Tonic activation of A(2A) adenosine receptors unmasks, and of A(1) receptors prevents, a facilitatory action of calcitonin gene-related peptide in the rat hippocampus

1 We investigated how manipulations of the degree of activation of adenosin e A(1) and A(2A) receptors influences the action of the neuropeptide. calci tonin gene-related peptide (CGRP) on synaptic transmission in hippocampal s lices. Field excitatory post-synaptic potentials (EPSPs) from the CAI area were recorded. 2 When applied alone, CGRP (1-30 nM) was without effect on held EPSPs. Howe ver, CGRP (10-30 nM) significantly increased the field EPSP slope when appl ied to hippocampal slices ill the presence of the A(1) receptor antagonist, 1,3-dipropyl-8-cyclopenthyl xanthine (DPCPX, 10 nM), or in the presence of the A(2A) adenosine receptor agonist CGS 21680 (10 nM). 3 The A(2A) receptor antagonist, ZM 241385 (10 nM) as well as adenosine dea minase (ADA, 2 U ml(-1)), prevented the enhancement of field EPSP slope cau sed by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this effect of CGRP requires the concomitant activation of Aza adenosine recepto rs by endogenous adenosine. 4 The protein kinase-A inhibitors, N-(2-guanidinoethyl)-5-isoquinolinesulfo nide (HA-1004, 10 mu M) and adenosine 3',5'-cyclic monophosphorothioate. Rp -isomer (Rp-cAMPS, 50 mu M), as well as the inhibitor of ATP-sensitive pota ssium (K-ATP) channels, glibenclamide (30 mu M), prevented the facilitation of synaptic transmission caused by CGRP (30 nM) in the presence of DPCPX ( 10 nM), suggesting that this effect of CGRP involves both K-ATP channels an d protein kinase-A. 5 It is concluded that the ability of CGRP to facilitate synaptic transmiss ion in the CA1 area of the hippocampus is under tight control by adenosine, with tonic A(1) receptor activation by endogenous adenosine 'braking' the action of CGRP, and the A(2A) receptors triggering this action.