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Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

Published online by Cambridge University Press:  26 June 2015

Amanda Juliana Sales  and
Sâmia Regiane Lourenço Joca
Amanda Juliana Sales
Affiliation:
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto-SP, Brazil
Sâmia Regiane Lourenço Joca*
Affiliation:
Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto-SP, Brazil Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Ribeirão Preto-SP, Brazil
*
Sâmia Joca, FCFRP-USP, Av Café, sn, Monte Alegre, Ribeirão Preto-SP 14040-903, Brazil. Tel: +55 163 315 4705; Fax: +55 163 315 4880; E-mail: samia@usp.br
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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 (0.1mg/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.

Conclusion

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.

Keywords

AntidepressantDNA methylationRG1085-AzaD
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 28 , Issue 1 , February 2016 , pp. 11 - 22
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Copyright
© Scandinavian College of Neuropsychopharmacology 2015 

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