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

Abstract

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.

Epigenetic regulation of Dnmt3a and Arc gene expression after electroconvulsive stimulation in the rat

“…Decitabine has previously been found to reduce global DNA methylation in the hippocampus of rats (Sales et al, 2011) and to prevent ECS-induced de novo methylation in mice (Guo et al, 2011). Therefore, we decided to inject rats with 0.4 mg·kg −1 decitabine or saline coinciding with ECS or sham treatment and sacrifice the animals after 4 h. An 80% increase in Dnmt3a expression was observed after saline-ECS as compared to saline-sham (p b 0.001, Fig.…”

“…Furthermore, there was a significant effect of decitabine on Dnmt3a expression after 48 h irrespective of ECS or sham. The attenuation of ECS-induced Dnmt3a upregulation suggests that the enzyme is indeed inhibited, which is supported by the observation of a global reduction in DNA methylation in rat hippocampus in a similar setting with the same drug dosage (Sales et al, 2011). ECS causes rapid active demethylation or de novo methylation at a high number of CpG sites in mouse dentate granule neurons (Guo et al, 2011).…”

“…We decided to do intraperitoneal (i.p.) injections as this has previously been demonstrated to effectively reduce global DNA methylation in the hippocampus (Sales et al, 2011). In our previous study, we measured DNA methylation in a gene region located immediately upstream of the 5′UTR.…”

Epigenetic mechanisms underlying the role of brain-derived neurotrophic factor in depression and response to antidepressants

“…Interestingly, the DNMT inhibitor RG108 reverses social-defeatinduced social avoidance to a similar extent as chronic treatment with the classical antidepressant fluoxetine (LaPlant et al, 2010). Moreover, the DNMT inhibitors 5-azaD, 5-azaC and RG108 exhibit antidepressant activity in the forced-swim test when injected systemically or in the hippocampus of rats (Sales et al, 2011), suggesting that hippocampal inhibition of DNMT is sufficient to exert antidepressant effects. Mechanistically, the targets of DNMT inhibitors mediating their antidepressant effects remain to be investigated.…”

Could decitabine treatment impair memory functions in humans?

“…For example, decitabine concentration used to inhibit LTP formation is 30 lM [6,7]. In an animal study, however, mice injected intraperitoneally with three consecutive doses of 0.4 mg/kg decitabine over 23 h show both increased BDNF protein levels and significant global DNA demethylation in hippocampus [27]. Total dose used in this experiment is comparable to MDS treatment schedules.…”