Chronic benzodiazepine administration. XI. Concurrent administration of PK11195 attenuates lorazepam discontinuation effects.
Chronic benzodiazepine administration. XI. Concurrent administration of PK11195 attenuates lorazepam discontinuation effects.
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长期服用苯二氮卓类药物。
DOI：
10.1038/npp.1993.30
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Shader,RI
中科院分区：
文献类型：
--
作者：
Byrnes,JJ;Miller,LG;Perkins,K;Greenblatt,DJ;Shader,RI
在小鼠模型中，停用苯二氮卓类药物与运动活动的改变和γ-氨基丁酸-A 受体的上调有关。先前的研究表明，同时施用化合物N-甲基-N-(甲基-1-丙基)氯-2-苯基-1-异auinoline-3-甲酰胺(PK1195)（一种“外周”位点苯二氮卓类拮抗剂）可以减弱劳拉西泮对耐受性和受体改变的影响。为了评估 PK11195 给药对苯二氮卓类药物停药的影响，我们给小鼠施用劳拉西泮（每天 2 mg/kg）、PK 11195（每天 1 至 10 mg/kg）或联合用药 7 天，然后在停药后第 1、4 和 7 天评估戊四唑诱导的癫痫阈值和苯二氮卓类药物结合。劳拉西泮停药后 4 天，癫痫发作阈值降低；每天同时服用 5 mg/kg PK11195 可减弱这种作用。每日 1 mg/kg 剂量的 PK11195 不会改变劳拉西泮的停药效应，而每日 10 mg/kg 剂量与 5 mg/kg 剂量没有差异。每天 10 mg/kg 的竞争性配体 Ro5-4864 可阻断 PK11195 对劳拉西泮停药的影响。劳拉西泮停药后 4 天，皮层和海马体内苯二氮卓受体结合增加。通过同时施用 PK1195，这种效应在海马体中减弱，但在皮质中没有减弱。这些数据表明，同时给予 PK11195 可能会减弱劳拉西泮的停药效应。
Benzodiazepine discontinuation is associated with alterations in motor activity and gamma-aminobutyric acid-A receptor upregulation in a mouse model. Prior studies indicate that concurrent administration of the compound N-methyl-N-(methyl-1-propyl) chloro-2-phenyl-1-isoauinoline-3-carboxamide (PK1195), a" peripheral" site benzodiazepine antagonist, can attenuate the effects of lorazepam on tolerance and receptor alterations. To evaluate the effects of PK11195 administration on benzodiazepine discontinuation, we administered lorazepam (2 mg/kg per day), PK 11195 (1 to 10 mg/kg per day) or the combination to mice for 7 days, and then evaluated pentylenetetrazole-induced seizure threshold and benzodiazepine binding at days 1, 4, and 7 after discontinuation. Seizure theshold was reduced at 4 days after lorazepam discontinuation; this effect was attenuated by coadministration of PK11195 at 5 mg/kg per day. Lorazepam discontinuation effects were not altered by PK11195 at 1 mg/kg per day, whereas the 10-mg/kg dose was not different from 5 mg/kg per day. The competitive ligand Ro5-4864 at 10 mg/kg per day, blocked the effects of PK11195 on lorazepam discontinuation. Benzodiazepine receptor binding in vivo was increased in the cortex and hippocampus at 4 days postlorazepam discontinuation. This effect was attenuated in the hippocampus but not in the cortex by concurrent administration of PK1195. These data indicate that concurrent administration of PK11195 may attenuate discontinuation effects of lorazepam.