title: Long-term imipramine treatment increases N-methyl-d-aspartate receptor activity and expression via epigenetic mechanisms.
abstract: 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 long-term effects of imipramine have not been identified. We tested these distinct effects in mouse cortical neurons and found that acute (30s) imipramine treatment decreased Ca(2+) influx through NMDA receptors, whereas long-term treatment (48h) increased Ca(2+) 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 quite 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.
authors.affiliation: Department of Epigenetic Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Nguyen An
authors.initials: NA
authors.lastname: Nghia
authors.affiliation: Department of Epigenetic Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan; Japan Science and Technology Agency (JST), CREST, 4-1-8 Honcho, Kawaguchi, Saitama, Japan. Electronic address: h-takae@nasu.bio.teikyo-u.ac.jp.
authors.forename: Takae
authors.initials: T
authors.lastname: Hirasawa
authors.affiliation: Department of Microbiology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Kasai
authors.affiliation: Department of Epigenetic Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan; Japan Science and Technology Agency (JST), CREST, 4-1-8 Honcho, Kawaguchi, Saitama, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Obata
authors.affiliation: Department of Microbiology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Moriishi
authors.affiliation: Faculty of Life and Environmental Sciences, University of Yamanashi, Takeda, Kofu, Yamanashi 409-8510, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Mochizuki
authors.affiliation: Department of Pharmacology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Schuichi
authors.initials: S
authors.lastname: Koizumi
authors.affiliation: Department of Epigenetic Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kubota
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D051379:Mice; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D006657:Histones; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D007099:Imipramine; D002118:Calcium
keywords: Epigenetics; Histone acetylation; Imipramine; NMDA receptor; NR2B; Neocortical neuron