Cross Talk Between A1and A2AAdenosine Receptors in the Hippocampus and Cortex of Young Adult and Old Rats

Abstract

Adenosine modulates synaptic transmission by acting on inhibitory A 1 and facilitatory A 2A receptors, the densities of which are modified in aged animals. We investigated how A 2A receptor activation influences A 1 receptor function and whether this interaction is modified in aged rats. In hippocampal and cortical nerve terminals from young adult (6 wk), but not old rats (24 mo), the A 2A receptor agonist, 2-[4-(2-carboxyethyl) phenethylamino]-5′- N-ethylcarboxamidoadenosine (CGS 21680; 30 nM) decreased the binding affinity of a selective A 1 receptor agonist, cyclopentyladenosine (CPA), an effect prevented by the A 2A antagonist, (4-(2-[7-amino-2-(2-furyl {1,2,4}-triazolo{2,3-a {1,3,5}triazin-5-yl-aminoethyl)phenol (ZM 241385, 20 nM). This effect of CGS 21680 required intact nerve terminals and was also observed in the absence of Ca 2+. This A 2A-induced “desensitization” of A 1 receptors was prevented by the protein kinase C inhibitor, chelerythrine (6 μM), and was not detected in the presence of the protein kinase C activator, phorbol-12,13-didecanoate (250 nM), which itself caused a reduction in binding affinity for CPA. The protein kinase A inhibitor, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (10 μM), and the protein kinase A activator, 8-Br-cAMP (1 mM), had no effects on the A 2A-induced A 1 receptor desensitization. This A 2A-induced A 1 receptor desensitization had a functional correlation because CGS 21680 (10 nM) attenuated by 40% the inhibition caused by CPA (10 nM) on CA1 area population spike amplitude in hippocampal slices. This A 2A/A 1 interaction may explain the attenuation by adenosine deaminase (2 U/ml), which removes tonic A 1 inhibition, of the facilitatory effect of CGS 21680 on synaptic transmission. The requirement of tonic A 1 receptor activation for CGS 21680 to induce facilitation of synaptic transmission was reinforced by the observation that the A 1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (20 nM) prevented CGS 21680 (10 nM) facilitation of population spike amplitude. The present results show the ability of A 2A receptors to control A 1 receptor function in a manner mediated by protein kinase C, but not protein kinase A, in young adult but not in aged rats.