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 potenti als in the CA(1) area. Blocking of the mitochondrial electron transpor t 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-dimethy lxanthine, an adenosine A(1) receptor antagonist. Cellular ATPase inhi bition 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 in dependent episode of hypoxia surmounted the adenosine A(1) receptor an tagonism and produced approximately 50% depression of synaptic transmi ssion. Depression of synaptic transmission by hypoxia, cyanide or 2,4- dinitrophenol is a result of rapid adenosine accumulation and activati on of extracellular adenosine A(1) receptors. Although this early depr ession of synaptic transmission is a consequence of inhibition of norm al mitochondrial function: it is not a result of depletion of cytosoli c ATP, since attempts to preserve ATP did not maintain synaptic transm ission during mitochondrial poisoning, and inhibitors of oxidative pho sphorylation did not produce synaptic depression. Copyright (C) 1996 E lsevier Science Ltd