Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes

Manao Kinoshita, Yuri Hirayama, Kayoko Fujishita, Keisuke Shibata, Youichi Shinozaki, Eiji Shigetomi, Akiko Takeda, Ha Pham Ngoc Le, Hideaki Hayashi, Miki Hiasa, Yoshinori Moriyama, Kazuhiro Ikenaka, Kenji F. Tanaka, Schuichi Koizumi

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)72-83
Number of pages12
JournalEBioMedicine
Volume32
DOIs
Publication statusPublished - Jun 1 2018

Fingerprint

Fluoxetine
Therapeutic Uses
Astrocytes
Nucleotides
Adenosine Triphosphate
Neuroglia
Exocytosis
Adenosine
Neurons
Purinergic P1 Receptors
Psychotropic Drugs
Brain-Derived Neurotrophic Factor
Metabolites
Knockout Mice

Keywords

  • Adenosine
  • Astrocytes
  • ATP
  • BDNF
  • Fluoxetine
  • Vesicular nucleotide transporter

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kinoshita, M., Hirayama, Y., Fujishita, K., Shibata, K., Shinozaki, Y., Shigetomi, E., ... Koizumi, S. (2018). Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes. EBioMedicine, 32, 72-83. https://doi.org/10.1016/j.ebiom.2018.05.036

Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes. / 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.

In: EBioMedicine, Vol. 32, 01.06.2018, p. 72-83.

Research output: Contribution to journalArticle

Kinoshita, M, Hirayama, Y, Fujishita, K, Shibata, K, Shinozaki, Y, Shigetomi, E, Takeda, A, Le, HPN, Hayashi, H, Hiasa, M, Moriyama, Y, Ikenaka, K, Tanaka, KF & Koizumi, S 2018, 'Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes', EBioMedicine, vol. 32, pp. 72-83. https://doi.org/10.1016/j.ebiom.2018.05.036
Kinoshita M, Hirayama Y, Fujishita K, Shibata K, Shinozaki Y, Shigetomi E et al. Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes. EBioMedicine. 2018 Jun 1;32:72-83. https://doi.org/10.1016/j.ebiom.2018.05.036
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. / Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes. In: EBioMedicine. 2018 ; Vol. 32. pp. 72-83.
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