Abstract
Many antiepileptic drugs act by modulation of ionotropic GABA(A) receptors or effects on extracellular GABA concentrations. Metabotropic GABA(B) receptors also affect neuronal excitability but are not recognized as a target of antiepileptic drugs. We investigated effects of GABA(B) receptors and antiepileptic drug vigabatrin on epileptiform discharges induced by 4-aminopyridine (4AP) in hippocampal brain slices from male mice. The GABA(B) receptor agonist baclofen caused dose-dependent reduction in frequency of 4AP-induced epileptiform discharges but did not affect amplitude or duration of discharges. The inhibitory effects of baclofen were blocked by GABA(B) receptor antagonist CGP55845 (CGP) and the K(+) channel blocker Ba(2+), indicating that baclofen was acting on GABA(B) receptors and activating GIRK channels. Baclofen effects were independent of GABA(A) receptors. Vigabatrin inhibits GABA transaminase, thereby increasing GABA concentrations. Pretreatment of brain slices with vigabatrin suppressed 4AP-induced discharges, significantly prolonging the latency to onset of spontaneous activity and reducing frequency of discharges. Similar to baclofen, vigabatrin effects on latency and frequency were reversed by GABA(B) antagonist CGP and the GIRK channel blocker Ba(2+) Vigabatrin had no effect on 4AP-induced activity in GABA transporter type 1 knock-out mice (GAT1KO), suggesting that vigabatrin effects are dependent on GAT1 function. Our results indicate for the first time that a clinically used antiepileptic drug (vigabatrin) suppresses in vitro epileptiform activity via activation of GABA(B) receptors and GIRK channels. Data are consistent with a model that depicts altered thermodynamic equilibrium of GAT1 after GABA transaminase inhibition that leads to elevated extracellular GABA concentration and activation of GABA(B) receptors.