Dataset Information

Flumazenil-Insensitive Benzodiazepine Effects in Recombinant ?? and Neuronal GABAA Receptors.

ABSTRACT: 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 (?1?2, ?2?2, ?3?2, ?4?2, ?5?2 and ?1?3) and native neuronal GABAA receptors using the whole-cell patch-clamp electrophysiology technique. The classical benzodiazepine diazepam (200 ?mol/L) and midazolam (200 ?mol/L) produced flumazenil-insensitive effects on ?1?2 receptor, whereas the imidazopyridine zolpidem failed to modulate the receptor. Flumazenil-insensitive effects of diazepam were also observed on the ?2?2, ?3?2 and ?5?2, but not ?4?2 receptors. Unlike ?2-containing receptors, the ?1?3 receptor was insensitive to diazepam. Moreover, the diazepam (200 ?mol/L) effects on some cortical neurons could not be fully antagonized by flumazenil (200 ?mol/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.

SUBMITTER: Lian JJ

PROVIDER: S-EPMC7139822 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Flumazenil-Insensitive Benzodiazepine Effects in Recombinant αβ and Neuronal GABAA Receptors.

Lian Jing-Jing JJ Cao Yan-Qing YQ Li Yu-Lei YL Yu Gang G Su Rui-Bin RB

Brain sciences 20200305 3

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-concent ...[more]

PMID: 32150806

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Project description:Neuroreceptor imaging in the nonhuman primate (NHP) is valuable for translational research approaches in humans. However, most NHP studies are conducted under anesthesia, which affects the interpretability of receptor binding measures. The aims of this study were to develop awake NHP imaging with minimal head restraint and to compare in vivo binding of the ?-aminobutyric acid type A (GABAA)-benzodiazepine radiotracer (11)C-flumazenil under anesthetized and awake conditions. We hypothesized that (11)C-flumazenil binding potential (BPND) would be higher in isoflurane-anesthetized monkeys.The small animal PET scanner was fitted to a mechanical device that raised and tilted the scanner 45° while the awake NHP was tilted back 35° in a custom chair for optimal brain positioning, which required acclimation of the animals to the chair, touch-screen tasks, intravenous catheter insertion, and tilting. For PET studies, the bolus-plus-constant infusion method was used for (11)C-flumazenil administration. Two rhesus monkeys were scanned under the awake (n = 6 scans) and isoflurane-anesthetized (n = 4 scans) conditions. An infrared camera was used to track head motion during PET scans. Under the awake condition, emission and head motion-tracking data were acquired for 40-75 min after injection. Anesthetized monkeys were scanned for 90 min. Cortisol measurements were acquired during awake and anesthetized scans. Equilibrium analysis was used for both the anesthetized (n = 4) and the awake (n = 5) datasets to compute mean BPND images in NHP template space, using the pons as a reference region. The percentage change per minute in radioactivity concentration was calculated in high- and low-binding regions to assess the quality of equilibrium.The monkeys acclimated to procedures in the NHP chair necessary to perform awake PET imaging. Image quality was comparable between awake and anesthetized conditions. The relationship between awake and anesthetized values was BPND (awake) = 0.94 BPND (anesthetized) + 0.36 (r(2) = 0.95). Cortisol levels were significantly higher under the awake condition (P < 0.05).We successfully performed awake NHP imaging with minimal head restraint. There was close agreement in (11)C-flumazenil BPND values between awake and anesthetized conditions.

Dataset Information

Flumazenil-Insensitive Benzodiazepine Effects in Recombinant ?? and Neuronal GABAA Receptors.

Publications

Flumazenil-Insensitive Benzodiazepine Effects in Recombinant αβ and Neuronal GABA<sub>A</sub> Receptors.

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