Effects of diazepam and two beta-carbolines on epileptic activity and on EEG and behavior in rats with absence seizures.

Abstract

In the present series of experiments, effects of a full benzodiazepine receptor agonist (diazepam) are described and compared with those of a partial benzodiazepine receptor agonist (ZK 91296) and an inverse partial benzodiazepine receptor agonist (FG 7142), both compounds of the beta-carboline family. In a rat model for generalized absence epilepsy, the anticonvulsant, the hypnotic and the myorelaxant properties were investigated, as well as effects on on-going behavior and effects on the electroencephalogram (EEG). While diazepam showed all behavioral and electrophysiological changes characteristic for the benzodiazepines, the partial agonist ZK 91296 reduced seizure activity without inducing any signs of sedation, sleepiness, myorelaxation and changes in behavior or EEG spectral content. The partial inverse agonist FG 7142 aggrevated epileptic activity, with slightly enhanced immobile behavior, suggesting some anxiogenic properties. The results not only demonstrate that the multiple effects of the benzodiazepines could be separated by these compounds, but also that the anticonvulsant activity is not related to changes in spectral content of the EEG. Because of its selective activity, ZK 91296 appears to be more suitable than diazepam in reducing seizure activity. Finally, FG 7142 seems a genuine partial inverse agonist which has some, but not all, of the inverse effects of a full agonist.