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Enhanced Adenosine A_2A Receptor Facilitation of Synaptic Transmission in the Hippocampus of Aged Rats

¹ Center for Neurosciences of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra; ² Laboratory of Neurosciences, Faculty of Medicine, University of Lisbon, 1649-028 Lisboa, Portugal

Submitted 7 October 2002; accepted in final form 7 December 2002

Adenosine either inhibits or facilitates synaptic transmission through A₁ 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 µM), but not by the protein kinase A inhibitor, H-89 (1 µM), the CGS21680-induced facilitation of fEPSP slope in aged rats was prevented by H-89 (1 µM) but not by chelerythrine (6 µM). Also, in contrast to the –receptor agonist, isoproterenol (30 µM), 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 [³H]CGS 21680 and the [³H]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 A₁ receptors into a direct protein kinase A dependent facilitation of synaptic transmission.