GABA-B receptor activation in the rat globus pallidus potently suppresses pentylenetetrazol-induced tonic seizures

To determine the involvement of the globus pallidus in mediating epilepsy, the effects of microinjection of a GABA uptake blocker (tiagabine), a benzodiazepine agonist (zolpidem) and a GABA-B receptor agonist (baclofen) on pentylenetetrazol (PTZ)-induced tonic seizure were examined in adult rats. Administration of PTZ induced tonic seizures in all control animals, accompanied with a 100% mortality rate. Pretreatment with bilateral intrapallidal microinjection of tiagabine (1 mM) suppressed the incidence of tonic seizures to 67.7% and reduced the mortality rate to 16.7%. Furthermore, the latency to tonic seizures was 1,275 ± 277 s, which was significantly longer than that of the corresponding control animals (319 ± 225 s). On the other hand, administration of zolpidem (1 mM) was without significant effects on the mortality rate, the incidence and latency of the tonic seizure. In sharp contrast, microinjection of baclofen (1mM) completely suppressed PTZ-induced tonic seizures and reduced the mortality rate to 0%. This effect was largely abolished by co-injection of the GABA-B receptor antagonist CGP55845. To elucidate the direct cellular action of baclofen, the excitability and membrane potential of globus pallidus neurons were studied by cell-attached and whole-cell patch-clamp recordings in the brain slice. Bath application of baclofen (50 µM) significantly reduced the firing of these neurons, and was often accompanied by a clear membrane hyperpolarization, in a CGP55845-sensitive manner. These data suggest that activation of GABA-B receptors in globus pallidus could significantly modulate PTZ-induced tonic seizures.