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.
