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Psychopharmacology (Berl). 1982;77(3):284-8. doi: 10.1007/BF00464581.
After 3 days of dosing rats with lorazepam (0.25 mg/kg), tolerance developed to its sedative effects. Recovery from this tolerance was rapid. No differences could be detected in undrugged behaviour 24 h after the last dose and no differences in response to a probe injection could be found when 2 drug-free days intervened between the chronic treatment and test dose. RO 15-1788 (1-4 mg/kg) antagonised the sedative effects of acute lorazepam (0.5 and 0.25 mg/kg), but chronic treatment with these doses concomitantly with lorazepam did not prevent the development of tolerance. However, 4 mg/kg RO 15-1788 administered for 5 days at the same time as lorazepam (0.5 mg/kg) and again 45 min later attenuated the development of tolerance. Plasma concentrations after acute and chronic treatment did not differ for 0.25 mg/kg lorazepam, but they were lower following chronic treatment with 0.5 mg/kg. Therefore the development of behavioural tolerance in rats to the sedative effects of benzodiazepines probably involves changes in benzodiazepine receptors, in addition to a pharmacokinetic contribution after treatment with high doses.
用劳拉西泮（0.25毫克/千克）给大鼠给药3天后，对其镇静作用产生了耐受性。从这种耐受性中恢复很快。在最后一剂后24小时，未用药行为未检测到差异，并且当在慢性治疗和测试剂量之间间隔2个无药日时，对探针注射的反应也未发现差异。RO 15 - 1788（1 - 4毫克/千克）拮抗急性劳拉西泮（0.5和0.25毫克/千克）的镇静作用，但用这些剂量与劳拉西泮同时进行慢性治疗并不能阻止耐受性的产生。然而，与劳拉西泮（0.5毫克/千克）同时给予4毫克/千克RO 15 - 1788持续5天，45分钟后再次给药可减弱耐受性的发展。急性和慢性治疗后，0.25毫克/千克劳拉西泮的血浆浓度没有差异，但0.5毫克/千克慢性治疗后的血浆浓度较低。因此，大鼠对苯二氮䓬类药物镇静作用的行为耐受性的发展可能除了高剂量治疗后的药代动力学作用外，还涉及苯二氮䓬受体的变化。
