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Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine

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Abstract

Rationale

Neuronal plasticity is associated with depression, probably as a result of modified expression of proteins important for cellular resiliency. It is therefore important to establish if and how antidepressant drugs may be able to regulate these mechanisms in order to achieve relevant clinical effects.

Objective

We investigated the effects of chronic treatment with agomelatine (an MT1/MT2 receptor agonist and 5-HT2C receptor antagonist) on the brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF-2), and activity-regulated cytoskeleton-associated protein (Arc).

Methods

Animals were treated for 21 days with agomelatine, venlafaxine, or a vehicle and sacrificed 1 h (6 p.m.) or 16 h after the last injection (9 a.m.) to evaluate the messenger RNA (mRNA) and protein expression of these neuroplastic markers in the hippocampus and prefrontal cortex.

Results

Agomelatine, but not venlafaxine, produced major transcriptional changes in the hippocampus, where significant up-regulations of BDNF and FGF-2 were observed. Both drugs up-regulated the Arc transcription levels. No effects were observed in the prefrontal cortex. Instead, the levels of BDNF protein were elevated by agomelatine in both regions: the effects of the drug on mRNA levels in the hippocampus and cortex are different, while the effects on the protein seem to have the same cumulative result, suggesting different modulatory mechanisms in the two regions.

Conclusions

Our data provide new information regarding the molecular mechanisms that contribute to the chronic effects of the new antidepressant agomelatine on brain function. The ability of agomelatine to modulate the expression of these neuroplastic molecules, which follows a circadian rhythm, may contribute to its antidepressant action.

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Acknowledgments

Special thanks to Dr J Richetto for contributing to part of this study.

Conflict of interest statement

C.G. and E.M. are employed by Servier. The authors F.C., R.M., G.R. and M.A.R. have no biomedical financial interests or potential conflicts of interest to declare.

This research has been supported by a grant from SERVIER to G.R.

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Authors and Affiliations

  1. Center of Neuropharmacology, Department of Pharmacological Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy

    Francesca Calabrese, Raffaella Molteni, Giorgio Racagni & Marco A. Riva

  2. Institut de Recherches Internationales Servier (I.R.I.S.), Courbevoie, France

    Cecilia Gabriel & Elisabeth Mocaer

  3. Genetic Unit, IRCCS San Giovanni di Dio, Fatebenefratelli, Brescia, Italy

    Giorgio Racagni

  4. Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy

    Giorgio Racagni & Marco A. Riva

Authors
  1. Francesca Calabrese
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  2. Raffaella Molteni
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  3. Cecilia Gabriel
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  4. Elisabeth Mocaer
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  5. Giorgio Racagni
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  6. Marco A. Riva
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Corresponding author

Correspondence to Marco A. Riva.

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Calabrese, F., Molteni, R., Gabriel, C. et al. Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine. Psychopharmacology 215, 267–275 (2011). https://doi.org/10.1007/s00213-010-2129-8

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  • DOI: https://doi.org/10.1007/s00213-010-2129-8

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