CONTINGENT INEFFICACY AND CONTINGENT TOLERANCE

这个项目的总体目标是研究现象学和 或有药物效应的生物底物。用火柴点燃 范例，我们已经证明了抗惊厥的功效 卡马西平和其他药物可能会受到时间因素的影响 关于药物管理和癫痫发作的陈述。意义重大 到目前为止，调查结果包括以下演示：1)或有 无效，因此临时陈述(即，在之前，但不是 电刺激后)杏仁核点燃时应用卡马西平 癫痫的发展，虽然不影响点燃的发展，产生 卡马西平抗惊厥作用的继发性难治性 完全点燃的癫痫发作(本应有效)；2) 或有耐受性，即完成点燃的动物 反复发作后出现对卡马西平的耐受性 在每次电击前而不是在电击后给药 刺激；3)通过以下治疗逆转或有耐受性 卡马西平在点燃发作或单独点燃发作后(无 药物)，但不是在一段时间内(没有药物或点燃刺激) 最多三周；4)丙戊酸盐或有不耐药，其中 因丙戊酸盐的偶然性呈现而点燃的动物 在每次刺激(这减缓了点燃的发展)之前， 丙戊酸盐无反应；与非或有暴露于 丙戊酸盐仍然对其抗癫痫作用敏感；5)交叉 丙戊酸盐耐药大鼠对卡马西平的耐受性； 丙戊酸盐点燃动物后这种效应的可逆性 6)卡马西平与卡马西平交叉耐受性 以及与外周型苯二氮卓类受体结合的配体 丙戊酸，但不在卡马西平和安定、氯硝西潘或 苯妥英钠；7)反映变化的癫痫阈值的变化 对卡马西平的反应；8)或有耐受性减慢 通过非偶然给药或点燃大鼠的方式发展 在较低的刺激电流下，但不是通过高剂量的卡马西平； 9)通过不同水平的 点燃刺激；10)NMDA拮抗剂MK-801或 钙通道拮抗剂尼莫地平对条件耐受性的影响 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.