Effect of amygdala kindling on the central nervous system effects of tiagabine: EEG effects versus brain GABA levels

1 The objective of this investigation was to determine the influence of amy gdala kindling on the pharmacodynamics of tiagabine in vivo, using quantita tive EEC parameters and extracellular GABA concentrations as pharmacodynami c endpoints. In integrated pharmacokinetic/pharmacodynamic (PK/PD) studies the time course of these effects was determined in conjunction with plasma concentrations following intravenous administration of 10 mg kg(-1). An 'ef fect compartment' model was used to derive individual concentration-effect relationships. 2 Tiagabine produced an increase in the amplitude of the 11.5-30 Hz frequen cy band of the EEG. The relationship between concentration and EEG effect w as non-linear and described by the Hill equation. In kindled rats the EC50 was reduced to 291 ng ml(-1) from the original value of 521 ng ml(-1) in co ntrols. The values of all other parameters were unchanged. 3 In kindled rats the baseline extracellular GABA concentration was increas ed to 1.58 mu M from 0.74 mu M in controls. The relationships between tiaga bine concentration and extracellular GABA concentration were again non-line ar and described by the Hill equation. No differences were observed between kindled rats and controls. In the synaptoneurosmal preparation in vitro no changes in the functioning of the GABA transporter were observed. 4 It is concluded that unlike the situation with midazolam, there is no res istance to the EEG effect of tiagabine in the kindling model of experimenta l epilepsy. The observed shift in the concentration-EEG effect relationship to lower concentrations can presumably be explained by the increase in the baseline GABA levels.