Sloan J W, Wala E P, Jing X, Holtman J R
Department of Anesthesiology, University of Kentucky, Lexington, KY 40536, USA.
Pharmacol Biochem Behav. 2000 Aug;66(4):751-64. doi: 10.1016/s0091-3057(00)00239-2.
These studies were undertaken to 1) determine whether repeated dosing with the peripheral benzodiazepine antagonist PK 11195 alters its ability to precipitate withdrawal abstinence in diazepam-dependent rats; 2) whether the administration of PK 11195 and the central benzodiazepine antagonist, flumazenil, 3 days apart to the same rat produces an ordering effect in the intensity of withdrawal abstinence; 3) whether there are gender differences in these effects. Age-matched male and female Sprague Dawley rats had capsules implanted weekly that contained approximately equal (mg/kg) doses of diazepam (120 and 90 mg, respectively) or empty capsules (controls). After 5 implants, the maximum precipitated withdrawal score (PAS(MAX)) induced by PK 11195 and/or flumazenil (10 mg/kg/IV, respectively) was measured. Repeated administration of PK 11195 (1x/day for 5 days) induced tolerance with regard to the intensity of the PAS(MAX) and with gender-related differences. When PK 11195 was administered weekly (5 weeks), rather than daily, tolerance did not develop in either sex. The PK 11195- and flumazenil-induced PAS(MAX) was not changed by the order in which they were administered. There were gender differences in that females had a higher PAS(MAX) after flumazenil than after PK 11195 and vocalized more after all treatments than males.
1）确定外周苯二氮䓬拮抗剂PK 11195重复给药是否会改变其在依赖地西泮的大鼠中引发戒断禁欲的能力；2）对同一只大鼠间隔3天分别给予PK 11195和中枢苯二氮䓬拮抗剂氟马西尼，是否会在戒断禁欲强度上产生顺序效应；3）这些效应是否存在性别差异。年龄匹配的雄性和雌性斯普拉格-道利大鼠每周植入胶囊，其中分别含有剂量大致相等（mg/kg）的地西泮（分别为120和90 mg）或空胶囊（对照组）。5次植入后，测量PK 11195和/或氟马西尼（分别为10 mg/kg静脉注射）诱导的最大戒断评分（PAS(MAX)）。重复给予PK 11195（每天1次，共5天）会导致对PAS(MAX)强度产生耐受性，并存在性别相关差异。当每周（5周）而非每天给予PK 11195时，两性均未产生耐受性。PK 11195和氟马西尼诱导的PAS(MAX)不受给药顺序的影响。存在性别差异，即雌性在接受氟马西尼后的PAS(MAX)高于接受PK 11195后的，并且在所有处理后雌性比雄性叫得更多。
