Takada K, Suzuki T, Hagen T, Cook J M, Katz J L
NIDA Addiction Research Center, Baltimore, Maryland 21224.
Life Sci. 1989;44(4):289-99. doi: 10.1016/0024-3205(89)90187-2.
Rats were trained to respond under 3-min fixed-interval schedules of food presentation, and effects of the benzodiazepine-receptor ligands, flumazenil, 2-(4-methoxy-phenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one (CGS 9895), 3-carbo-t-butoxy-beta-carboline (beta-CCtB), and beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) were assessed before and after the induction of tolerance to chlordiazepoxide. Before daily administration of chlordiazepoxide, none of the antagonists produced appreciable effects on rates of responding up to doses of 32.0 mg/kg i.p. beta-CCE was the only antagonist studied at a higher dose (100.0 mg/kg i.p.), which decreased response rates. After 23 days of daily chlordiazepoxide administration (oral doses started at 10 and increased to 100 mg/kg/day by the 17th day), dose-effect curves for chlordiazepoxide were shifted to the right by about one-half log unit. Subjects were also more sensitive to the flumazenil, CGS 9895, and beta-CCtB, however, since these drugs produced only small effects in non-tolerant subjects, precise estimates of the degree of the shift in dose-effect curves could not be estimated. However, there were differences in the changes in the dose-effect curves induced by chlordiazepoxide tolerance. These results suggest differences in mechanism of action of antagonists in tolerant and non-tolerant subjects, and further that the sensitivity that is induced to antagonists in tolerant subjects is not conferred equally to all drugs having benzodiazepine antagonist activity.
将大鼠训练至在3分钟固定间隔的食物呈现时间表下做出反应，并在诱导对氯氮卓产生耐受性之前和之后评估苯二氮卓受体配体氟马西尼、2-(4-甲氧基苯基)-吡唑并[4,3-c]喹啉-3(5H)-酮（CGS 9895）、3-叔丁氧羰基-β-咔啉（β-CCtB）和β-咔啉-3-羧酸乙酯（β-CCE）的作用。在每日给予氯氮卓之前，高达32.0 mg/kg腹腔注射剂量的拮抗剂均未对反应率产生明显影响。β-CCE是唯一在更高剂量（100.0 mg/kg腹腔注射）下研究的拮抗剂，其降低了反应率。在每日给予氯氮卓23天后（口服剂量从10开始，到第17天增加至100 mg/kg/天），氯氮卓的剂量-效应曲线向右移动了约半个对数单位。然而，由于这些药物在未耐受的受试者中仅产生微小影响，因此无法精确估计剂量-效应曲线的移动程度。不过，氯氮卓耐受性诱导的剂量-效应曲线变化存在差异。这些结果表明，拮抗剂在耐受和未耐受受试者中的作用机制存在差异，进一步表明在耐受受试者中诱导产生的对拮抗剂的敏感性并非同等赋予所有具有苯二氮卓拮抗剂活性的药物。
