Abstract
Carbamazepine produces dose-related anticonvulsant effects in epilepsy models including the genetically epilepsy-prone rat (GEPR) model and the rat maximal electroshock model. Dose–response relationships are quantitatively different among the models. Against electroshock seizures in Sprague–Dawley rats the ED 50 dose is 7.5 mg/kg whereas the ED 50 against audiogenic seizures in severe seizure GEPRs (GEPR-9s) is 3 mg/kg. In contrast, the ED 50 in moderate seizure GEPRs (GEPR-3s) is 25 mg/kg. The present study was designed to ascribe dose–response differences among the three rat strains to pharmacokinetic or pharmacodynamic factors. After systemic carbamazepine, pharmacokinetic studies revealed differences in area under the concentration-vs.-time curve. In other experiments, carbamazepine-induced serotonin release from hippocampus was used as a pharmacodynamic marker. In a concentration-controlled design using intracerebral microdialysis, hippocampal carbamazepine infusions produced similar concentration–response relations for the three rat strains. These data support the hypothesis that dose–response differences among the three rat strains are primarily pharmacokinetic in nature.
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