Contingent tolerance to carbamazepine is associated with lowering of amygdala-kindled seizure thresholds

Abstract

Amygdala-kindled seizure thresholds were studied in animals which were or were not tolerant to the anticonvulsant effects of carbamazepine. The seizure threshold was defined as the lowest current that elicited a major motor seizure (stage 3 or greater). Amygdala-kindled rats received carbamazepine, once daily, either before each electrical stimulation (carba-before) or after each stimulation (carba-after). The rats given carbamazepine before, but not after, each once-daily kindling stimulation became tolerant to its anticonvulsant effects. Following this manipulation, seizure thresholds were redetermined in both groups of animals while medication-free. The carba-before (i.e., tolerant) animals showed a decreased seizure threshold, while the carba-after (i.e., nontolerant) animals showed no change. Tolerance to carbamazepine was reversed by giving the rats kindled seizures for a period of 7 days without drug; nontolerant animals received the same stimulation and seizures. When seizure thresholds were reevaluated, the carba-before animals (now not tolerant) had returned to their pretolerance values, while the carba-after group again showed no change. This effect of carbamazepine tolerance and its reversal being associated with respective decreases and increases in basal seizure threshold was replicated two more times. In each case the change in the generalized seizure threshold mirrored the change in responsivity of the animals to carbamazepine. These findings, consistent with the formulations of Siegel regarding conditioned compensatory response mechanisms mediating contingent drug tolerance, may have important clinical and theoretical implications.