Imipramine, a major antidepressant, is known to inhibit the re-uptake of serotonin and noradrenaline, which is thought to contribute to the recovery from depression. It has recently been reported that imipramine can acutely inhibit NMDA receptor activity. However, it is not known about the long-term effect of imipramine on NMDA receptor. Therefore, we investigated the acute and long-term effects of imipramine on NMDA receptor in primary cortex neurons obtained from mice at embryonic Day 15 (E15) using fluorescence calcium imaging.
As a result, the acute (30 sec) imipramine treatment dose-dependently decreased the intracellular calcium ([Ca²⁺]_i) influx mediated by NMDA receptors. However, the long-term treatment of imipramine (48 hrs) increased [Ca²⁺]_i influx mediated by NMDA receptors. Furthermore, the long-term treatment induced the increase in expression of NR2B protein, one of the subunit of NMDA receptors. To evaluate the mechanism, we investigate the HDAC activity and expression following 48 hr imipramine treatment, the result showed the global HDAC activity, together with HDAC3 and HDAC4 protein expressions, were decreased in imipramine-treated neurons. Moreover, acetyl histone H3K9 and H3K27 expression were increased at both the global level and the local chromatin of NR2B promoter genes following 48 hr-treated imipramine. Taken together, these results suggested that imipramine has two kind of effect, acute and long-term, on NMDA receptors and imipramine directly enhances NR2B expression through epigenetic regulation mediated by HDAC acitivity.