Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/α1-preferring antagonist β-CCt in squirrel monkeys
Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/α1-preferring antagonist β-CCt in squirrel monkeys
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DOI：
10.1007/s00213-002-1189-9
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发表时间：
2002-11-01
影响因子：
3.4
通讯作者：
Ma, CR
中科院分区：
文献类型：
--
作者：
Platt, DM;Rowlett, JK;Ma, CR
理论基础：阐明苯二氮卓类药物行为效应的受体机制，应能开发出临床疗效更好、副作用更少的药物。目的：探讨GABA(A)/α(1)受体在苯二氮类药物镇静和运动损伤中的作用。方法：用GABA(A)/α(1)受体激动剂唑吡坦和非选择性苯二氮卓类受体激动剂三唑仑单独及与GABA(A)/α(1)受体拮抗剂β-CCT和非选择性苯二氮卓类拮抗剂氟马西尼联合应用。在30分钟的实验过程中，所有正常行为的发生情况，如运动、环境和自我指导行为，以及副作用，如共济失调、休息和平卧姿势，都被评分。结果：唑吡坦和三唑仑可剂量依赖性地减少小鼠的运动和环境导向行为，增加共济失调和卧位。三唑仑，但不是唑吡坦，也会产生物种--在一定剂量下的典型休息姿势。氟马西尼拮抗唑吡坦和三唑仑的所有行为效应，而β-CCT仅拮抗唑吡坦和三唑仑诱导的共济失调。结论：GABA(A)/α(1)受体机制似乎在苯二氮类激动剂对松鼠猴子的共济失调效应中起关键作用，与最近转基因小鼠的结果相似。与这些最近的研究结果相反，除了α(1)亚单位介导的机制之外，GABA(A)机制可能在苯二氮类药物对松鼠猴子的镇静/催眠作用中发挥更重要的作用。
Rationale: Delineation of the receptor mechanisms underlying the behavioral effects of benzodiazepines should allow for the development of drugs with improved clinical utility and reduced side effects. Objectives: The purpose of the present study was to investigate the role of GABA(A)/alpha(1) receptors in the sedative and motor-impairing effects of benzodiazepines. Methods: Squirrel monkeys were tested with the GABA(A)/alpha(1)-preferring agonist zolpidem and the nonselective benzodiazepine agonist triazolam alone and in combination with the GABA(A)/alpha(1)-preferring antagonist beta-CCt and the nonselective benzodiazepine antagonist flumazenil. During 30-min experimental sessions, all occurrences of normal behaviors like locomotion, environment- and self-directed behaviors, as well as side effects such as ataxia, rest and procumbent postures were scored. Results: Zolpidem and triazolam produced dose-dependent reductions in locomotion and environment-directed behavior and increased ataxia and procumbent posture. Triazolam, but not zolpidem, also engendered species-typical rest posture at some doses. Flumazenil antagonized all of the behavioral effects of zolpidem and triazolam, whereas beta-CCt antagonized only zolpidem- and triazolam-induced ataxia. Conclusions: GABA(A)/alpha(1) receptor mechanisms appear to play a key role in the ataxic effects of benzodiazepine agonists in squirrel monkeys, similar to recent results with transgenic mice. In contrast to the findings of these recent studies, GABA(A) mechanisms other than or in addition to those mediated at the alpha(1) subunit may play a more important role in the sedative/hypnotic effects of benzodiazepines in squirrel monkeys.