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• W2989228045 endingPage "117033" @default.
• W2989228045 startingPage "117033" @default.
• W2989228045 abstract "Benzodiazepines (BZDs) produce various pharmacological actions by binding to and allosterically regulating GABAA receptors. Several in vitro studies have demonstrated diazepam, the prototypic BZD, produces a high-dose action that cannot be countered with the classical BZD-binding site antagonist flumazenil. Here, we investigate the existence and behavioral relevance of non-classical BZD binding sites in zebrafish larvae. Zebrafish larvae were treated with a series of BZDs alone or combined with flumazenil, bicuculline (a non-selective GABAA receptor antagonist), or RO 15–4513 (a general BZD antagonist and a proposed antagonist interacting with α+/β− interfaces in α4/6/β3δ receptors), and their locomotor activities and behavioral phenotypes were recorded. Diazepam-induced hypolocomotion (sedation-like state) at low doses (10 and 20 mg L−1) was effectively antagonized by flumazenil or bicuculline, while diazepam-induced immobility (anesthesia-like state) at higher dose (30 mg L−1) was prevented by bicuculline (3 mg L−1) but not flumazenil, even at doses up to 150 mg L−1. Ro 15–4513 also failed to efficiently antagonize diazepam-induced immobility. Immobility induced by high dose of another 1,4-BZD, clonazepam, was also resistant to flumazenil. These results provide direct in vivo evidence for non-classical BZD-binding sites, which may be located at the second transmembrane domain of GABAA receptors and contribute to BZD-induced anesthesia." @default.
• W2989228045 created "2019-11-22" @default.
• W2989228045 creator A5008617323 @default.
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• W2989228045 date "2019-12-01" @default.
• W2989228045 modified "2023-09-26" @default.
• W2989228045 title "Flumazenil-insensitive benzodiazepine binding sites in GABAA receptors contribute to benzodiazepine-induced immobility in zebrafish larvae" @default.
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• W2989228045 doi "https://doi.org/10.1016/j.lfs.2019.117033" @default.
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