Enhanced adenosine A2A receptor facilitation of synaptic transmission in the hippocampus of aged rats

Adenosine either inhibits or facilitates synaptic transmission through A(1) or A(2A) receptors, respectively. Since A(2A) receptor density increases in the limbic cortex of aged ( 24 mo) compared with young adult rats ( 2 mo), we tested if A(2A) receptor modulation of synaptic transmission was also increased in aged rats. The A(2A) receptor agonist, CGS21680 (10 nM), caused a larger facilitation of the field excitatory postsynaptic potential (fEPSP) slope in hippocampal slices of aged (38%) than in young rats (19%), an effect prevented by the A(2A) receptor antagonist, ZM241385 (20 nM). In contrast to young rats, where CGS21680 facilitation of fEPSPs is prevented by the protein kinase C inhibitor, chelerythrine ( 6 muM), but not by the protein kinase A inhibitor, H-89 ( 1 muM), the CGS21680-induced facilitation of fEPSP slope in aged rats was prevented by H-89 ( 1 muM) but not by chelerythrine ( 6 muM). Also, in contrast to the beta-receptor agonist, isoproterenol ( 30 muM), CGS21680 ( 100 - 1,000 nM) enhanced cAMP levels in hippocampal nerve terminals of aged but not young rats. Finally, we observed a significant increase of both the binding density of [H-3] CGS 21680 and the [H-3] ZM241385 as well as of the anti-A(2A) receptor immunoreactivity in hippocampal nerve terminal membranes from aged compared with young rats. This shows that A(2A) receptor-mediated facilitation of hippocampal synaptic transmission is larger in aged than young rats due to increased A(2A) receptor density in nerve terminals and to the modified transducing system operated by A(2A) receptors, from a protein kinase C mediated control of A(1) receptors into a direct protein kinase A dependent facilitation of synaptic transmission.