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Evidence that sedative effects of benzodiazepines involve unexpected GABAA receptor subtypes: Quantitative observation studies in rhesus monkeys

Duke, Angela N., Meng, Zhiqiang, Platt, Donna M., Atack, John R., Dawson, Gerard R., Reynolds, David S., Tiruveedhula, V. V. N. Phani Babu, Li, Guanguan, Stephen, Michael Rajesh, Sieghart, Werner, Cook, James M. and Rowlett, James K. 2018. Evidence that sedative effects of benzodiazepines involve unexpected GABAA receptor subtypes: Quantitative observation studies in rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics 366 (1) , pp. 145-157. 10.1124/jpet.118.249250

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In nonhuman primates we tested a new set of behavioral categories for observable sedative effects using pediatric anesthesiology classifications as a basis. Using quantitative behavioral observation techniques in rhesus monkeys, we examined the effects of alprazolam and diazepam (nonselective benzodiazepines), zolpidem (preferential binding to α1 subunit-containing GABAA receptors), HZ-166 (8-ethynyl-6-(2′-pyridine)-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester; functionally selective with relatively high intrinsic efficacy for α2 and α3 subunit-containing GABAA receptors), MRK-696 [7-cyclobutyl-6-(2-methyl-2H-1,2,4-triazol-2-ylmethoxy)-3-(2-flurophenyl)-1,2,4-triazolo(4,3-b)pyridazine; no selectivity but partial intrinsic activity], and TPA023B 6,2′-diflouro-5′-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile; partial intrinsic efficacy and selectivity for α2, α3, α5 subunit-containing GABAA receptors]. We further examined the role of α1 subunit-containing GABAA receptors in benzodiazepine-induced sedative effects by pretreating animals with the α1 subunit-preferring antagonist β-carboline-3-carboxylate-t-butyl ester (βCCT). Increasing doses of alprazolam and diazepam resulted in the emergence of observable ataxia, rest/sleep posture, and moderate and deep sedation. In contrast, zolpidem engendered dose-dependent observable ataxia and deep sedation but not rest/sleep posture or moderate sedation, and HZ-166 and TPA023 induced primarily rest/sleep posture. MRK-696 induced rest/sleep posture and observable ataxia. Zolpidem, but no other compounds, significantly increased tactile/oral exploration. The sedative effects engendered by alprazolam, diazepam, and zolpidem generally were attenuated by βCCT pretreatments, whereas rest/sleep posture and suppression of tactile/oral exploration were insensitive to βCCT administration. These data suggest that α2/3-containing GABAA receptor subtypes unexpectedly may mediate a mild form of sedation (rest/sleep posture), whereas α1-containing GABAA receptors may play a role in moderate/deep sedation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
ISSN: 0022-3565
Date of Acceptance: 30 April 2018
Last Modified: 22 Jul 2019 12:54

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