title: Carbamazepine, but not valproate, displays pharmacoresistance in lamotrigine-resistant amygdala kindled rats.
abstract: The voltage gated sodium channel (VGSC) blocker lamotrigine (LTG), when administered during kindling acquisition, leads to the development of resistance to LTG. The present study aimed to assess whether LTG-resistant amygdala-kindled rats display subsequent resistance to the VGSC blocker carbamazepine (CBZ) and the broad-spectrum antiepileptic drug (AED) sodium valproate (VPA). Two groups of male Sprague Dawley rats received either 0.5% methylcellulose (MC) or LTG (5mg/kg, i.p.) 1h before each amygdala kindling stimulation. Treatments were stopped once both the groups were fully kindled. Two days later, both groups were challenged with a higher dose of LTG (15mg/kg, i.p.) to verify LTG-resistance in the experimental group (i.e., LTG-pretreated rats). The efficacy of CBZ and VPA was then evaluated in both groups. A higher dose of LTG blocked fully kindled seizures in the vehicle-treated rats but not seizures in the LTG-treated group. The mean seizure score, of the control group (1.2±0.3) was significantly lower (P<.05) than that of the LTG-treated population (3.5±0.7; n=8). A lower percent of the population in the control group was observed to display a generalized stage 4-5 seizure compared to the experimental group (i.e., those that received LTG during kindling acquisition) (28.5% vs. 62%, respectively). Interestingly, CBZ (10, 20, and 40mg/kg) displayed a dose-dependent anticonvulsant effect in the vehicle-kindled group, but was less effective in LTG-treated animals. In contrast, VPA (300mg/kg) effectively blocked the behavioral seizure and decreased the afterdischarge duration (ADD) in both vehicle and LTG groups. These findings suggest that the LTG-resistant, amygdala-kindled rat may represent a novel model of pharmacoresistant epilepsy.
authors.affiliation: Anticonvulsant Drug Development (ADD) Program, Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Srivastava
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use*; D004351:Drug Resistance / Q000187:drug effects / Q000502:physiology; D004827:Epilepsy / Q000503:physiopathology / Q000517:prevention & control*; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D000077213:Lamotrigine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D002220:Carbamazepine; D014635:Valproic Acid; D000077213:Lamotrigine