INVOLVEMENT OF GABA(A) RECEPTORS IN CONVULSANT-INDUCED EPILEPTIFORM ACTIVITY IN RAT NEOCORTEX IN-VITRO

The role of gamma-aminobutyric acid B (GABA(B)) receptors in the gener ation 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) re ceptor-mediated inhibition was not sufficient to induce epileptiform a ctivity. in the presence of the GABA(A) receptor antagonist bicucullin e (10 mu M) and at suprathreshold stimulation, the GABA(B) receptor an tagonist CGP 35348 (10-300 mu M) significantly potentiated epileptifor m activity. With stimulation at threshold intensity, low concentration s of CGP 35348 (10-30 mu M) potentiated bicuculline-induced activity, whereas higher concentrations (100-300 mu M) invariably led to a rever sible suppression of stimulus-evoked epileptiform discharges. CGP 3534 8 also enhanced picrotoxin-induced epileptiform activity, but at highe r concentrations it was considerably less effective in suppressing suc h epileptiform discharges. The GABA uptake inhibitor nipecotic acid pa rtially mimicked the actions of CGP 35348: with stimulation at thresho ld intensity, it reversibly suppressed bicuculline-induced epileptifor m field potentials, but it did not influence epileptiform activity ind uced by picrotoxin. We conclude that a postsynaptic blockade of GABA(B ) receptors induces an amplification of epileptiform activity in neoco rtical slices disinhibited by GABA(A) receptor antagonists. An additio nal blockade of presynaptic GABA(B) receptors, especially under condit ions of weak stimulation of the neurons, reduces the inhibitory auto-f eedback control of GABA release, leading to a displacement of competit ive antagonists from the postsynaptic GABA(A) receptor and hence, to a suppression of epileptiform activity induced by competitive GABA(A) r eceptor antagonists.