In order to investigate the mechanism of action of
anticonvulsant drugs, we examined the effects of
carbamazepine (CBZ) and
antiepilepsirine (AE) on convulsions and on brain
biogenic amines in genetically
epilepsy-prone rats (GEPR). AE was an effective
anticonvulsant in moderate seizure GEPR (GEPR-3, ED50 = 65.5 mg/kg) and in severe seizure GEPR (GEPR-9, ED50 = 68.5 mg/kg). Because GEPR are known to have deficiencies in brain
norepinephrine (NE) and
serotonin (5-HT), which are of etiologic significance in their seizure predisposition, we evaluated the effects of
anticonvulsant doses of CBZ and AE on dialyzable NE,
5-HT and their metabolites. Dialysis probes were stereotaxically inserted into hippocampi of awake and unrestrained GEPR-3 and GEPR-9. Either AE (100 mg/kg in GEPR-3; 100 mg/kg in GEPR-9) or CBZ (45 mg/kg in GEPR-3; 6 mg/kg in GEPR-9) was administered i.p. after establishing basal release. Significant increases in dialyzable
5-HT, but not NE, were seen at the approximate time to peak
anticonvulsant effect for each
drug in both strains. The changes in
5-HT release remained closely associated with the
anticonvulsant actions after i.v. administration of either AE (40 mg/kg) or CBZ (25 mg/kg) in GEPR-3. Pretreatment of GEPR-9 with
p-chlorophenylalanine depleted brain
5-HT and greatly diminished the
anticonvulsant effectiveness of both drugs. We conclude that both CBZ and AE are effective
anticonvulsants in GEPR and that enhancement of serotonergic transmission may contribute to the
anticonvulsant effect of these drugs.