Quetiapine treatment reverses depressive-like behavior and reduces DNA methyltransferase activity induced by maternal deprivation

Abstract

Stress in early life has been appointed as an important phenomenon in the onset of depression and poor response to treatment with classical antidepressants. Furthermore, childhood trauma triggers epigenetic changes, which are associated with the pathophysiology of major depressive disorder (MDD). Treatment with atypical antipsychotics such as quetiapine, exerts therapeutic effect for MDD patients and induces epigenetic changes. This study aimed to analyze the effect of chronic treatment with quetiapine (20mg/kg) on depressive-like behavior of rats submitted to maternal deprivation (MD), as well as the activity of histone acetylation by the enzymes histone acetyl transferases (HAT) and deacetylases (HDAC) and DNA methylation, through DNA methyltransferase enzyme (DNMT) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus. Maternally deprived rats had a depressive-like behavior in the forced swimming test and an increase in the HDAC and DNMT activities in the hippocampus and NAc. Treatment with quetiapine reversed depressive-like behavior and reduced the DNMT activity in the hippocampus. This is the first study to show the antidepressant-like effect of quetiapine in animals subjected to MD and a protective effect by quetiapine in reducing epigenetic changes induced by stress in early life. These results reinforce an important role of quetiapine as therapy for MDD.

Effects of maternal separation and antidepressant drug on epigenetic regulation of the brain‐derived neurotrophic factor exon I promoter in the adult rat hippocampus

“…MS promotes change in the expression of DNMT1 and DNMT3a, which are representative of maintenance and de novo methyltransferase activity, respectively. Our findings are consistent with a previous study showing that MS (3 h daily from PND 1 to PND 10) increased DNMT activity in the hippocampus of adult rats . Another study found an increase in DNMT1 expression in the dentate gyrus‐derived neural precursor cells of adult rats subjected to MS (3 h daily from PND 2 to PND 14) .…”

“…ESC reversed hypermethylation of the p11 gene promoter in the prefrontal cortex of a genetic rat model of depression and reduced mRNA expression of DNMT1 and DNMT3a . A more recent study found that the antipsychotic drug, quetiapine, reversed depression‐like behavior and increased maternal deprivation‐induced DNMT activity in the hippocampus . We found that chronic ESC treatment clearly prevented the MS‐induced decreases in DNMT1 and DNMT3a expression in the adult hippocampus.…”

“…71 A more recent study found that the antipsychotic drug, quetiapine, reversed depression-like behavior and increased maternal deprivation-induced DNMT activity in the hippocampus. 67 We found that chronic ESC treatment clearly prevented the MS-induced decreases in DNMT1 and DNMT3a expression in the adult hippocampus. Our study, together with others, provides evidence supporting the hypothesis that antidepressant drugs may exert direct epigenetic effects.…”

“…Our findings are consistent with a previous study showing that MS (3 h daily from PND 1 to PND 10) increased DNMT activity in the hippocampus of adult rats. 67 Another study found an increase in DNMT1 expression in the dentate gyrusderived neural precursor cells of adult rats subjected to MS (3 h daily from PND 2 to PND 14). 68 Moreover, the authors reported that MS attenuated the neural differentiation of adult neural precursor cells, which was reversed by a DNMT inhibitor.…”

“…Contrary to these findings, one study found that DNMT1 and DNMT3a mRNA levels were reduced in the medial prefrontal cortex of maltreated rats, 62 and another found no change in DNMT activity in the prefrontal cortex of MS rats. 67 It may be that the DNMT response to ELS is different in the hippocampus and prefrontal cortex.…”