McMahon Lance R, Gerak Lisa R, France Charles P
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA.
J Pharmacol Exp Ther. 2006 Aug;318(2):907-13. doi: 10.1124/jpet.106.103168. Epub 2006 May 16.
In benzodiazepine (BZ)-dependent animals, the effects of negative GABA(A) modulators at BZ sites are not clearly related to differences in negative efficacy (i.e., inverse agonist activity). A flumazenil discriminative stimulus in diazepam (5.6 mg/kg/day)-treated rhesus monkeys was used to test the hypothesis that the effects of negative GABA(A) modulators at BZ sites do not vary as a function of efficacy in BZ-dependent animals. Negative GABA(A) modulators varying in efficacy were studied in combination with positive modulators acting at different modulatory sites (BZ, barbiturate, and neuroactive steroid sites). The negative modulators Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]benzodiazepine-3-carboxylate) and ethyl beta-carboline-3-carboxylate (beta-CCE) substituted for the flumazenil discriminative stimulus. Acute pretreatment with diazepam (3.2 and 10 mg/kg s.c., in addition to 5.6 mg/kg/day p.o.), pentobarbital (3.2 and 10 mg/kg), or pregnanolone (1 and 3.2 mg/kg) attenuated the flumazenil discriminative stimulus and also attenuated the flumazenil-like discriminative stimulus effects of Ro 15-4513 and beta-CCE. Attenuation of the discriminative stimulus effects of flumazenil, Ro 15-4513, and beta-CCE did not systematically vary as a function of negative efficacy. Compared with their discriminative stimulus effects in untreated monkeys discriminating midazolam, both pregnanolone and pentobarbital were relatively more potent than diazepam in attenuating the discriminative stimulus effects of flumazenil, Ro 15-4513, and beta-CCE in diazepam-treated monkeys. These results show that the discriminative stimulus effects of BZ-site neutral and negative modulators are not different in BZ-dependent animals trained to discriminate flumazenil, and extend the results of a previous study showing that positive modulators acting at non-BZ sites are especially potent in attenuating the effects of flumazenil in diazepam-treated monkeys (i.e., diazepam withdrawal).
在对苯二氮䓬（BZ）产生依赖的动物中，BZ位点上的负性GABA(A)调节剂的作用与负性效能（即反向激动剂活性）的差异并无明显关联。在接受地西泮（5.6毫克/千克/天）治疗的恒河猴中，使用氟马西尼辨别性刺激来检验以下假设：在对BZ产生依赖的动物中，BZ位点上的负性GABA(A)调节剂的作用不会因效能不同而有所变化。研究了效能各异的负性GABA(A)调节剂与作用于不同调节位点（BZ、巴比妥酸盐和神经活性甾体位点）的正性调节剂联合使用的情况。负性调节剂Ro 15 - 4513（8 - 叠氮基 - 6 - 二氢 - 5 - 甲基 - 6 - 氧代 - 4H - 咪唑并[1,5 - α]-[1,4]苯二氮䓬 - 3 - 羧酸乙酯）和β - 咔啉 - 3 - 羧酸乙酯（β - CCE）替代了氟马西尼辨别性刺激。用地西泮（除口服5.6毫克/千克/天外，皮下注射3.2和10毫克/千克）、戊巴比妥（3.2和10毫克/千克）或孕烷醇酮（1和3.2毫克/千克）进行急性预处理，可减弱氟马西尼辨别性刺激，同时也减弱了Ro 15 - 4513和β - CCE的氟马西尼样辨别性刺激作用。氟马西尼、Ro 15 - 4513和β - CCE辨别性刺激作用的减弱并未随负性效能而系统地变化。与在辨别咪达唑仑的未治疗猴子中的辨别性刺激作用相比，在接受地西泮治疗的猴子中，孕烷醇酮和戊巴比妥在减弱氟马西尼、Ro 15 - 4513和β - CCE的辨别性刺激作用方面比地西泮相对更有效。这些结果表明，在经过训练辨别氟马西尼的对BZ产生依赖的动物中，BZ位点中性和负性调节剂的辨别性刺激作用并无差异，并扩展了先前一项研究的结果，该研究表明作用于非BZ位点的正性调节剂在减弱地西泮治疗猴子中氟马西尼的作用方面（即地西泮戒断）特别有效。
