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Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes

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....

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Detalles Bibliográficos
Autores principales: Kinoshita, Manao, Hirayama, Yuri, Fujishita, Kayoko, Shibata, Keisuke, Shinozaki, Youichi, Shigetomi, Eiji, Takeda, Akiko, Le, Ha Pham Ngoc, Hayashi, Hideaki, Hiasa, Miki, Moriyama, Yoshinori, Ikenaka, Kazuhiro, Tanaka, Kenji F., Koizumi, Schuichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020856/
https://www.ncbi.nlm.nih.gov/pubmed/29887330
http://dx.doi.org/10.1016/j.ebiom.2018.05.036
Descripción
Sumario: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 P2Y(11) 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.