Tolerance to the anticonvulsant effects of lamotrigine on amygdala kindled seizures: cross-tolerance to carbamazepine but not valproate or diazepam.
Using an amygdala-kindled seizure paradigm, we evaluated the acute and chronic anticonvulsant effects of lamotrigine (LTG). Lamotrigine produced dose-dependent inhibitory effects on seizure stage, afterdischarge (AD), and seizure duration. Lamotrigine (15 mg/kg) also increased the afterdischarge and seizure thresholds. Following repeated LTG administration and stimulation at 48-h intervals, tolerance developed to LTG's (15 mg/kg) anticonvulsant effects, and cross-tolerance was observed to the anticonvulsant effects of carbamazepine (CBZ, 15 mg/kg). In a separate group of kindled rats, CBZ (15 mg/kg) was repeatedly administered to induce tolerance. This led to a partial cross-tolerance to LTG, manifesting as an increased rate of tolerance development to LTG, and seizures following the first injection in some animals, which were not observed in CBZ-nontolerant controls. When these rats were made fully tolerant to LTG and then exposed to higher doses of LTG (30 and 50 mg/kg), no anticonvulsant effects were observed. In contrast, higher doses of CBZ (30 mg/kg) did restore efficacy in CBZ-tolerant animals. Cross-tolerance from LTG to valproate and diazepam was not observed, although cross-tolerance from CBZ to valproate has been reported previously. These data suggest that LTG has both shared and distinct anticonvulsant mechanisms from those of CBZ on amygdala-kindled seizures. The implications of these results for clinical therapeutics remain to be evaluated.
Krupp
E
E
Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Heynen
T
T
Li
X L
XL
Post
R M
RM
Weiss
S R
SR
D000679:Amygdala / Q000187:drug effects* / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D002220:Carbamazepine / Q000008:administration & dosage / Q000494:pharmacology*; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D007696:Kindling, Neurologic / Q000187:drug effects; D000077213:Lamotrigine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism*; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology
D000927:Anticonvulsants; D014227:Triazines; D002220:Carbamazepine; D014635:Valproic Acid; D003975:Diazepam; D000077213:Lamotrigine