CONTINGENT INEFFICACY AND CONTINGENT TOLERANCE

本项目研究的现象学和生物基板， 偶然的药物效应 使用火种范例，我们已经证明了 卡马西平和其他药物的抗惊厥效果 受与给药相关的时间因素操纵， 癫痫表现 重要的发现包括： 以下：1）或有无效性，即或有陈述 在杏仁核点燃癫痫发作发展过程中卡马西平的作用（即， 在电刺激之前，但不是在电刺激之后），同时不影响 点燃发展，产生了随后的耐火性， 卡马西平对完全点燃癫痫的抗惊厥作用 (when它应该是有效的）; 2）偶然容忍，其中 完成点燃癫痫发作的动物对以下药物产生耐受性： 卡马西平后，重复给药的药物之前，但 而不是在每次电刺激之后; 3）偶然耐受逆转 通过在点燃癫痫发作或点燃后用卡马西平治疗， 单独癫痫发作（无药物），但不通过时间关闭（无药物或点燃 刺激）或单独药物治疗（无癫痫发作）; 4）偶然的 丙戊酸盐不应性，其中动物被丙戊酸盐点燃， 每次刺激前丙戊酸盐的偶然出现（ 减慢点燃发展），变为丙戊酸盐无反应;这些 与非特遣队-丙戊酸盐暴露仍然敏感， 其抗惊厥作用; 5）交叉耐受卡马西平 丙戊酸盐难治性大鼠;通过点燃研究该效应的可逆性 每次刺激后给予丙戊酸盐的动物，持续1周; 6） 卡马西平和配体之间的偶然交叉耐受性 外周型苯二氮卓受体和丙戊酸盐，但不 卡马西平与地西泮、氯硝西泮或苯妥英之间; 7） 癫痫发作阈值的改变反映了反应性的变化 8）通过非- 或通过在较低刺激下点燃大鼠 电流，但不是由更高剂量的卡马西平; 9）调制 不同水平点燃刺激点燃癫痫发作阈值; 10)NMDA拮抗剂MK-801或钙离子通道无影响 拮抗剂尼莫地平对偶然耐受性发展的影响和11）a 许多神经化学相关的偶然耐受， 代表GABA-A中一个亚组的神经元诱导的适应性丧失， 系统以及肽mRNA、营养因子和立即早期 基因; 11）对地西泮的偶然耐受性的神经化学相关性 与中观察到的重叠但不相同 卡马西平耐受性; 12）对联合用药的耐受性发展较慢 卡马西平（15 mg/kg）和丙戊酸盐（低剂量--150 mg/kg）。

This project studies the phenomenology and biological substrates of contingent drug effects. Using a kindling paradigm, we have demonstrated that the anticonvulsant efficacy of carbamazepine and other drugs can be manipulated by temporal factors relating to drug administration and seizure presentation. Significant findings include demonstration of the following: 1) contingent inefficacy, whereby the contingent presentation of carbamazepine during amygdala kindling seizure development (i.e., before, but not after electrical stimulation), while not affecting kindling development, produced a subsequent refractoriness to carbamazepine's anticonvulsant effects on completed kindled seizures (when it should have been effective); 2) contingent tolerance, in which animals that have completed kindled seizures develop tolerance to carbamazepine following repeated administration of the drug prior to, but not after, each electrical stimulation; 3) contingent tolerance reversal by treatment with carbamazepine after the kindled seizures or kindled seizures alone (no drug), but not by time off (no drug or kindling stimulation) or drug treatment alone (no seizures); 4) contingent refractoriness to valproate, in which animals hat were kindled with the contingent presentation of valproate before each stimulation (which slowed kindling development), became valproate non-responsive; those kindled with non-contingents-exposure to valproate remained sensitive to its anticonvulsant effects; 5) cross tolerance to carbamazepine in valproate-refractory rats; nd reversibility of this effect by kindling the animals with valproate after each stimulation for one week; 6) contingent cross tolerance between carbamazepine and a ligand that binds the peripheral-type benzodiazepine receptor, and valproate, but not between carbamazepine and diazepam, clonazepam or phenytoin; 7) alterations in seizure threshold which mirror the changes in responsivity to carbamazepine; 8) slowing of contingent tolerance development by non- contingent drug presentation or by kindling the rats at lower stimulation currents, but not by higher doses of carbamazepine; 9) modulation of kindled seizure thresholds by different levels of kindling stimulation; 10) no effect of the NMDA antagonist MK-801 or the calcium channel antagonist nimodipine on contingent tolerance development and 11) a number of neurochemical correlates of contingent tolerance which represent a loss of a subset of seizure-induced adaptations in the GABA-A system as well as in peptide mRNAs, trophic factors, and immediate early genes; 11) neurochemical correlates of contingent tolerance to diazepam which overlap with but are not identical to those observed in carbamazepine tolerance; 12) slower tolerance development to combined treatment with carbamazepine (15 mg/kg) and valproate (low dose--150 mg/kg) compared to either one alone.