Täuber Marcus, Calame-Droz Elisabeth, Prut Laetitia, Rudolph Uwe, Crestani Florence
Institut of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Eur J Neurosci. 2003 Nov;18(9):2599-604. doi: 10.1046/j.1460-9568.2003.02988.x.
Classical benzodiazepines such as diazepam are widely used tranquillisers and hypnotics in various neuropsychiatric diseases including alcohol-related disorders. One of the major drawbacks of benzodiazepine therapy, however, is an exacerbation of the sedative and hypnotic effects associated with alcohol intake, even at low doses. Even though the gamma-aminobutyric acid (GABA)A receptor complex is a common target for the actions of both classes of drugs, the molecular mechanisms underlying the enhanced pharmacological properties of the combined use of benzodiazepines and alcohol remain to be identified. The present experiments aimed at clarifying which of the GABAA receptor subtypes mediate the augmented hypnotic-like and sedative effects of combined diazepam and alcohol using the righting reflex and motor activity assays, respectively, in histidine-to-arginine point mutated mice that possess diazepam-insensitive alpha1-, alpha2-, alpha3- or alpha5-GABAA receptors. The combination of diazepam (2 or 3 mg/kg) and ethanol (3 g/kg) induced loss of righting reflex with a significantly dose-dependent increase of the latency to its full recovery in wild-type, alpha1(H101R), alpha3(H126R) and alpha5(H105R) but not in alpha2(H101R) mice. A combined treatment with diazepam (1 mg/kg) and ethanol (2.5 g/kg) precipitated motor inhibition similarly in wild-type and alpha2(H101R) mice. Responsiveness of the alpha2(H101R) mice to ethanol alone was similar to that of wild-type mice. These results demonstrate that induction of loss of righting reflex by combined diazepam and alcohol is closely dependent on the activation of the alpha2-GABAA receptors by the benzodiazepine whereas precipitation of sedation involves GABAA receptors other than the alpha2-GABAA receptors.
经典苯二氮䓬类药物如地西泮，是广泛用于包括酒精相关障碍在内的各种神经精神疾病的镇静剂和催眠药。然而，苯二氮䓬类药物治疗的主要缺点之一是，即使在低剂量下，也会加剧与酒精摄入相关的镇静和催眠作用。尽管γ-氨基丁酸（GABA）A受体复合物是这两类药物作用的共同靶点，但苯二氮䓬类药物与酒精联合使用时增强药理特性的分子机制仍有待确定。本实验旨在通过在具有对地西泮不敏感的α1-、α2-、α3-或α5-GABAA受体的组氨酸到精氨酸点突变小鼠中分别使用翻正反射和运动活动测定，来阐明哪些GABAA受体亚型介导地西泮和酒精联合使用时增强的类催眠和镇静作用。地西泮（2或3mg/kg）和乙醇（3g/kg）的联合使用在野生型、α1（H101R）、α3（H126R）和α5（H105R）小鼠中诱导翻正反射丧失，其完全恢复的潜伏期显著剂量依赖性增加，但在α2（H101R）小鼠中未出现。地西泮（1mg/kg）和乙醇（2.5g/kg）的联合治疗在野生型和α2（H101R）小鼠中同样引起运动抑制。α2（H101R）小鼠对单独乙醇的反应性与野生型小鼠相似。这些结果表明，地西泮和酒精联合使用诱导翻正反射丧失密切依赖于苯二氮䓬对α2-GABAA受体的激活，而镇静的发生涉及α2-GABAA受体以外的GABAA受体。
