Direct assay of adenosine 3',5'-monophosphate (cyclic AMP) in guinea-pig cerebral cortex in vitro has shown that an alpha adrenergic receptor that was previously found to increase tissue content of cyclic AMP requires the co-presence of adenosine. This alpha adrenergic receptor complex was characterized with blocking agents and contrasted with other activities by examining the effect of other biogenic amines on cyclic AMP content in the presence of adenosine. Phentolamine (but not propranolol) reduced the potentiated response to norepinephrine (NE) (or epinephrine) plus adenosine to the level seen with adenosine alone. Theophylline, an adenosine antagonist, blocked the entire effect of NE plus adenosine. The failure of a high Mg++/Ca++ ratio to block the effect of NE plus adenosine argues against indirect mediation of the alpha receptor effect via the release of K+ or via an unknown neurohumoral agent. The complex variety of potentiative interactions between biogenic amines and adenosine is unique to brain. These interactions may be explained by the proposed existence of both independent and dependent receptors. The dependent receptors respond only to the co-presence of two or more neurohumoral agents. An alternative explanation would involve a compartmentally selective impairment of cyclic AMP degradation.