CONTINGENT INEFFICACY AND CONTINGENT TOLERANCE

这个项目的总体目标是研究现象学和 慢性和偶发药物效应的生物底物。使用 点燃范式，我们已经证明了抗惊厥的功效 卡马西平和其他药物，可以通过时间来操纵 与给药和癫痫发作有关的因素。 迄今为止的重大发现包括以下方面的论证：1) 或有无效，由此或有提出 卡马西平在杏仁核点燃癫痫发展过程中(即，之前， 但不是在电刺激之后)，同时不影响点火 开发，产生了随后对卡马西平的耐受性 对完全性点燃发作的抗惊厥作用(当它应该有 有效)；2)或有耐受性，在这种情况下， 完全性点燃发作后对卡马西平的耐受性 在每次服药前而不是在服药后重复服药 电刺激；3)通过治疗逆转或有耐受性 卡马西平在点燃发作或点燃发作后使用 单独；4)对丙戊酸盐的或有抵抗力，其中动物 都被丙戊酸盐的临时呈现点燃了 刺激(它减缓了点燃的发展)，变成了丙戊酸盐 无反应；非或有接触丙戊酸盐点燃的大鼠 对其抗惊厥作用仍然敏感；5)交叉耐受性 丙戊酸盐耐药大鼠的卡马西平及其可逆性 每次刺激后用丙戊酸盐点燃动物的效果 1周；6)卡马西平和卡马西平的偶发交叉耐受性 PK-11195(外周型苯二氮卓受体的拮抗剂)， 和丙戊酸酯，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偶发耐受形成的影响 和11)或有耐受性的若干神经化学相关因素 这代表着癫痫诱导的适应的一个子集的丢失 GABAA系统，以及在多肽mRNA、营养因子和 即刻早期基因；11)突发事件的神经化学相关性 对安定的耐受性与观察到的 卡马西平；对联合治疗的耐受性发展缓慢 卡马西平(15毫克/公斤)和丙戊酸盐(小剂量--150毫克/公斤) 与任何一种药物相比；药物的振荡模式 某些情况下对卡马西平和丙戊酸盐的反应性 重复给药和点燃刺激(即，最低限度 有效剂量或较低刺激强度)。

The overall objectives of this project are to study the phenomenology and biological substrates of chronic and 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 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 by kindled seizures alone; 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; rats 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) contingent cross tolerance between carbamazepine and PK-11195 (an antagonist at 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 GABAA system, as well as in peptide mRNA's, trophic factors, and immediate early genes; 11) neurochemical correlates of contingent tolerance to diazepem which overlap with those observed for carbamazepine; 12) slower tolerance development to combined treatment with carbamazepine (15 mg/kg) and valproate (low dose--150 mg/kg) compared to either one alone; 16) oscillatory patterns of drug responsivity to carbamazepine and valproate under certain circumstances of repeated drug administration and kindling stimulation (i.e., minimally effective doses or lower stimulation intensities).