Blockade of alcohol's amnestic activity in humans by an α5 subtype benzodiazepine receptor inverse agonist
Blockade of alcohol's amnestic activity in humans by an α5 subtype benzodiazepine receptor inverse agonist
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DOI：
10.1016/j.neuropharm.2007.08.008
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发表时间：
2007-12-01
影响因子：
4.7
通讯作者：
Lingford-Hughes, Anne R.
中科院分区：
文献类型：
--
作者：
Nutt, David J.;Besson, Marie;Lingford-Hughes, Anne R.
酒精对人产生许多主观和客观的影响，包括愉悦、镇静、焦虑，以及损害眼球运动和记忆。在人类志愿者中，我们使用了一种新获得的GABA-A/苯二氮卓类受体反向激动剂，它对α 5亚型（a5IA）具有选择性，以评估该亚型在介导酒精对大脑的这些影响中的作用。我们发现酒精（平均呼吸浓度150 mg/100 ml）几乎完全阻断了单词列表学习的显著损伤，并且部分但不显著地逆转了主观镇静，而对其他测量如中毒、喜欢和眼球运动减慢没有影响。这种作用不是由于酒精动力学的改变，因此首次证明了选择性地减少GABA-A受体在特定受体亚型上的功能可以抵消酒精在人体中的某些作用。它也支持了α 5亚型在记忆中起关键作用的越来越多的证据。其他GABA-A受体亚型的逆激动剂可能被证明能够逆转酒精的其他作用，因此为理解酒精在人脑中的作用和治疗人类酒精相关疾病提供了一种新的方法。(c) 2007 Elsevier Ltd.版权所有。
Alcohol produces many subjective and objective effects in man including pleasure, sedation, anxiolysis, plus impaired eye movements and memory. In human volunteers we have used a newly available GABA-A/benzodiazepine receptor inverse agonist that is selective for the alpha 5 subtype (a5IA) to evaluate the role of this subtype in mediating these effects of alcohol on the brain, After pre-treatment with a5IA, we found almost complete blockade of the marked impairment caused by alcohol (mean breath concentration 150 mg/100 ml) of word list learning and partial but non-significant reversal of subjective sedation without effects on other measure such as intoxication, liking, and slowing of eye movements. This action was not due to alterations in alcohol kinetics and so provides the first proof of concept that selectively decreasing GABA-A receptor function at a specific receptor subtype can offset some actions of alcohol in humans. It also supports growing evidence for a key role of the alpha 5 subtype in memory. Inverse agonists at other GABA-A receptor subtypes may prove able to reverse other actions of alcohol, and so offer a new approach to understanding the actions of alcohol in the human brain and in the treatment of alcohol related disorders in humans. (c) 2007 Elsevier Ltd. All rights reserved.