The anticonvulsant effectiveness of the benzodiazepine antagonists RO 15-1788, CGS-8216 and PK-11195 were evaluated against threshold and suprathreshold (400 μA) stimulation in fully amygdaloid-kindled rats. Pretreatment with either RO 15-1788 (3, 10 and 30 mg/kg), CGS-8216 (3,10 and 30 mg/kg) or PK-11195 (10 and 60 mg/kg) failed in this study to modify consistently either the afterdischarge thresholds or elicited suprathreshold seizures or duration of afterdischarge. Using a double injection paradigm, the effectiveness of these three benzodiazepine antagonists to reverse the anticonvulsant and behavioral effects of diazepam were studied. When diazepam (3 mg/kg) was injected 15 min before or after a second injection of the vehicle control DMSO (0.25 mg/kg), a significant reduction in the duration of afterdischarge and seizure rank, elicited by a suprathreshold stimulation in amygdaloid-kindled rats, occurred. When either CGS 8216 (10 mg/kg)or RO 15-1788 (10 mg/kg) were given 15 min before diazepam (3 mg/kg) prior to stimulation, the anticonvulsant properties of diazepam were blocked. When RO 15-1788 (10 mg/kg) was given 15 min after diazepam, antagonism of the anticonvulsant effects on diazepam was shown. However, when either CGS-8216 (10 mg/kg) or PK-11195 (10 and 60 mg/kg) were given 15 min after diazepam (3 mg/kg), the anticonvulsant properties of diazepam were not blocked. The anticonvulsant effects of diazepam were reversed when CGS-8216 (10 mg/kg) was given 5 min after diazepam (3 mg/kg) or when a larger dose (30 mg/kg) was given at the same 15 min interval. Previous work has shown that the benzodiazepine antagonist, RO 15-1788 can inhibit the acquisition of amygdaloid-kindling, while the data in the present study point to the lack of significant anticonvulsant effectiveness of these three benzodiazepine antagonists in the fully amygdaloid-kindled model of epilepsy in the rat. Both of the "central" benzodiapine antagonists (RO 15-1788 and CGS-8216) demonstrated the ability to reverse the anticonvulsant effectiveness of diazepam in this model, when given before or after administration of diazepam. Appropriate doses and injection intervals were necessary to demonstrate the antagonism by CGS-8216 given after diazepam. Large doses of the "peripheral" benzodiazepine antagonist, PK-11195 failed to demonstrate intrinsic anticonvulsant properties or the ability to reverse the anticonvulsant effectiveness of diazepam in this model.
- RO 15-1788
- seizure threshold
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Drug Discovery