Contingent tolerance to carbamazepine is not affected by calcium-channel or NMDA receptor blockers.
We previously demonstrated that tolerance to carbamazepine's anticonvulsant effects occurs only with contingent presentation of the drug relative to the seizure (i.e., drug administration before but not after the 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 this model. Thus, we evaluated the effects on contingent tolerance development 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 experienced seizures with each stimulation. In three separate studies, MK-801 (0.3 and 0.15 mg/kg), an NMDA receptor antagonist, and nimodipine (20 mg/kg), an L-type calcium channel blocker, were coadministered with carbamazepine prior to each kindling stimulation to evaluate the rate of tolerance development compared to controls. No effect of either drug was seen on the rate of contingent tolerance development to carbamazepine, suggesting that neither NMDA receptors nor L-type calcium channels are critically involved in this type of tolerance. The contingent 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.
Weiss
S R
SR
Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892.
Post
R M
RM
Anthony
P
P
Ferrer
J
J
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002220:Carbamazepine / Q000008:administration & dosage / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004361:Drug Tolerance; D004558:Electric Stimulation; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D009553:Nimodipine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D002121:Calcium Channel Blockers; D016194:Receptors, N-Methyl-D-Aspartate; D002220:Carbamazepine; D009553:Nimodipine; D016291:Dizocilpine Maleate