Cross talk between A(1) and A(2A) adenosine receptors in the hippocampus and cortex of young adult and old rats

Adenosine modulates synaptic transmission by acting on inhibitory A(1) and facilitatory A(2A) receptors, the densities of which are modified in aged a nimals. We investigated how A(2A) receptor activation influences A(1) recep tor function and whether this interaction is modified in aged rats. In hipp ocampal and cortical nerve terminals from young adult (6 wk), but not old r ats (24 mo), the A(2A) receptor agonist, 2-[4-(2-carboxyethyl) phenethylami no]-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 n M). This effect of CGS 21680 required intact nerve terminals and was also o bserved in the absence of Ca2+. This A(2A)-induced "desensitization" of A(1 ) receptors was prevented by the protein kinase C inhibitor, chelerythrine (6 mu M), and was not detected in the presence of the protein kinase C acti vator, phorbol-12,13-didecanoate (250 nM), which itself caused a reduction in binding affinity for CPA. The protein kinase A inhibitor, N-(2-guanidino ethyl)-5-isoquinolinesulfonamide (10 mu M), and the protein kinase A activa tor, 8-Br-cAMP (1 mM), had no effects on the A(2A)-induced A(1) receptor de sensitization. This A(2A)-induced A(1) receptor desensitization had a funct ional correlation because CGS 21680 (10 nM) attenuated by 40% the inhibitio n caused by CPA (10 nM) on CA1 area population spike amplitude in hippocamp al slices. This A(2A)/A(1) interaction may explain the attenuation by adeno sine deaminase (2 U/ml), which removes tonic A(1) inhibition, of the facili tatory effect of CGS 21680 on synaptic transmission. The requirement of ton ic A(1) receptor activation for CGS 21680 to induce facilitation of synapti c transmission was reinforced by the observation that the A(1) receptor ant agonist, 1,3-dipropyl-8-cyclopentylxanthine (20 nM) prevented CGS 21680 (10 nM) facilitation of population spike amplitude. The present results show t he ability of A(2A) receptors to control A(1) receptor function in a manner mediated by protein kinase C, but not protein kinase A(1) in young adult b ut not in aged rats.