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 journalArticlepeer-review

71 Citations (Scopus)


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
Publication statusPublished - 2018 Jun


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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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