Involvement of GABA(B) receptors in convulsant-induced epileptiform activity in rat neocortex in vitro.

Abstract

The role of gamma-aminobutyric acid B (GABA(B)) receptors in the generation and maintenance of bicuculline-induced epileptiform activity in rat neocortical slices was studied using electrophysiological methods. A block of GABA(B) receptors in the presence of functional GABA(A) receptor-mediated inhibition was not sufficient to induce epileptiform activity. In the presence of the GABA(A) receptor antagonist bicuculline (10 microM) and at suprathreshold stimulation, the GABA(B) receptor antagonist CGP 35348 (10-300 microM) significantly potentiated epileptiform activity. With stimulation at threshold intensity, low concentrations of CGP 35348 (10-30 microM) potentiated bicuculline-induced activity, whereas higher concentrations (100-300 microM) invariably led to a reversible suppression of stimulus-evoked epileptiform discharges. CGP 35348 also enhanced picrotoxin-induced epileptiform activity, but at higher concentrations it was considerably less effective in suppressing such epileptiform discharges. The GABA uptake inhibitor nipecotic acid partially mimicked the actions of CGP 35348: with stimulation at threshold intensity, it reversibly suppressed bicuculline-induced epileptiform field potentials, but it did not influence epileptiform activity induced by picrotoxin. We conclude that a postsynaptic blockade of GABA(B) receptors induces an amplification of epileptiform activity in neocortical slices disinhibited by GABA(A) receptor antagonists. An additional blockade of presynaptic GABA(B) receptors, especially under conditions of weak stimulation of the neurons, reduces the inhibitory auto-feedback control of GABA release, leading to a displacement of competitive antagonists from the postsynaptic GABA(A) receptor and hence, to a suppression of epileptiform activity induced by competitive GABA(A) receptor antagonists.