title: Amitriptyline induces brain-derived neurotrophic factor (BDNF) mRNA expression through ERK-dependent modulation of multiple BDNF mRNA variants in primary cultured rat cortical astrocytes and microglia.
abstract: A significant role of brain-derived neurotrophic factor (BDNF) has been previously implicated in the therapeutic effect of antidepressants. To ascertain the contribution of specific cell types in the brain that produce BDNF following antidepressant treatment, the effects of the tricyclic antidepressant amitriptyline on rat primary neuronal, astrocytic and microglial cortical cultures were examined. Amitriptyline increased the expression of BDNF mRNA in astrocytic and microglial cultures but not neuronal cultures. Antidepressants with distinct mechanisms of action, such as clomipramine, duloxetine and fluvoxamine, also increased BDNF mRNA expression in astrocytic and microglial cultures. There are multiple BDNF mRNA variants (exon I, IIA, IV and VI) expressed in astrocytes and microglia and the variant induced by antidepressants has yet to be elaborated. Treatment with antidepressants increased the expression of exon I, IV and VI in astrocyte and microglia. Clomipramine alone significantly upregulated expression of exon IIA. The amitriptyline-induced expression of both total and individual BDNF mRNA variants (exon I, IV and VI) were blocked by MEK inhibitor U0126, indicating MEK/ERK signaling is required in the expression of BDNF. These findings indicate that non-neural cells are a significant target of antidepressants and further support the contention that glial production of BDNF is crucial role in the therapeutic effect of antidepressants. The current data suggest that targeting of glial function could lead to the development of antidepressants with a truly novel mechanism of action.
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan. Electronic address: hisaokak@hiroshima-u.ac.jp.
authors.forename: Kazue
authors.initials: K
authors.lastname: Hisaoka-Nakashima
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan; Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyama, Kure, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kajitani
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shigetou
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Kasai
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Matsumoto
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Yokoe
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
authors.forename: Honami
authors.initials: H
authors.lastname: Azuma
authors.affiliation: Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyama, Kure, Japan; Department of Psychiatry, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyama, Kure, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takebayashi
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000929:Antidepressive Agents, Tricyclic; D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D000639:Amitriptyline
keywords: Amitriptyline; Antidepressant; Astrocyte; BDNF; Major depressive disorder; Microglia