title: Antidepressant acts on astrocytes leading to an increase in the expression of neurotrophic/growth factors: differential regulation of FGF-2 by noradrenaline.
abstract: Recently, multiple neurotrophic/growth factors have been proposed to play an important role in the therapeutic action of antidepressants. In this study, we prepared astrocyte- and neuron-enriched cultures from the neonatal rat cortex, and examined the changes in neurotrophic/growth factor expression by antidepressant treatment using real-time PCR. Treatment with amitriptyline (a tricyclic antidepressant) significantly increased the expression of fibroblast growth factor-2 (FGF-2), brain-derived neurotrophic factor, vascular endothelial growth factor and glial cell line-derived neurotrophic factor mRNA with a different time course in astrocyte cultures, but not in neuron-enriched cultures. Only the expression of FGF-2 was higher in astrocyte cultures than in neuron-enriched cultures. We focused on the FGF-2 production in astrocytes. Several different classes of antidepressants, but not non-antidepressants, also induced FGF-2 mRNA expression. Noradrenaline (NA) is known to induce FGF-2 expression in astrocyte cultures, as with antidepressants. Therefore, we also assessed the mechanism of NA-induced FGF-2 expression, in comparison to amitriptyline. NA increased the FGF-2 mRNA expression via α1 and β-adrenergic receptors; however, the amitriptyline-induced FGF-2 mRNA expression was not mediated via these adrenergic receptors. Furthermore, the amitriptyline-induced FGF-2 mRNA expression was completely blocked by cycloheximide (an inhibitor of protein synthesis), while the NA-induced FGF-2 mRNA was not. These data suggest that the regulation of FGF-2 mRNA expression by amitriptyline was distinct from that by NA. Taken together, antidepressant-stimulated astrocytes may therefore be important mediators that produce several neurotrophic/growth factors, especially FGF-2, through a monoamine-independent and a de novo protein synthesis-dependent mechanism.
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kajitani
authors.forename: Kazue
authors.initials: K
authors.lastname: Hisaoka-Nakashima
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.forename: Mami
authors.initials: M
authors.lastname: Okada-Tsuchioka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneko
authors.forename: Miho
authors.initials: M
authors.lastname: Kasai
authors.forename: Chiyo
authors.initials: C
authors.lastname: Shibasaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
authors.forename: Minoru
authors.initials: M
authors.lastname: Takebayashi
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015306:Biogenic Monoamines / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D009414:Nerve Growth Factors; D011619:Psychotropic Drugs; D012333:RNA, Messenger; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D016222:Fibroblast Growth Factor 2; D000639:Amitriptyline; D003513:Cycloheximide; D009638:Norepinephrine