Mechanistic aspects of cell type and drug specific inhibition of DNA methyltransferase 1

The notion that epigenetic processes may be crucially implicated in the development of psychiatric diseases raised the question whether psychoactive drugs may impact on the epigenetic machinery. Here we explored specificity and mode of action of the inhibitory effect of the tricyclic antidepressant (AD) amitriptyline (AMI) on DNA methyltransferase (DNMT) activity in cortical astrocytes. We found that another tricyclic antidepressant, imipramine, as well as the SSRI paroxetine, but not venlafaxine, carbamazepine or valproic acid decreased DNMT activity, while a trend was observed for citalopram. Surprisingly, DNMT activity in primary cortical neurons and subventricular neural stem cells (NSCs) was not changed upon AD treatment, indicating a cell type specific effect. Among the established mammalian DNMTs we identified DNMT1 as target of psychoactive drugs. The reduction of enzymatic DNMT1 activity was not caused by diminished expression, and also not by a direct drug action on DNMT1. Therefore, we tested various modulators of DNMT1 activity, including S-adenosyl homocysteine, NAA10 and CDKL5 levels as well as sumoylation and phosphorylation dependent interaction with PCNA and UHRF1. Altogether, our study presents a model where ADs impact on DNMT1 activity in a cell-type dependent and drug-specific fashion. Hence, it contributes to the understanding of antidepressants mode of action and may add to the development of novel treatment regimes.