{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T03:48:27Z","timestamp":1761709707519,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T00:00:00Z","timestamp":1583366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Gamma-aminobutyric acid, type A (GABAA) receptors are complex heterogeneous pentamers with various drug binding sites. Several lines of evidence suggest that benzodiazepines modulate certain GABAA receptors in a flumazenil-insensitive manner, possibly via binding sites other than the classical ones. However, GABAA receptor subtypes that contain non-classical benzodiazepine binding sites are not systemically studied. The present study investigated the high-concentration effects of three benzodiazepines and their sensitivity to flumazenil on different recombinant (\u03b11\u03b22, \u03b12\u03b22, \u03b13\u03b22, \u03b14\u03b22, \u03b15\u03b22 and \u03b11\u03b23) and native neuronal GABAA receptors using the whole-cell patch-clamp electrophysiology technique. The classical benzodiazepine diazepam (200 \u03bcmol\/L) and midazolam (200 \u03bcmol\/L) produced flumazenil-insensitive effects on \u03b11\u03b22 receptor, whereas the imidazopyridine zolpidem failed to modulate the receptor. Flumazenil-insensitive effects of diazepam were also observed on the \u03b12\u03b22, \u03b13\u03b22 and \u03b15\u03b22, but not \u03b14\u03b22 receptors. Unlike \u03b22-containing receptors, the \u03b11\u03b23 receptor was insensitive to diazepam. Moreover, the diazepam (200 \u03bcmol\/L) effects on some cortical neurons could not be fully antagonized by flumazenil (200 \u03bcmol\/L). These findings suggested that the non-classical (flumazenil-insensitive) benzodiazepine effects depended on certain receptor subtypes and benzodiazepine structures and may be important for designing of subtype- or binding site- specific drugs.<\/jats:p>","DOI":"10.3390\/brainsci10030150","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T07:33:46Z","timestamp":1583480026000},"page":"150","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Flumazenil-Insensitive Benzodiazepine Effects in Recombinant \u03b1\u03b2 and Neuronal GABAA Receptors"],"prefix":"10.3390","volume":"10","author":[{"given":"Jing-Jing","family":"Lian","sequence":"first","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Qing","family":"Cao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Lei","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui-Bin","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.5664\/jcsm.26525","article-title":"GABAA Receptors: Subtypes, regional distribution, and function","volume":"2","author":"Nutt","year":"2006","journal-title":"J. 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