CONTINGENT 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： 无效性，由此偶然呈现（即，以前，但不是 杏仁核点燃时卡马西平的作用 癫痫发作的发展，而不影响点燃的发展，产生 随后对卡马西平的抗惊厥作用无效， 完成点燃癫痫发作（当它应该是有效的）; 2） 偶然耐受性，即动物完成点燃后， 反复发作后，癫痫发作对卡马西平产生耐受性 在每次电刺激之前而不是之后施用药物， 刺激; 3）通过以下治疗的偶然耐受逆转： 卡马西平点燃癫痫发作后或点燃癫痫发作单独（没有 药物），但不能通过停药（无药物或点燃刺激） 最长3周; 4）丙戊酸盐偶发性不应，其中 因偶然给予丙戊酸盐而点燃的动物 在每次刺激（这减缓了点燃的发展）之前， 丙戊酸盐无反应;非偶然暴露于 丙戊酸盐仍对其抗惊厥作用敏感; 5）交叉 丙戊酸盐难治性大鼠对卡马西平的耐受性;以及 通过丙戊酸盐点燃动物， 6）卡马西平与卡马西平之间的交叉耐受性 和结合外周型苯二氮卓受体的配体， 丙戊酸，但不包括卡马西平和地西泮、氯硝西泮或 苯妥英; 7）癫痫发作阈值的变化，反映了变化 对卡马西平的反应性; 8）减缓偶然耐受性 通过非偶然的药物呈递或通过点燃大鼠 在较低的刺激电流，但不是由较高剂量的卡马西平; 9)不同水平的多巴胺对点燃癫痫发作阈值的调节作用 点燃刺激; 10）NMDA拮抗剂MK-801或 钙通道拮抗剂尼莫地平对偶然耐受的影响 发展

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 (i.e., before, but not after electrical stimulation) of carbamazepine during amygdala kindling seizure development, 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) for periods of up to three weeks; 4) contingent refractoriness to valproate, in which animals that were kindled with the contingent presentation of valproate before each stimulation (which slowed kindling development), became valproate non-responsive; those kindled with non-contingent exposure to valproate remained sensitive to its anticonvulsant effects; 5) cross tolerance to carbamazepine in valproate-refractory rats; and reversibility of this effect by kindling the animals with valproate after each stimulation for one week; 6) cross tolerance between carbamazepine and a ligand that binds the peripheral-type benzodiazepine receptor and valproic acid, 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.