title: Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels.
abstract: OBJECTIVE
  Stress increases DNA methylation and decreases the expression of genes involved in neural plasticity, while treatment with DNA methyltransferase inhibitors (DNMTi) increases gene expression and induces antidepressant-like effects in preclinical models. Therefore, the aim of the present work was to further investigate the potential antidepressant-like effect induced by DNMTi by evaluating the behavioural effects induced by associating DNMTi treatment with conventional antidepressant drugs in mice submitted to the forced swimming test (FST). In addition, brain levels of DNA methylation were also investigated.
  
  
  METHODS
  Mice received systemic injections of 5-aza-2'-deoxycytidine (5-AzaD, 0.1, 0.2 mg/kg), RG108 (0.1, 0.2, 0.4 mg/kg), desipramine (DES, 2.5, 5, 10 mg/kg) or fluoxetine (FLX, 5, 10, 20, 30 mg/kg) and were submitted to the FST or to the open field test (OFT). Additional groups received a combination of subeffective doses of 5-AzaD or RG108 (DNMTi) with subeffective doses of DES or FLX (antidepressants).
  
  
  RESULTS
  Subeffective doses of RG108 (0.1 mg/kg) or 5-AzaD (0.1 mg/kg) in association with subeffective doses of DES (2.5 mg/kg) or FLX (10 mg/kg) induced significant antidepressant-like effects. Effective doses of RG108 (0.2 mg/kg), 5-AzaD (0.2 mg/kg), DES (10 mg/kg) and FLX (20 mg/kg) atenuated stress-induced changes in DNA methylation levels in the hippocampus and prefrontal cortex. None of the treatments induced locomotor effects in the OFT.
  
  
  CONCLUSIONS
  These results suggest that DNMTi potentiate the behavioural effects of antidepressant drugs in the FST and that antidepressants, as well as DNMTi, are able to modulate stress-induced changes in DNA methylation in brain regions closely associated with the neurobiology of depression.
authors.affiliation: 1Department of Pharmacology,School of Medicine of Ribeirão Preto,University of São Paulo,Ribeirão Preto-SP,Brazil.
authors.forename: Amanda Juliana
authors.initials: AJ
authors.lastname: Sales
authors.affiliation: 2Department of Physics and Chemistry,School of Pharmaceutical Sciences of Ribeirão Preto,University of São Paulo,Ribeirão Preto-SP,Brazil.
authors.forename: Sâmia Regiane Lourenço
authors.initials: SR
authors.lastname: Joca
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D013550:Swimming / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; C485852:Dmap1 protein, mouse; D012097:Repressor Proteins
keywords: 5-AzaD; Antidepressant; DNA methylation; RG108