A depletable pool of adenosine in area CA1 of the rat hippocampus

Adenosine plays a major modulatory and neuroprotective role in the mammalia n CNS. During cerebral metabolic stress, such as hypoxia or ischemia, the i ncrease in extracellular adenosine inhibits excitatory synaptic transmissio n onto vulnerable neurons via presynaptic adenosine A(1) receptors, thereby reducing the activation of postsynaptic glutamate receptors. Using a combi nation of extracellular and whole-cell recordings in the CA1 region of hipp ocampal slices from 12- to 24-d-old rats, we have found that this protectiv e depression of synaptic transmission weakens with repeated exposure to hyp oxia, thereby allowing potentially damaging excitation to both persist for longer during oxygen deprivation and recover more rapidly on reoxygenation. This phenomenon is unlikely to involve A(1) receptor desensitization or im paired nucleoside transport. Instead, by using the selective A(1) antagonis t 8-cyclopentyl-1,3- dipropylxanthine and a novel adenosine sensor, we demo nstrate that adenosine production is reduced with repeated episodes of hypo xia. Furthermore, this adenosine depletion can be reversed at least partial ly either by the application of exogenous adenosine, but not by a stable A( 1) agonist, N-6-cyclopentyladenosine, or by endogenous means by prolonged ( 2 hr) recovery between hypoxic episodes. Given the vital neuroprotective ro le of adenosine, these findings suggest that depletion of adenosine may und erlie the increased neuronal vulnerability to repetitive or secondary hypox ia/ischemia in cerebrovascular disease and head injury.