The interaction between vigabatrin and diazepam on the electroencephalogram during active behaviour in rats: an isobolic analysis

To test whether polytherapy with two gamma-aminobutyric acid (GABA) -ergic drugs might be clinically relevant for epilepsy treatment, effects on spike and wave discharges, the fraction of time spent being behaviourally active, and the background electroencephalogram (EEG) during behavioural activity of vigabatrin (15 - 500 mg/kg i.p.) and diazepam (1.25 - 10 mg/kg i.p.) were compared with their combination (dose ratio 1:25) in rats. Isobolic analyses were performed to describe the interactions. Unfortunately, no conclusions can be drawn concerning the interaction of both drugs on the spike and wave discharge activity because the effect of diazepam was shown to be dominant. Only vigabatrin decreased the behavioural activity, whereas there was a trend towards a decrease after diazepam. All treatments dose dependently increased the power in the beta frequency band. Unfortunately, the dose ratio was not optimal to describe the interaction. The theta peak frequency was dose dependently decreased after all treatments. There was a synergistic interaction between the two drugs on this variable. These data support both the idea that an increase in power in the beta frequency band can serve as a biomarker for GABAergic inhibition and the suggestion that clinically effective anxiolytics decrease the theta peak frequency. Furthermore, we show that on different variables, there might be different optimal dosage combinations, which might complicate the clinical application of polytherapy. (C) 2004 Elsevier B.V. All rights reserved.