CONNTINGENT INEFFICACY AND CONTINGENT TOLERANCE

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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 of carbamazepine (i.e., before, but not after electrical stimulation) during amygdala kindling seizure development does not affect kindling development but, nonetheless, produces a subsequent refractoriness to carbamazepine's anticonvulsant effects on completed kindled seizures (when it is ordinarily 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) cross tolerance between carbamazepine and a PK-11195 (a ligand that binds peripheral-type benzodiazepine receptors), and valproic acid, but not between carbamazepine and diazepam; 6) alterations in seizure threshold which mirror the changes in responsivity to carbamazepine.