Elsevier

Biological Psychiatry

Volume 59, Issue 11, 1 June 2006, Pages 1087-1096
Biological Psychiatry

Original article
Agomelatine, a New Antidepressant, Induces Regional Changes in Hippocampal Neurogenesis

https://doi.org/10.1016/j.biopsych.2005.11.025Get rights and content

Background

Antidepressant treatments increase neural plasticity and adult neurogenesis, especially in the hippocampus. Here, we determined the effects of agomelatine (S-20098), a new antidepressant, on various phases of neurogenesis in the dentate gyrus of adult rat.

Methods

Animals were injected with agomelatine for different time periods. Immunostaining for bromodeoxyuridine, neuron specific nuclear protein, and glial fibrillary acid protein, as well as for the highly polysialylated form of neuronal cell adhesion molecule and doublecortin, was used to detect changes in cell proliferation, neurogenesis, and survival. Cell death was estimated by terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling and cresyl violet staining.

Results

Chronic (3 weeks) but not acute (4 hours) or subchronic (1 week) administration of agomelatine increased cell proliferation and neurogenesis in the ventral dentate gyrus, a region notably implicated in response to emotion, which is consistent with the antidepressant–anxiolytic properties of the drug. Extending agomelatine treatment over several weeks, however, increases survival of newly formed neurons in the entire dentate gyrus. Finally, agomelatine treatment does not affect mature granule cells.

Conclusions

This study shows that an antidepressant can affect differentially various stages of neurogenesis in the dorsal and ventral hippocampus. Altogether, these changes lead to a pronounced augmentation in the total number of new granule cells.

Section snippets

Animals

Adult 8-week-old male Wistar rats (220–240 g; Iffa Credo, l’Arbresles, France) were group-housed (three per cage) in a temperature-controlled room (21°C) and maintained on a 12-hour light/dark cycle with free access to food and water. This study was carried out in accordance with the French Agriculture and Forestry Ministry (decree 87848, license 01498). There were five to seven rats per group.

Treatment

The dose of agomelatine used in the present study was chosen on the basis of its activity in various

Hippocampus

The BrdU-labeled cells are located in the SGZ and frequently associated in clusters shortly after injection (Figure 3A). The total numbers of BrdU-positive cells were not significantly different over time in the acute (4 hours), subchronic (1 week), and chronic (3 weeks) control groups (Figure 4A). Although no effect was observed after 4 hours or 1 week of agomelatine treatment, a tendency toward an increase was observed in 3-week-treated rats (Figure 4A). Then a separate analysis was conducted

Discussion

Agomelatine is a new drug with demonstrated antidepressant activity in both preclinical animal models of depression (Bourin et al 2004, Papp et al 2003) and in patients with major depressive disorders (Loo et al 2002b, Loo et al 2003). Here, we demonstrate that chronic administration of agomelatine increases the absolute number of newly formed granule neurons in the DG of nonstressed rats. Beside the stimulatory effect of agomelatine on cell proliferation and neurogenesis, agomelatine increases

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