Influence of lipopolysaccharide on diazepam-modified loss of righting reflex duration by pentobarbital treatment in mice

Yoshihisa Kitamura, Shiho Hongo, Yoshiaki Yamashita, Shinpei Yagi, Kanami Otsuki, Akihisa Miki, Ayumi Okada, Soichiro Ushio, Satoru Esumi, Toshiaki Sendo

Research output: Contribution to journalArticlepeer-review

Abstract

Benzodiazepine receptor agonists are widely prescribed therapeutic agents, alter gamma-aminobutyric acid (GABA)A receptor function, and have hypnotic, anxiolytic, anticonvulsant, and antispastic effects. GABAA receptor activity increases under systemic inflammatory conditions. We investigated the effect of benzodiazepine receptor agonists on pentobarbital-induced loss of righting reflex (LORR) duration using a mouse model of lipopolysaccharide (LPS)-induced inflammation. We assessed pentobarbital-induced LORR duration 24 h after LPS treatment in mice. Additionally, we examined the microglial response by immunohistochemistry and serum IL-6 and TNF-α concentrations in mice. LPS treatment significantly increased the duration of pentobarbital-induced LORR in mice treated with benzodiazepine receptor agonists (diazepam and brotizolam) and a GABAA receptor agonist (muscimol) compared to that of mice treated with vehicle. These effects were blocked by bicuculline, a GABAA receptor antagonist. LPS significantly increased the number of ionized calcium binding adapter molecule-1-positive hippocampal cells 2 and 24 h after treatment. The enhancing effect of diazepam in LPS-treated mice was significantly reduced by minocycline. These findings suggest that LPS enhances pentobarbital-induced LORR duration in mice treated with benzodiazepine via GABAA receptor activity.

Original languageEnglish
Pages (from-to)231-238
Number of pages8
JournalEuropean Journal of Pharmacology
Volume842
DOIs
Publication statusPublished - Jan 5 2019

Keywords

  • Benzodiazepine receptor agonist
  • GABA receptor
  • Inflammation
  • Lipopolysaccharide
  • Microglia
  • Minocycline

ASJC Scopus subject areas

  • Pharmacology

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