Epigenetic mechanisms, such as DNA methylation (is regulated by DNMTs), are thought to play an important role in the neurobiology of depression. In this sense, we demonstrated that inhibitors DNA methylation have antidepressant-like effect in animals submitted to forced swimming test and tail suspension. Objectives: Whereas DNMTs inhibitors have different mechanism of action the conventional antidepressants, this study will test the hypothesis that these drugs induce the same behavioral effect but acute and long term. In addition, we will evaluate if the stress would be able to induce change in the mRNA and DNA methylation levels in different genes associated with depression and regulated by epigenetic mechanisms (BDNF, TrkB, 5-HT1A, NMDA, AMPA) in different brain structures (dorsal and ventral hippocampus, and prefrontal cortex) and whether these changes were attenuated by treatment with acute administration of DNMTs inhibitors and chronis adinistration of antidepressants. Methods: Rats will be submitted to the inescapable shocks (IC) or habituation (Hab) and will receive systemic injection of DNMTs inhibitors, 5-Azad (0.1, 0.2 and 0.4 mg / kg; n=10-12/group) and RG108 (0.2, 0.4 and 0.6 mg / kg; n=10-12/group), antidepressants, imipramine (15 mg / kg; n=10-12/group) or fluoxetine (20 mg / kg; n=10-12/group) or vehicle for 1 (acute group) or 7 days (chronic group) and submitted to the learned helplessness test on the last day. Additionally, a group will be submitted only to the pre-test and will receive the treatments, and the last injection will be administered 1 hour before sacrifice (n=10-12/group). The animals will be anesthetized, decapitated and dissected the brain structures for RNA and methylated DNA isolation for subsequent quantification by real time qPCR.
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