Modification by arachidonic acid of extracellular adenosine metabolism andneuromodulatory action in the rat hippocampus

Adenosine and arachidonate (AA) fulfil opposite modulatory roles, arachidon ate facilitating and adenosine inhibiting cellular responses. To understand if there is an inter-play between these two neuromodulatory systems, we in vestigated the effect of AA on extracellular adenosine metabolism in hippoc ampal nerve terminals. AA (30 muM) facilitated by 67% adenosine evoked rele ase and by 45% ATP evoked release. These effects were not significantly mod ified upon blockade of lipooxygenase or cyclooxygenase and were attenuated (52-61%) by the protein kinase C inhibitor, chelerythrine (6 muM). The ecto -5'-nucleotidase inhibitor, alpha,beta -methylene ADP (100 muM), caused a l arger inhibition (54%) of adenosine release in the presence of AA (30 muM) compared with control (37% inhibition) indicating that the AA-induced extra cellular adenosine accumulation is mostly originated from an increased rele ase and extracellular catabolism of ATP. This AA-induced extracellular aden osine accumulation is further potentiated by an AA-induced decrease (48%) o f adenosine transporters capacity. AA (30 muM) increased by 36-42% the toni c inhibition by endogenous extracellular adenosine of adenosine A(1) recept ors in the modulation of acetylcholine release and of CA1 hippocampal synap tic transmission in hippocampal slices. These results indicate that AA incr eases tonic adenosine modulation as a possible feedback loop to limit AA fa cilitation of neuronal excitability.