Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats

Sara Morley-Fletcher, Jerome Mairesse, Amelie Soumier, Mounira Banasr, Francesca Fagioli, Cecilia Gabriel, Elisabeth Mocaer, Annie Daszuta, Bruce McEwen, Ferdinando Nicoletti, Stefania MacCari

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale and objectives: The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 melatonin receptor agonist/5-HT2c serotonin receptor antagonist. Results: Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3-or 6-week treatment with agomelatine (40-50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a " diseasedependent" drug. Conclusions: These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders.

Original languageEnglish
Pages (from-to)301-313
Number of pages13
JournalPsychopharmacology
Volume217
Issue number3
DOIs
Publication statusPublished - 2011

Keywords

  • Adult neurogenesis
  • Agomelatine
  • Fluoxetine
  • Metabotropic glutamate receptors
  • Phospho-CREB
  • Prenatal stress
  • Ventral hippocampus

ASJC Scopus subject areas

  • Pharmacology

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