Evans S M, Johanson C E
Department of Psychiatry, Pritzker School of Medicine, University of Chicago, Illinois.
J Pharmacol Exp Ther. 1989 Jan;248(1):29-38.
Five pigeons were trained to discriminate injections of midazolam (1.0 or 3.0 mg/kg i.m.) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. When other benzodiazepines were tested, they consistently produced greater than 80% of midazolam-appropriate responding. The order of potency for substituting for midazolam was triazolam greater than alprazolam = diazepam = lorazepam greater than midazolam greater than flurazepam = nitrazepam greater than nordiazepam. The barbiturate phenobarbital (10-100 mg/kg) substituted for midazolam in three of four pigeons whereas pentobarbital (1.0-30 mg/kg) substituted in only two of five pigeons. Several nonbenzodiazepine anxiolytics were also evaluated. Methaqualone (3.0-56 mg/kg) substituted in only one of four pigeons and meprobamate (30-100 mg/kg) failed to substitute in any pigeon tested. CL 218,872, when administered either i.m. (0.3-30 mg/kg) or p.o. (1.0-56 mg/kg), and buspirone (0.3-30 mg/kg) did not substitute for midazolam. Compounds from pharmacological classes not related to midazolam also failed to substitute for midazolam. Pretreatment with the benzodiazepine antagonist flumazenil (Ro 15-1788; 0.03-1.0 mg/kg) antagonized the discriminative stimulus properties of midazolam in a dose-related manner in all pigeons tested. However, this antagonism could not be overcome with increasing doses of midazolam in all pigeons. The results of the present study demonstrate that midazolam is an effective discriminative stimulus in the pigeon. Benzodiazepine anxiolytics, but not other compounds with sedative and/or anxiolytic properties, were found to reliably substitute for midazolam. These results suggest that the discriminative stimulus effects of midazolam are pharmacologically selective.
训练了五只鸽子，使其能在固定比例为30的食物递送时间表下，区分咪达唑仑（1.0或3.0毫克/千克，肌肉注射）和生理盐水注射。当测试其他苯二氮䓬类药物时，它们始终产生超过80%的与咪达唑仑相符的反应。替代咪达唑仑的效力顺序为三唑仑大于阿普唑仑 = 地西泮 = 劳拉西泮大于咪达唑仑大于氟西泮 = 硝西泮大于去甲西泮。巴比妥类药物苯巴比妥（10 - 100毫克/千克）在四只鸽子中的三只中替代了咪达唑仑，而戊巴比妥（1.0 - 30毫克/千克）仅在五只鸽子中的两只中替代了咪达唑仑。还评估了几种非苯二氮䓬类抗焦虑药。甲喹酮（3.0 - 56毫克/千克）仅在四只鸽子中的一只中替代了咪达唑仑，而甲丙氨酯（30 - 100毫克/千克）在任何测试的鸽子中都未能替代。CL 218,872，无论是肌肉注射（0.3 - 30毫克/千克）还是口服（1.0 - 56毫克/千克）给药，以及丁螺环酮（0.3 - 30毫克/千克）都不能替代咪达唑仑。与咪达唑仑无关的药理学类别的化合物也不能替代咪达唑仑。用苯二氮䓬类拮抗剂氟马西尼（Ro 15 - 1788；0.03 - 1.0毫克/千克）预处理，在所有测试的鸽子中，以剂量相关的方式拮抗了咪达唑仑的辨别刺激特性。然而，并非所有鸽子都能通过增加咪达唑仑的剂量来克服这种拮抗作用。本研究结果表明，咪达唑仑在鸽子中是一种有效的辨别刺激物。发现苯二氮䓬类抗焦虑药，而非其他具有镇静和/或抗焦虑特性的化合物，能可靠地替代咪达唑仑。这些结果表明，咪达唑仑的辨别刺激作用在药理学上具有选择性。
