Tiagabine is a new
anticonvulsant drug that blocks the uptake of
GABA, prolonging the action of this inhibitory transmitter. In the present study the effects of systemically administered
tiagabine [30 mg/kg, ip (ED50)] were examined on audiogenic seizure (AGS) severity and neuronal firing in the inferior colliculus (IC) in the freely moving genetically
epilepsy-prone rat (GEPR-9). The IC is known to be critical to AGS initiation. The effects of focal microinjection of
tiagabine into the IC were also examined. Bilateral focal microinjection of
tiagabine into the IC significantly reduced seizure severity in the GEPR-9. Systemically administered
tiagabine also produced a significant reduction in seizure severity in the GEPR-9.
Tiagabine produced a reduction in IC (central nucleus) neuronal firing, which was significant only at high acoustic intensities (90-105 dB), concomitant with the considerable reduction in seizure severity. These data are consistent with enhancement by
tiagabine of
gamma-aminobutyric acid (
GABA)-mediated inhibition in IC, which is most prominent at high acoustic intensities. The time course of the reduction in neuronal firing of IC neurons paralleled the reduction in seizure severity. Previous studies have shown that two forms of
GABA-mediated inhibition (intensity-induced and offset inhibition) in IC neurons are most prominent at high stimulus intensities, which are required to induce AGS. The blockade of
GABA uptake by
tiagabine may act to inhibit audiogenic
seizures, in part, by intensifying these naturally occurring forms of acoustically evoked inhibition in inferior colliculus neurons.