CONTINGENT INEFFICACY AND CONTINGENT TOLERANCE

这个项目研究的是现象学和生物底物 或有毒品效应。使用点燃范式，我们已经演示了 卡马西平和其他药物的抗惊厥效果可以 受与给药有关的时间因素操纵和 癫痫发作的陈述。重大发现包括证明了 如下：1)或有无效，即或有陈述 卡马西平在杏仁核点燃癫痫发展过程中的作用(即， 电刺激之前，但不是在电刺激之后)，同时不影响 点燃了发展，产生了随后难以驾驭的 卡马西平对完全性点燃发作的抗惊厥作用 (当它本应有效时)；2)或有容忍，其中 完成点燃癫痫发作的动物对 卡马西平在之前反复服用该药后，但 不在每次电刺激后；3)或有耐受性逆转 在点燃癫痫或点燃后用卡马西平治疗 单独发作(不吸毒)，但不休息(不吸毒或点燃) 刺激)或单纯药物治疗(无癫痫发作)；4)或有 对丙戊酸盐不耐药，在这种情况下动物被点燃 丙戊酸盐在每次刺激前的偶然性表现( 点燃发育减慢)，丙戊酸盐变得无反应；那些 与非特遣队点燃-暴露于丙戊酸盐仍然对 抗惊厥作用；5)对卡马西平的交叉耐受性 丙戊酸盐耐药大鼠；点燃可逆性 丙戊酸组动物在每次刺激后持续一周； 卡马西平与结合配体的偶发交叉耐受性 外周型苯二氮卓类受体和丙戊酸盐，但不是 卡马西平与安定、氯硝西潘或苯妥英之间；7) 反映反应性变化的癫痫阈值的变化 卡马西平；8)非卡马西平减缓或有耐受发展 偶然给药或通过低刺激点燃大鼠 电流，但不是通过更高剂量的卡马西平；9)调制 不同水平的点燃刺激可点燃惊厥阈值； 10)NMDA拮抗剂MK-801或钙通道无作用 拮抗剂尼莫地平对偶发耐受性发展的影响 或有耐受性的神经化学相关因素的数量 代表GABA-A中癫痫诱导的适应的一个子集的丢失 系统以及多肽mRNA、营养因子和即刻早期 基因；11)安定或有耐受性的神经化学相关性 它们与观察到的那些重叠但不完全相同 卡马西平耐受性；12)联合用药的耐受性发展缓慢 卡马西平(15 mg/kg)和丙戊酸盐(小剂量-150)治疗 Mg/kg)与单独使用其中任何一种进行比较。

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.