Evidence That Sedative Effects of Benzodiazepines Involve Unexpected GABAA Receptor Subtypes: Quantitative Observation Studies in Rhesus Monkeys
Evidence That Sedative Effects of Benzodiazepines Involve Unexpected GABAA Receptor Subtypes: Quantitative Observation Studies in Rhesus Monkeys
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DOI：
10.1124/jpet.118.249250
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发表时间：
2018-07-01
影响因子：
3.5
通讯作者：
Rowlett, James K.
中科院分区：
文献类型：
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作者：
Duke, Angela N.;Meng, Zhiqiang;Rowlett, James K.
在非人灵长类动物中，我们使用儿科麻醉学分类作为基础，测试了一组新的行为类别，以观察到镇静作用。采用定量行为观察技术在恒河猴，我们检查了阿普唑仑和地西泮的影响（非选择性苯二氮卓类）、唑吡坦（优先结合含α 1亚基的GABA（A）受体），HZ-166（8-乙炔基-6-（2 '-吡啶）-4H-2，5，10 b-三氮杂-苯并[e]甘菊环-3-羧酸乙酯;对含有α 2和α 3亚基的GABA（A）受体具有相对高的内在功效的功能选择性），MRK-696 [7-环丁基-6-甲基-N-（2-甲基-N-苯基）-N-（2-甲基）-N-（2-（2-甲基-2H-1，2，4-三唑-2-基甲氧基）-3-（2-氟苯基）-1，2，4-三唑并（4，3-B）哒嗪;无选择性，但具有部分固有活性]和TPA 023 B 6，2 ′-二氟-5 ′-[3-（1-羟基-1-甲基乙基）咪唑并[1，2-B][1，2，4]三嗪-7-基]联苯-2-腈;对含α 2、α 3、α 5亚基的GABA（A）受体的部分内在功效和选择性]。我们通过用α 1亚单位偏好拮抗剂β-咔啉-3-羧酸叔丁酯（β CCT）预处理动物，进一步研究了含α 1亚单位的GABA（A）受体在苯二氮卓诱导的镇静作用中的作用。阿普唑仑和地西泮剂量增加导致出现可观察到的共济失调、休息/睡眠姿势以及中度和深度镇静。相比之下，唑吡坦产生剂量依赖性的可观察到的共济失调和深度镇静，但不是休息/睡眠姿势或中度镇静，HZ-166和TPA 023主要诱导休息/睡眠姿势。MRK-696诱导休息/睡眠姿势和可观察到的共济失调。唑吡坦，但没有其他化合物，显着增加触觉/口腔探索。阿普唑仑、地西泮和唑吡坦产生的镇静作用通常通过β CCT预处理减弱，而休息/睡眠姿势和触觉/口腔探索抑制对β CCT给药不敏感。这些数据表明，含α 2/3的GABA（A）受体亚型意外地可能介导轻度镇静（休息/睡眠姿势），而含α 1的GABA（A）受体可能在中度/深度镇静中发挥作用。
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 alpha 1 subunit-containing GABA(A) 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 alpha 2 and alpha 3 subunit-containing GABA(A) 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 alpha 2, alpha 3, alpha 5 subunit-containing GABA(A) receptors]. We further examined the role of alpha 1 subunit-containing GABA(A) receptors in benzodiazepine-induced sedative effects by pretreating animals with the alpha 1 subunit-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (beta CCT). 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 beta CCT pretreatments, whereas rest/sleep posture and suppression of tactile/oral exploration were insensitive to beta CCT administration. These data suggest that alpha 2/3-containing GABA(A) receptor subtypes unexpectedly may mediate a mild form of sedation (rest/sleep posture), whereas alpha 1-containing GABA(A) receptors may play a role in moderate/deep sedation.