RATIONALEBenzodiazepines are known to evoke changes in cortical electrophysiological activity that can be correlated with action at distinct γ-aminobutyric acid type A (GABA_A) receptor subtypes.OBJECTIVESWe used electroencephalography (EEG) paired with electromyography (EMG) to evaluate the role of α1 subunit-containing GABA_A receptors (α1GABA_ARs) in benzodiazepine-induced sedation and changes in EEG band frequencies during the active phase of the light/dark cycle.METHODSMale Sprague-Dawley rats (N = 4/drug) were surgically instrumented with EEG/EMG electrodes. The rats were injected i.p. with zolpidem, an α1GABA_AR-preferring compound, or L-838,417, which has selective efficacy for α2/3/5 subunit-containing GABA_ARs (i.e., α1GABA_AR-sparing compound), in comparison with the non-selective benzodiazepine, triazolam.RESULTSAll ligands evaluated induced changes in sleep-wake states during the active phase consistent with an increase in slow-wave sleep (SWS). The degree of SWS increase appeared to be related to the magnitude of delta power band changes induced by the ligands, with the strongest effects engendered by the α1GABA_AR-preferring drug zolpidem and the weakest effects by the α1GABA_AR-sparing compound, L-838,417. Consistent with other research, a selective increase in beta band power was observed with L-838,417, which may be associated with α2GABA_AR-mediated anxiolysis.CONCLUSIONSOverall, these findings support the establishment of pharmaco-EEG "signatures" for identifying subtype-selective GABA_A modulators in vivo.

01 Dec 2021·Journal of NeuroinflammationQ1 · MEDICINE

MD2 contributes to the pathogenesis of perioperative neurocognitive disorder via the regulation of α5GABAA receptors in aged mice

Q1 · MEDICINE

ArticleOA

Author: Fang, Zongping ; Xu, Feifei ; Hou, Wugang ; Zhao, Jianshuai ; Xiong, Lize ; Guo, Yaru ; Deng, Jiao ; Zhang, Jinming ; Zuo, Wenqiang ; Dong, Hailong ; Fan, Ze ; Han, Jing

AbstractBackgroundPerioperative neurocognitive disorder (PND) is a long-term postoperative complication in elderly surgical patients. The underlying mechanism of PND is unclear, and no effective therapies are currently available. It is believed that neuroinflammation plays an important role in triggering PND. The secreted glycoprotein myeloid differentiation factor 2 (MD2) functions as an activator of the Toll-like receptor 4 (TLR4) inflammatory pathway, and α5GABAA receptors (α5GABAARs) are known to play a key role in regulating inflammation-induced cognitive deficits. Thus, in this study, we aimed to investigate the role of MD2 in PND and determine whether α5GABAARs are involved in the function of MD2.MethodsEighteen-month-old C57BL/6J mice were subjected to laparotomy under isoflurane anesthesia to induce PND. The Barnes maze was used to assess spatial reference learning and memory, and the expression of hippocampal MD2 was assayed by western blotting. MD2 expression was downregulated by bilateral injection of AAV-shMD2 into the hippocampus or tail vein injection of the synthetic MD2 degrading peptide Tat-CIRP-CMA (TCM) to evaluate the effect of MD2. Primary cultured neurons from brain tissue block containing cortices and hippocampus were treated with Tat-CIRP-CMA to investigate whether downregulating MD2 expression affected the expression of α5GABAARs. Electrophysiology was employed to measure tonic currents. For α5GABAARs intervention experiments, L-655,708 and L-838,417 were used to inhibit or activate α5GABAARs, respectively.ResultsSurgery under inhaled isoflurane anesthesia induced cognitive impairments and elevated the expression of MD2 in the hippocampus. Downregulation of MD2 expression by AAV-shMD2 or Tat-CIRP-CMA improved the spatial reference learning and memory in animals subjected to anesthesia and surgery. Furthermore, Tat-CIRP-CMA treatment decreased the expression of membrane α5GABAARs and tonic currents in CA1 pyramidal neurons in the hippocampus. Inhibition of α5GABAARs by L-655,708 alleviated cognitive impairments after anesthesia and surgery. More importantly, activation of α5GABAARs by L-838,417 abrogated the protective effects of Tat-CIRP-CMA against anesthesia and surgery-induced spatial reference learning and memory deficits.ConclusionsMD2 contributes to the occurrence of PND by regulating α5GABAARs in aged mice, and Tat-CIRP-CMA is a promising neuroprotectant against PND.

01 Aug 2020·Drug and Alcohol DependenceQ2 · MEDICINE

GABAA Receptor Subtypes and the Reinforcing Effects of Benzodiazepines in Remifentanil-Experienced Rhesus Monkeys

Q2 · MEDICINE

Article

Author: Rowlett, James K ; Berro, Lais F

BACKGROUNDOpioid-use disorder is associated with a high degree of co-abuse with benzodiazepines. While the mechanisms underlying the co-abuse of opioids and benzodiazepines remain unknown, α1 subunit-containing GABA_A receptors may play a critical role in the reinforcing effects of benzodiazepine-type compounds, depending on whether the monkeys have a history of benzodiazepine or stimulant self-administration. The present study extended our prior research by comparing the reinforcing effects of a compound lacking activity at α1 subunit-containing GABA_A receptors with the reinforcing effects of non-selective GABA_A receptor positive allosteric modulators in monkeys with a history of opioid self-administration.METHODSThe reinforcing effects of L-838,417 (partial intrinsic efficacy at α2, α3, and α5 subunit-containing GABA_A receptors, but no efficacy at α1 subunit-containing GABA_A receptors, i.e., "α1-sparing compound") were compared with those of the non-selective GABA_A receptor partial modulator MRK-696, and non-selective GABA_A receptor full modulators, triazolam and lorazepam, in rhesus monkeys (n = 3) experienced in remifentanil self-administration under a progressive-ratio schedule of intravenous drug injection.RESULTSNeither the partial modulator nor the α1-sparing compound were self-administered above vehicle levels. The full modulators triazolam and lorazepam were self-administered significantly above vehicle levels, albeit at lower levels than remifentanil.CONCLUSIONSOur findings suggest that relatively high efficacy at one or more GABA_A receptor subtypes is required for a compound to have reinforcing effects in monkeys with a history of remifentanil self-administration, in contrast to monkeys with benzodiazepine or stimulant self-administration histories.

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Preclinical	GB	Merck Sharp & Dohme Corp.	-

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