Pharmacologic characterization of the neurotransmitter-sensitive cyclic AMP-second messenger systems of brain has proven to be a complex and difficult endeavor. At least two types of receptor appear to be involved in the mediation of the effects of NE on cyclic AMP content. One of these receptor systems appears to mediate the potentiation by NE of the effect of adenosine of cyclic AMP accumulation. The cellular heterogeneity of brain has retarded the determination of the mechanism underlying the synergistic interaction of catecholamines and adenosine. An attempt to use clonal cell lines to examine the action of NE and adenosine on cyclic AMP content has resulted in the demonstration that adenosine acts in a hormone-like fashion to stimulate adenylate cyclase activity. However, the studies did not shed light on the mechanism of synergism. An increasing number of reports are appearing which support the idea that the responsiveness of cells to neuronally released NE may involve adaptive changes in the responsiveness of the cyclic AMP-second messenger system which compensate for chronic over- or underproduction of the first messenger, NE. Evidence was presented that such a regulatory process may be operative in rat cerebral cortex. Our studies of catecholamine-induced loss of responsiveness in human astrocytoma cells have led us to the conclusion that the loss in the capacity of the cells to accumulate cyclic AMP is a result of a loss in the capacity to synthesize cyclic AMP. However, it is probable that different cells make use of different mechanisms (e.g., changes in phosphodiesterase activity) to regulate their ability to respond to hormones or neurotransmitters. The physiologic importance of this level of regulation of responsiveness to hormones is not known at this time.