The amplitude of the orthodromically evoked population spike (PS) of CA1 neurons was used to investigate quantitatively adenosine receptor antagonism in guinea pig hippocampal slices. Increasing concentrations of the highly selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 3-100 nM) produced parallel, rightward shifts of the dose-response curve for the N6-cyclopentyladenosine (CPA)-induced decrease in PS amplitude. Schild plot analyses of the respective antagonism data obtained in both the presence and virtual absence of endogenous adenosine yielded apparent dissociation constants (KD) of DPCPX at the hippocampal A1 receptor of 3.3 and 3.6 nM, respectively. This indicates that the inhibitory tonus generated by endogenously produced adenosine is due to tonic activation of A1 receptors. The KD values agree well with the binding affinity of DPCPX to A1 receptors determined in brain tissue sections. Since, in our preparation, Schild plot analyses of DPCPX antagonism revealed KD values close to those reported for other tissues, it is concluded that the central A1 receptor mediating adenosinergic inhibition is pharmacologically not distinct from A1 receptors identified in peripheral tissues.