CONTINGENT TOLERANCE TO CARBAMAZEPINE IS NOT AFFECTED BY CALCIUM-CHANNEL OR NMDA RECEPTOR BLOCKERS

We previously demonstrated that tolerance to carbamazepine's anticonvu lsant effects occurs only with contingent presentation of the drug rel ative to the seizure (i.e., drug administration before but not after t he seizure). Moreover, this tolerance can be reversed by altering the contingencies of drug administration (e.g., giving the drug after the seizure has occurred) without discontinuation of drug treatment. These findings imply an associative component to tolerance development in t his model. Thus, we evaluated the effects on contingent tolerance deve lopment of two agents that have been shown to affect rate of tolerance development and acquisition or retention in other learning paradigms. Rats were electrically kindled in the amygdala until they reliably ex perienced seizures with each stimulation. In three separate studies, M K-801 (0.3 and 0.15 mg/kg), an NMDA receptor antagonist, and nimodipin e (20 mg/kg), an L-type calcium channel blocker, were coadministered w ith carbamazepine prior to each kindling stimulation to evaluate the r ate of tolerance development compared to controls. No effect of either drug was seen on the rate of contingent tolerance development to carb amazepine, suggesting that neither NMDA receptors nor L-type calcium c hannels are critically involved in this type of tolerance. The conting ent tolerance paradigm may, however, prove useful in elucidating novel biochemical mechanisms of associative learning that might ultimately be explored in clinical situations where tolerance is a problem.