EXTRACELLULAR ADENOSINE CONCENTRATIONS IN HIPPOCAMPAL BRAIN-SLICES AND THE TONIC INHIBITORY MODULATION OF EVOKED EXCITATORY RESPONSES

Because adenosine is taken up rapidly and metabolized by brain tissue, it has been difficult to establish its true pharmacological potency a nd, for similar reasons, to determine the basal extracellular concentr ations of adenosine in brain. In the present studies, we used several independent pharmacological approaches to estimate these parameters, u sing the adenosine-mediated inhibition of the field excitatory postsyn aptic potential evoked in the CA1 region of rat hippocampal slices as the biological response. The experiments used dipyridamole and S-(4-ni trobenzyl)-6-thioinosine to inhibit adenosine uptake, competitive aden osine receptor antagonists to shift adenosine dose response curves to the right, and corrected for the effect of endogenous adenosine on dos e-response curves. These approaches suggested that the EC(50) for aden osine for depressing field excitatory postsynaptic potentials is in th e range of 600 to 760 nM. Basal extracellular adenosine concentrations in brain slices were then estimated from the responses induced by sup erfusion with adenosine receptor antagonists. The estimates for the me an endogenous extracellular adenosine concentrations were in the range of 140 to 200 nM, although there was substantial variation in estimat es for individual slices. These values fall within the range of estima ted extracellular concentrations of adenosine in intact brain based on microdialysis studies, but are significantly below those estimated us ing biochemical techniques for measurement of total adenosine in brain tissue; this suggests that a substantial fraction of tissue adenosine is in a compartment that does not communicate directly with the extra cellular space.