title: Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine.
abstract: BACKGROUND
  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 MT(1)/MT(2) receptor agonist and 5-HT(2C) 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.
authors.affiliation: Center of Neuropharmacology, Department of Pharmacological Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Calabrese
authors.forename: Raffaella
authors.initials: R
authors.lastname: Molteni
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gabriel
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mocaer
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D000069470:Venlafaxine Hydrochloride; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D003511:Cyclohexanols; D016222:Fibroblast Growth Factor 2; D000069470:Venlafaxine Hydrochloride; C084711:agomelatine; D009281:Naphthalenes