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).
