BLOCKADE OF GABA(B) RECEPTORS FACILITATES MUSCARINIC AGONIST-INDUCED EPILEPTIFORM ACTIVITY IN IMMATURE RAT PIRIFORM CORTEX IN-VITRO

The effects of the selective GABA(B) receptor antagonist [3-[[(3,4-dic hlorophenyl)methyl]amino]propyl] (diethoxymethyl) phosphinic acid (CGP 52432) on muscarinic (mAChR) and metabotropic glutamate (mGluR) re re sponsiveness were studied in slices of piriform cortex from both immat ure (P16-P22) and adult (greater than or equal to P40) rats, using a c onventional intracellular recording technique. In both adult and immat ure slices, CGP 52432(1 mu M) had no effect on neuronal membrane prope rties, whereas it selectively abolished the late inhibitory postsynapt ic potential (IPSP) evoked by local electrical stimulation of associat ion fibre terminals. Age-related changes in mAChR (but not mGluR) resp onsiveness were also detected. In adult neurones, bath-application of the mAChR agonist oxotremorine-M (OXO-M, 10 mu M). or the selective mG luR agonist 1S,3R-amino-cyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD ; 10 mu M) evoked similar membrane depolarization and inhibition of ev oked excitatory postsynaptic potentials (EPSPs). However, while 1S,3R- ACPD and OXO-M produced indistinguishable slow excitatory effects in i mmature slices, during superfusion with OXO-M, neurones exhibited spon taneous paroxysmal depolarizing shifts (PDSs) that were suppressed in the presence of atropine (1 mu M) or the selective GABA, receptor agon ist beta-parachlorophenyl-gamma-aminobutyric acid [(-)baclofen; 10 mu M] Also, application of OXO-M resulted in a pronounced prolongation (r ather than a decrease) of electrically evoked postsynaptic potentials (PSPs) which now exhibited recurrent superimposed spike discharges. In adult slices, in the continuous presence of CGP 52432 (1 mu M: 20 min pre-incubation), a subsequent exposure to 10 mu M OXO-M or 1S,3R-ACPD failed to induce any spontaneous epileptiform activity, and evoked PS Ps were consistently suppressed. In contrast, in immature slices, afte r incubation in CGP 52432 (1 mu M; 20 min), a subsequent application o f a low dose of OXO-M (2.5 mu M), which was inactive per se, was able to produce spontaneous PDSs and a prolongation of evoked PSPs. We conc lude that a reduction in GABA(B)-mediated synaptic inhibition in immat ure slices (in co-operation with other factors) may contribute to the facilitation of excitatory neurotransmission and therefore play a role in the generation of mAChR-induced epileptiform activity.