REDUCED ADENOSINE UPTAKE ACCELERATES ISCHEMIC BLOCK OF POPULATION SPIKES IN HIPPOCAMPAL SLICES FROM STREPTOZOTOCIN-TREATED DIABETIC RATS

We have used rats with streptozotocin-induced diabetes to investigate the effects of hyperglycaemia-mediated impaired nucleoside uptake on t he actions of endogenous adenosine in hippocampal slices. In control t issue under conditions of anoxia and aglycaemia the rise in the extrac ellular adenosine concentration resulted in complete inhibition of syn aptic activity in about 2 min. In slices from previously hyperglycaemi c rats the inhibition of synaptically mediated responses occurred sign ificantly faster, although this change could be prevented by insulin t reatment. Application of the selective adenosine Al receptor antagonis t [8-cyclopentyl-1,3-dipropylxanthine (DPCPX)] prevented the anoxia/ag lycaemia-mediated inhibition and, furthermore, abolished the differenc es in the electrophysiological responses between control and diabetic tissue. The effects of impaired nucleoside uptake could be mimicked in control slices by applying the nucleoside uptake blocker hydroxynitro benzylthioinosine (HNBTI). This had the effect of speeding up the rate of anoxia/aglycaemia-induced synaptic inhibition in control tissue to that seen in diabetic tissue, However, such treatment had no effect o n the responses in diabetic tissue as expected if the HNBTI-sensitive uptake process was already inhibited by the chronic hyperglycaemia. Th e impairment of nucleoside uptake by chronic hyperglycaemia results in the potentiation of the modulatory actions of endogenous adenosine in the central nervous system. Such an alteration in adenosine function may be important in explaining behavioural and pathological changes as sociated with diabetes mellitus.