CONNTINGENT INEFFICACY AND CONTINGENT TOLERANCE

这个项目的总体目标是研究现象学， 偶然药物效应的生物基质。用火种 范例，我们已经证明，抗惊厥疗效的 卡马西平和其他药物，可以通过时间因素来操纵 与药物管理和癫痫表现有关。显著 迄今为止的调查结果包括以下方面： 无效，由此卡马西平的偶然出现（即， 在杏仁核点燃过程中， 癫痫发作的发展不影响点燃的发展，但是， 对卡马西平的抗惊厥药产生后续的无效性 对完全点燃癫痫发作的影响（通常有效时）; 2） 偶然性耐受，即完成癫痫发作的动物 在重复给药后对卡马西平产生耐受性 药物之前，但不是之后，每个电刺激; 3）偶然的 点燃后用卡马西平治疗耐受性逆转 癫痫发作或点燃癫痫发作单独（无药物），但不是由时间关闭（无药物） 或点燃刺激）长达三周的时间; 4）交叉 卡马西平和PK-11195（一种结合 外周型苯二氮卓受体）和丙戊酸，但不 卡马西平和地西泮之间的差异; 6）癫痫发作阈值的改变 反映了对卡马西平反应性的变化。

The overall objectives of this project are to study 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, could be manipulated by temporal factors relating to drug administration and seizure presentation. Significant findings to date include demonstration of the following: 1) contingent inefficacy, whereby the contingent presentation of carbamazepine (i.e., before, but not after electrical stimulation) during amygdala kindling seizure development does not affect kindling development but, nonetheless, produces a subsequent refractoriness to carbamazepine's anticonvulsant effects on completed kindled seizures (when it is ordinarily 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) for periods of up to three weeks; 4) cross tolerance between carbamazepine and a PK-11195 (a ligand that binds peripheral-type benzodiazepine receptors), and valproic acid, but not between carbamazepine and diazepam; 6) alterations in seizure threshold which mirror the changes in responsivity to carbamazepine.