agomelatine on cell proliferation, maturation, and survival and investigated the cellular mechanisms underlying these effects. Agomelatine increased the ratio of mature vs immature neurons and enhanced neurite outgrowth of granular cells, suggesting an acceleration of maturation. The influence of agomelatine on maturation and survival was accompanied by a selective increase in the levels of BDNF (brain-derived neurotrophic factor) vs those of VEGF (vascular endothelial factor) and IGF-1 (insulin-like growth factor 1), which were not affected. Agomelatine also activated several cellular signals (extracellular signal-regulated kinase1/2, protein kinase B, and glycogen synthase kinase 3beta) known to be modulated by antidepressants and implicated in the control of proliferation/survival. Furthermore, as agomelatine possesses both melatonergic agonist and serotonergic (5-HT(2C)) antagonist properties, we determined whether melatonin and 5-HT(2C) receptor antagonists similarly influence cell proliferation and survival. Only the 5-HT(2C) receptor antagonists, SB243,213 or S32006, but not melatonin, mimicked the effects of agomelatine on cell proliferation in VH. The promoting effect of agomelatine on survival was not reproduced by the 5-HT(2C) receptor antagonists or melatonin alone. However, it was blocked by a melatonin antagonist, S22153. These results show that agomelatine treatment facilitates all stages of neurogenesis and suggest that a joint effect of melatonin agonism and 5HT(2C) antagonism may be involved in promotion by agomelatine of survival in the hippocampus.