Antidepressant‐like effect induced by systemic and intra‐hippocampal administration of DNA methylation inhibitors

BACKGROUND AND PURPOSE: Epigenetic modifications are thought to play an important role in the neurobiology of depression. Antidepressant treatment induces histone acetylation in the hippocampus, which is associated with transcriptional activation, whereas stress increases DNA methylation, which is associated with transcriptional repression. Because the specific involvement of DNA methylation in the regulation of depressive-like behaviours is not yet known, we have investigated the effects induced by systemic or intra-hippocampal administration of inhibitors of DNA methyltransferase (DNMT) in rats submitted to a range of behavioural tests. EXPERIMENTAL APPROACH: Rats received i.p. injections of 5-aza-2-deoxycytidine (5-azaD, 0.1-0.8 mg·kg(-1) ), 5-azacytidine (5-azaC, 0.4-3.2 mg·kg(-1) ), imipramine (15 mg·kg(-1) ) or vehicle and were submitted to the forced swimming test (FST) or open field test (OFT). Other groups of rats received intra-hippocampal injection of DNMT inhibitors. KEY RESULTS: Systemic administration of DNMT inhibitors induced a dose-dependent antidepressant-like effect, which was followed by decreased DNA methylation and increased brain-derived neurotrophic factor (BDNF) levels in the hippocampus. Hippocampal inhibition of DNA methylation induced similar behavioural effects. No treatment induced any locomotor effects in the OFT. Antidepressant-like effects of 5-azaD were confirmed in mice submitted to the FST or the tail suspension test. CONCLUSIONS AND IMPLICATIONS: Systemic, as well as hippocampal, inhibition of DNA methylation induced antidepressant-like effects. These effects could be associated with increased hippocampal expression of BDNF. Our data give further support to the hypothesis that DNA methylation is an important epigenetic mechanism involved in the development of depressive-like behaviours.