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

• Published in: European journal of pharmacology Vol. 904; p. 174195
• Main Authors: Matsumoto, Daiki, Ushio, Soichiro, Wada, Yudai, Noda, Yukiko, Esumi, Satoru, Izushi, Yasuhisa, Kitamura, Yoshihisa, Sendo, Toshiaki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05-08-2021
• Subjects: Animals; Anti-Anxiety Agents - pharmacology; Anti-Anxiety Agents - toxicity; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Anxiety; Anxiety - prevention & control; Behavior, Animal - drug effects; Bicuculline - pharmacology; Bicuculline - therapeutic use; Bumetanide; Bumetanide - pharmacology; Bumetanide - therapeutic use; Diazepam; Diazepam - pharmacology; Diazepam - toxicity; Emotions - drug effects; Flumazenil - pharmacology; Flumazenil - therapeutic use; GABA-A Receptor Agonists - adverse effects; GABA-A Receptor Agonists - pharmacology; GABA-A Receptor Antagonists - pharmacology; GABA-A Receptor Antagonists - therapeutic use; Inflammation; Inflammation - chemically induced; Inflammation - complications; Lipopolysaccharide; Lipopolysaccharides - toxicity; Male; Mice; Mice, Inbred ICR; Minocycline - pharmacology; Minocycline - therapeutic use; Motor Activity - drug effects; NKCC1; Sodium Potassium Chloride Symporter Inhibitors - pharmacology; Sodium Potassium Chloride Symporter Inhibitors - therapeutic use; Lipopolysaccharide; Anxiety; Inflammation; NKCC1; Bumetanide; Diazepam
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174195

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.
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