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

Benzodiazepine receptor agonists are widely prescribed therapeutic agents, alter gamma-aminobutyric acid (GABA)_A receptor function, and have hypnotic, anxiolytic, anticonvulsant, and antispastic effects. GABA_A 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 GABA_A receptor agonist (muscimol) compared to that of mice treated with vehicle. These effects were blocked by bicuculline, a GABA_A 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 GABA_A receptor activity.