Adenosine is a neuromodulator that protects neurons from hypoxia. This effect is attributed to the ability of adenosine A(1) receptors (A(1)R) to inhibit excitatory synaptic transmission. However, A(1)R activation also protects non-brain tissues from hypoxic insults by controlling metabolism. Thus, we now tested the hypothesis that A(1)R-mediated neuroprotection after a hypoxic insult in superfused hippocampal slices also involves the control of neuronal and astrocytic metabolism. A 90-min hypoxia insult increased lactate, alanine, and pyruvate levels and decreased energy charge (EC), phosphocreatine/creatine ratio, and glutamine content. These metabolic modifications were fully recovered after reoxygenation for 3h. The presence of the A(1)R-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine stimulated glycolysis, prevented the hypoxia-induced decrease of EC, and increased the levels of GABA. A(1)R blockade further blunted the recovery of metabolism on reoxygenation after hypoxia, as typified by a sustained decreased EC and an increased mitochondrial metabolism, as confirmed by a greater [U-C-13]glucose oxidation through the tricarboxylic acid cycle. These results demonstrate that A(1)R blockade prevents the recovery of hypoxia-induced metabolic alterations during reoxygenation, which indicates that the ability of A(1)R to control primary metabolism in the brain tissue may be a hitherto unrecognized mechanism of A(1)R-mediated neuroprotection.