Mechanism of adenosine accumulation in the hippocampal slice during energy deprivation

The mechanism by which adenosine accumulates in the hippocampal slice during energy deprivation was investigated by examining the adenosine A(1) receptor mediated depression of synaptically evoked field potentials in the CA(1) area. Blocking of the mitochondrial electron transport chain with 200 mu M sodium cyanide or mitochondrial uncoupling with 50 mu M 2,4-dinitrophenol both produced a rapid depression of synaptic transmission that was antagonised by 1 mu M 8-cyclopentyl-1,3-dimethylxanthine, an adenosine A(1) receptor antagonist. Cellular ATPase inhibition or elevation of cytosolic phosphocreatine failed to alter the 2,4-dinitrophenol induced depression of synaptic transmission. Attempts to block mitochondrial ATP synthesis with 3 mu M oligomycin or 75 mu M atractyloside did not cause depression of synaptic transmission. 100 mu M iodotubercidin, an adenosine kinase inhibitor, alone produced a depression of synaptic transmission that was completely reversed by 1 mu M 8-cyclopentyl-1,3-dimethylxanthine; however, a simultaneous or independent episode of hypoxia surmounted the adenosine A(1) receptor antagonism and produced approximately 50% depression of synaptic transmission. Depression of synaptic transmission by hypoxia, cyanide or 2,4-dinitrophenol is a result of rapid adenosine accumulation and activation of extracellular adenosine A(1) receptors. Although this early depression of synaptic transmission is a consequence of inhibition of normal mitochondrial function: it is not a result of depletion of cytosolic ATP, since attempts to preserve ATP did not maintain synaptic transmission during mitochondrial poisoning, and inhibitors of oxidative phosphorylation did not produce synaptic depression. Copyright (C) 1996 Elsevier Science Ltd