Purinergic P2 receptors trigger adenosine release leading to adenosine A2A receptor activation and facilitation of long-term potentiation in rat hippocampal slices.

Electrophysiological recordings were used to investigate the effects of ATP analogues on theta-burst-induced long-term potentiation (LTP) in rat hippocampal slices. alpha,beta-Methylene ATP (alpha,beta-MeATP; 20 microM) decreased LTP from 36+/-9% to 17+/-5%, an effect prevented by adenosine A(1) receptor blockade in accordance with the localised catabolism of ATP analogues into adenosine, leading to adenosine A(1) receptor activation. Thus, to probe the role of extracellular ATP, all experiments were performed with the A(1) receptor selective antagonist, 1,3-dipropyl-8-cyclopentylxanthine (50 nM). In these conditions, alpha,beta-MeATP or 5'-adenylylimido-diphosphate (beta,gamma-ImATP; 20 microM) facilitated LTP by 120%, an effect prevented by the P2 receptor antagonists, pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS; 20 microM) or suramin (75 microM), as well as by the P2X(1/3)-selective antagonist 8-(benzamido)naphthalene-1,3,5-trisulfonate (10 microM). The facilitations of LTP by either alpha,beta-MeATP or beta,gamma-ImATP (20 microM) were also prevented by both 4-(2-[7-amino-2-(2-furyl(1,2,4)-triazolo(2,3a)-(1,3,5)triazin-5-yl-amino]ethyl)phenol (50 nM) or 7-2(-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (50 nM), antagonists of facilitatory adenosine A(2A) receptors, were occluded by the A(2A) receptor agonist, CGS 21680 (10 nM) and were prevented by the protein kinase C inhibitor, chelerythrine (6 microM) and unaffected by the protein kinase A inhibitor, H89 (1 microM). Furthermore, beta,gamma-ImATP (20 microM) enhanced [(3)H]adenosine outflow from rat hippocampal slices by nearly 150%, an effect prevented by PPADS (20 microM) or suramin (75 microM). The adenosine transport inhibitors, nitrobenzylthioinosine (5 microM) and dipyridamole (10 microM) also prevented beta,gamma-ImATP (20 microM)-induced [(3)H]adenosine outflow and facilitation of LTP. These results suggest that ATP analogues facilitate LTP through P2 receptor activation that mainly triggers adenosine release leading to the activation of adenosine A(2A) receptors.