Adenosine causes an increase in the concentration of cyclic AMP in mouse neuroblastoma cells. The amount of increase observed in intracellular cyclic AMP levels due to exogenous adenosine depends greatly on the concentration of a specific cyclic AMP phosphodiesterase inhibitor, 4-(-3-butoxy-4-methoxybenzyl)-2-imidazolidinone. Unstimulated concentrations of cyclic AMP were 29-40 pmol/mg of protein, and concentrations after addition of 0.2 mM adenosine were usually twice as high. The presence of 0.7 mM inhibitor along with 0.2 mM adenosine caused an increase in cyclic AMP levels up to 1000-2000 pmol/mg of protein.In the presence of 0.7 mM inhibitor, 2 /AM adenosine gives a half-maximal cyclic AMP elevation. Theophylline blocked the elevation of cyclic AMP concentrations caused by exogenous adenosine. The data show that the cyclic AMP system of mouse neuroblastoma has the necessary receptor components to respond positively to exogenous adenosine. The results presented support a direct effect of adenosine, mediated through its control of intracellular levels, on neuronal elements of the nervous system. Data now accumulating on cyclic AMP (cAMP) and the nervous system tend to indicate that transmitter substances perform a modulatory role on the activity of various nervous tissues by affecting intracellular cAMP levels (1, 2). In a recent article (3) the data were reviewed which support the occurrence of "purinergic nerves" whose principal transmitter substance is a purine nucleotide. Adenosine itself produces striking increases in cAMP concentrations of brain slices by interacting with a receptor that appears to be distinct from those associated with known or putative neurotransmitters (i.e., norepinephrine, acetylcholine, or serotonin) or neurohormones (histamine and prostaglandins) (4)(5)(6)(7)(8). Increases in free adenosine concentrations, which paralleled the observed enhancement of cAMP concentration, were observed in brain slices treated with various depolarizing agents (8-10). Adenosine also interacts synergistically with norepinephrine, serotonin, and histamine in elevating cAMP concentration in brain (6)(7)(8). In addition, cAMP levels in brain slices were not elevated by a second treatment of histamine or norepinephrine alone, but were responsive to these agents during a second application when adenosine was present (11).To define which cells of the nervous system were responding to which cAMP stimulatory agent, investigators studied various homogeneous neuronal and glial tissue cultures. cAMP concentrations were increased by catecholamines in rat glial cells, and by histamine, catecholamines, and adenosine in human glial (astrocytoma) cells (12-15). In the only homogeneous nerve tissue culture investigated, mouse neuroblastomas, the cAMP level responded to certain prostaglandins but not to histamine, catecholamines, and adenosine (16). These data suggested that the cAMP responses produced in brain slices by histamine, catecholamines, and adenosine may be mainly due to the glial elements, and the p...