@article{5e1bceb5b0d0493aa7129eb40ce77c3a,
title = "Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes",
abstract = "Although psychotropic drugs act on neurons and glial cells, how glia respond, and whether glial responses are involved in therapeutic effects are poorly understood. Here, we show that fluoxetine (FLX), an anti-depressant, mediates its anti-depressive effect by increasing the gliotransmission of ATP. FLX increased ATP exocytosis via vesicular nucleotide transporter (VNUT). FLX-induced anti-depressive behavior was decreased in astrocyte-selective VNUT-knockout mice or when VNUT was deleted in mice, but it was increased when astrocyte-selective VNUT was overexpressed in mice. This suggests that VNUT-dependent astrocytic ATP exocytosis has a critical role in the therapeutic effect of FLX. Released ATP and its metabolite adenosine act on P2Y11 and adenosine A2b receptors expressed by astrocytes, causing an increase in brain-derived neurotrophic factor in astrocytes. These findings suggest that in addition to neurons, FLX acts on astrocytes and mediates its therapeutic effects by increasing ATP gliotransmission.",
keywords = "ATP, Adenosine, Astrocytes, BDNF, Fluoxetine, Vesicular nucleotide transporter",
author = "Manao Kinoshita and Yuri Hirayama and Kayoko Fujishita and Keisuke Shibata and Youichi Shinozaki and Eiji Shigetomi and Akiko Takeda and Le, {Ha Pham Ngoc} and Hideaki Hayashi and Miki Hiasa and Yoshinori Moriyama and Kazuhiro Ikenaka and Tanaka, {Kenji F.} and Schuichi Koizumi",
note = "Funding Information: This study was supported by grants from JSPS KAKENHI ( 3507 , 25116512 , 25117003 , 16H04669 , and 18H05121 ) to SK, Grants-in-Aid from Japan Agency for Medical Research and Development (AMED)-CREST ( 15652227 ) to SK, JST CREST ( 14532115 ) to SK, Takeda Science Foundation to SK, The Kurata Grants ( 1305 ) to SK, Takahashi Industrial and Economic Research Foundation ( 040 ) to SK and SENSHIN Medical Research Foundation to SK. Funding Information: This study was supported by grants from JSPS KAKENHI (3507, 25116512, 25117003, 16H04669, and 18H05121) to SK, Grants-in-Aid from Japan Agency for Medical Research and Development (AMED)-CREST (15652227) to SK, JST CREST (14532115) to SK, Takeda Science Foundation to SK, The Kurata Grants (1305) to SK, Takahashi Industrial and Economic Research Foundation (040) to SK and SENSHIN Medical Research Foundation to SK. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = jun,
doi = "10.1016/j.ebiom.2018.05.036",
language = "English",
volume = "32",
pages = "72--83",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}