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|Title:||On the regulation of ischaemia-induced glutamate efflux from rat cortex by GABA; in vitro studies with GABA, clomethiazole and pentobarbitone.|
|Citation:||BR J PHARMACOL, 2000, 130 (5), pp. 1124-1130|
|Abstract:||Prisms of adult rat cortex were maintained in vitro in either aerobic conditions (control) or conditions simulating an acute ischaemic challenge (hypoxia with no added glucose). Endogenous glutamate efflux increased with time in ischaemic conditions, being 2.7 fold higher than control efflux at 45 min. Returning prisms to control solution after 20 min of simulated ischaemia resulted in glutamate efflux returning to near-control values. Endogenous GABA efflux in ischaemic conditions also increased, being 4.5 fold higher than control efflux at 45 min. Ischaemia-induced glutamate efflux was not accompanied by increased lactate dehydrogenase efflux and was unaltered by omitting calcium from the extra-cellular solution and adding EGTA (0.1 mM). Both GABA and the GABA-mimetic clomethiazole inhibited ischaemia-induced glutamate efflux, with IC(50) values of 26 and 24 microM respectively. The maximum inhibition by either drug was 60 - 70%. Bicuculline (10 microM) abolished the inhibitory effect of GABA (100 microM) but not clomethiazole (100 microM). Picrotoxin (100 microM) abolished the action of both GABA and clomethiazole. Pentobarbitone inhibited glutamate efflux at 100 - 300 microM (maximal inhibition: 39%). Bicuculline (10 microM) abolished this effect. These data suggest that ischaemia-induced glutamate efflux from rat cerebral cortex is calcium-independent and not due to cell damage up to 45 min. The inhibitory effect of GABA, clomethiazole and pentobarbitone on ischaemia-induced glutamate efflux appears to be mediated by GABA(A) receptors. The results suggest that clomethiazole, unlike pentobarbitone, is able to activate the GABAA receptor-linked chloride channel directly and not merely potentiate the effect of endogenous GABA.|
|Appears in Collections:||Published Articles, Dept. of Cardiovascular Sciences|
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