Tonic activation of A2A adenosine receptors unmasks, and of A1 receptors prevents, a facilitatory action of calcitonin gene-related peptide in the rat hippocampus

© 2000 Macmillan Publishers LtdWe investigated how manipulations of the degree of activation of adenosine A1 and A2A receptors influences the action of the neuropeptide, calcitonin gene-related peptide (CGRP) on synaptic transmission in hippocampal slices. Field excitatory post-synaptic potentials (EPSPs) from the CA1 area were recorded. When applied alone, CGRP (1 - 30 nM) was without effect on field EPSPs. However, CGRP (10 - 30 nM) significantly increased the field EPSP slope when applied to hippocampal slices in the presence of the A1 receptor antagonist, 1,3-dipropyl-8-cyclopenthyl xanthine (DPCPX, 10 nM), or in the presence of the A2A adenosine receptor agonist CGS 21680 (10 nM). The A2A receptor antagonist, ZM 241385 (10 nM) as well as adenosine deaminase (ADA, 2 U ml7 1), prevented the enhancement of field EPSP slope caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this effect of CGRP requires the concomitant activation of A2A adenosine receptors by endogenous adenosine. The protein kinase-A inhibitors, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004,10 μM) and adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS, 50 μM), as well as the inhibitor of ATP-sensitive potassium (KATP) channels, glibenclamide (30 μM), prevented the facilitation of synaptic transmission caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this e ect of CGRP involves both KATP channels and protein kinase-A. It is concluded that the ability of CGRP to facilitate synaptic transmission in the CA1 area of the hippocampus is under tight control by adenosine, with tonic A1 receptor activation by endogenous adenosine `braking' the action of CGRP, and the A2A receptors triggering this action.Fundacão para a Ciência e Tecnologia and European Unio