On the regulation of ischaemia-induced glutamate efflux from rat cortex byGABA; in vitro studies with GABA, clomethiazole and pentobarbitone

1 Prisms of adult rat cortex were maintained in vitro in either aerobic con ditions (control) or conditions simulating an acute ischaemic challenge (hy poxia with no added glucose). 2 Endogenous glutamate efflux increased with time in ischaemic conditions, being 2.7 fold higher than control efflux at 45 min. Returning prisms to co ntrol solution after 20 min of simulated ischaemia resulted in glutamate ef flux returning to near-control values. Endogenous GABA efflux in ischaemic conditions also increased, being 4.5 fold higher than control efflux at 45 min. 3 Ischaemia-induced glutamate efflux was not accompanied by increased lacta te dehydrogenase efflux and was unaltered by omitting calcium from the extr a-cellular solution and adding EGTA 4 Both GABA and the GABA-mimetic clomethiazole inhibited ischaemia-induced glutamate efflux, with IC50 values of 26 and 24 mu M respectively. The maxi mum inhibition by either drug was 60 - 70%. Bicuculline (10 mu M) abolished the inhibitory effect of GABA (100 mu M) but not clomethiazole (100 mu M). Picrotoxin (100 mu M) abolished the action of both GABA and clomethiazole. 5 Pentobarbitone inhibited glutamate efflux at 100-300 mu M (maximal inhibi tion: 39%). Bicuculline (10 mu M) abolished this effect. 6 These data suggest that ischaemia-induced glutamate efflux from rat cereb ral cortex is calcium-independent and not due to cell damage up to 45 min. The inhibitory effect of GABA, clomethiazole and pentobarbitone on ischaemi a-induced glutamate efflux appears to be mediated by GABAA receptors. The r esults suggest that clomethiazole, unlike pentobarbitone, is able to activa te the GABAA receptor-linked chloride channel directly and not merely poten tiate the effect of endogenous GABA.