Long-term imipramine treatment increases N-methyl-D-aspartate receptor activity and expression via epigenetic mechanisms

摘要

Imipramine, a major antidepressant, is known to inhibit reuptake of serotonin and norepinephrine, which contributes to recovery from major depressive disorder. It has recently been reported that acute imipramine treatment inhibits N-methyl-D-aspartate (NMDA) receptor activity. However, the mechanisms underlying lung term effects of imipramine have nor been identified. We rested these distinct effects in mouse cortical neurons and found that acute (30 s) imipramine treatment decreased Ca2+ influx through NMDA receptors, whereas long term treatment (48 h) increased Ca2+ influx via the same receptors. Furthermore, long term treatment increased NMDA receptor 2B (NR2B) subunit expression via epigenetic changes, including increased acetylation of histones H3K9 and H3K27 in the NR2B promoter and decreased activity of histone deacetylase 3 (HDAC3) and HDAC4. These results suggest that the long term effects of imipramine on NMDA receptors are quire different from its acute effects. Furthermore, increased NR2B expression via epigenetic alterations might be a part of the mechanism responsible for this long-term effect. (C) 2015 Elsevier B.V. All rights reserved.