CHRONIC BENZODIAZEPINE ADMINISTRATION .7. BEHAVIORAL TOLERANCE AND WITHDRAWAL AND RECEPTOR ALTERATIONS ASSOCIATED WITH CLONAZEPAM ADMINISTRATION
CHRONIC BENZODIAZEPINE ADMINISTRATION .7. BEHAVIORAL TOLERANCE AND WITHDRAWAL AND RECEPTOR ALTERATIONS ASSOCIATED WITH CLONAZEPAM ADMINISTRATION
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DOI：
10.1007/bf02244183
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发表时间：
1991-01-01
影响因子：
3.4
通讯作者：
MILLER, LG
中科院分区：
文献类型：
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作者：
GALPERN, WR;LUMPKIN, M;MILLER, LG
氯硝西泮给药在临床应用中可能导致耐受和戒断综合征。 为了评估该药物在小鼠模型中的作用，我们给予氯硝西泮（1.5 mg/kg/天）1-14天，并评价了旷场活动、皮质氯硝西泮浓度以及GABA（A）受体的结合和功能。 我们还在停药7天后的第1、2、4和7天评估了相同的参数。 在慢性治疗期间，氯硝西泮对运动活动的影响在第7天产生耐受性，并持续至第14天。 皮质氯硝西泮浓度在此期间没有显着变化。 氯硝西泮在第7天和第14天降低了皮质中苯二氮卓受体的体内结合，但在其他区域没有变化。 体外测定的结合也在这些点降低。 皮质中TBPS（叔丁基双环硫代磷酸酯）结合率略有下降，但不显著。 在第7天和第14天，蝇蕈醇刺激的氯化物摄取也降低。 氯硝西泮停药后，旷场活动在第1天恢复至对照值，但在第4天增加至基线以上。 体内和体外的苯二氮卓结合以及TBPS结合在第4天增加。 在这一点上，蝇蕈醇刺激的氯化物摄取也增加。 这些结果表明，慢性氯硝西泮给药与耐受性的运动效应，与中断的影响，并与受体的改变，在小鼠模型。 氯硝西泮在这方面与其他苯二氮卓类药物相似。
Clonazepam administration may lead to tolerance and "withdrawal" syndromes in clinical use. To assess the effects of this drug in a mouse model, we administered clonazepam (1.5 mg/kg/day) for 1-14 days and evaluated open-field activity, cortical clonazepam concentrations, and binding and function at the GABA(A) receptor. We also evaluated the same parameters at 1, 2, 4 and 7 days after discontinuation of 7 days of clonazepam administration. During chronic treatment, tolerance developed to the effects of clonazepam on motor activity at 7 days and persisted to 14 days. Cortical clonazepam concentrations did not change significantly during this period. Benzodiazepine receptor binding in vivo was decreased in cortex at days 7 and 14 of clonazepam, but was unchanged in other regions. Binding determined in vitro was also decreased at these points. TBPS (t-butylbicyclophosphorothionate) binding in cortex was slightly, but not significantly, decreased. Muscimol-stimulated chloride uptake was also decreased at days 7 and 14. After clonazepam discontinuation, open-field activity returned to control values at 1 day but was increased above baseline at 4 days. Benzodiazepine binding in vivo and in vitro, as well as TBPS binding, were increased at 4 days. Muscimol-stimulated chloride uptake was also increased at this point. These results indicate that chronic clonazepam administration is associated with tolerance to motoric effects, with discontinuation effects, and with receptor alterations in a mouse model. Clonazepam is similar to other benzodiazepines in this regard.