INHIBITION BY ATP OF HIPPOCAMPAL SYNAPTIC TRANSMISSION REQUIRES LOCALIZED EXTRACELLULAR CATABOLISM BY ECTO-NUCLEOTIDASES INTO ADENOSINE ANDCHANNELING TO ADENOSINE A(1) RECEPTORS

ATP analogs substituted in the gamma-phosphorus (ATP gamma S, beta,gam ma-imido-ATP, and beta,gamma-methylene-ATP) were used to probe the inv olvement of P-2 receptors in the modulation of synaptic transmission i n the hippocampus, because their extracellular catabolism was virtuall y not detected in CA1 slices. ATP and gamma-substituted analogs were e quipotent to inhibit synaptic transmission in CA1 pyramid synapses (IC 50 of 17-22 mu M). The inhibitory effect of ATP and gamma-phosphorus-s ubstituted ATP analogs (30 mu M) was not modified by the P-2 receptor antagonist suramin (100 mu M), was inhibited by 42-49% by the ecto-5'- nucleotidase inhibitor and alpha,beta-methylene ADP (100 mu M), was in hibited by 74-85% by 2 U/ml adenosine deaminase (which converts adenos ine into its inactive metabolite-inosine), and was nearly prevented by the adenosine A(1) receptor antagonist 1,3-dipropyl-8-cyclopentylxant hine (10 nM). Stronger support for the involvement of extracellular ad enosine formation as a main requirement for the inhibitory effect of A TP and gamma-substituted ATP analogs was the observation that an inhib itor of adenosine uptake, dipyridamole (20 mu M), potentiated by 92-12 4% the inhibitory effect of ATP and gamma-substituted ATP analogs (10 mu M), a potentiation similar to that obtained for 10 mu M adenosine ( 113%). Thus, the present results indicate that inhibition by extracell ular ATP of hippocampal synaptic transmission requires localized extra cellular catabolism by ecto-nucleotidases and channeling of the genera ted adenosine to adenosine A(1) receptors.