Bumetanide prevents diazepam-modified anxiety-like behavior in lipopolysaccharide-treated mice

Daiki Matsumoto, Soichiro Ushio, Yudai Wada, Yukiko Noda, Satoru Esumi, Yasuhisa Izushi, Yoshihisa Kitamura, Toshiaki Sendo

Research output: Contribution to journalArticlepeer-review

Abstract

Benzodiazepine receptor agonists are widely prescribed therapeutic agents that alter gamma-aminobutyric acid (GABA)A receptor activity and have anxiolytic effects. Post-operative use of benzodiazepines is a risk factor of delirium. Inflammatory conditions alter the anxiolytic effects of benzodiazepine. We investigated the effect of diazepam, a typical benzodiazepine anxiolytic, on changes in the emotional behavior of mice in a hole-board test after lipopolysaccharide (LPS) treatment. Diazepam dose-dependently increased the number of head-dips at doses that did not alter locomotor activity; however, diazepam dose-dependently significantly decreased the number of head-dips at doses that did not alter locomotor activity in LPS-treated mice. Flumazenil, a benzodiazepine receptor antagonist, normalized the decrease in head-dipping behavior caused by diazepam treatment in normal and LPS-treated mice. The decrease of the head-dipping effect caused by diazepam was attenuated by minocycline in LPS-treated mice. We further found that the decrease in head-dipping behavior caused by diazepam was blocked by bumetanide, a Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) antagonist, in LPS-treated mice. These findings suggest that diazepam induces the anxiety-like behavior under inflammation conditions, and may cause the GABAA receptor dysfunction associated with the chloride plasticity mediated by NKCC1, which contributes to benzodiazepine-induced delirium after surgery.

Original languageEnglish
Article number174195
JournalEuropean Journal of Pharmacology
Volume904
DOIs
Publication statusPublished - Aug 5 2021

Keywords

  • Anxiety
  • Bumetanide
  • Diazepam
  • Inflammation
  • Lipopolysaccharide
  • NKCC1

ASJC Scopus subject areas

  • Pharmacology

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