Extracellular adenosine 3':5'-cyclic monophosphate (cAMP) is a potential source of the inhibitory neuromodulator adenosine in the brain. Previous work has demonstrated that cAMP, which is formed intracellularly, can be transported into the extracellular space and subsequently catabolized to adenosine. However, the physiological conditions under which cAMP release might lead to adenosine formation and activation of adenosine receptors are not well understood. In this study we demonstrate that superfusion of hippocampal slices with cAMP or forskolin led to the formation of extracellular adenosine which activated adenosine receptors in a manner comparable to that seen with adenosine superfusion. In contrast, application of brief pulses of cAMP onto the cell bodies of CA1 pyramidal neurons failed to produce an adenosine receptor-mediated response, while application of brief pulses of adenosine or AMP elicited significant responses. These data suggest that large, prolonged increases in extracellular cAMP levels can result in the formation of extracellular adenosine and the activation of adenosine receptors, but brief increases in cAMP levels in the vicinity of individual neurons cannot. These findings imply that increases in cAMP levels may lead to relatively slow increases in extracellular adenosine, as opposed to the fast, spatially restricted increases that would occur following the release of other adenine nucleotides.