Although serotonin regulates synthesis of the neurotrophic factor S-100 beta by astrocytes, its ability to affect nerve growth factor (NGF) synthesis has never been examined. We report here that there is a correlation between the effect of serotonin on cyclic adenosine monophosphate (cAMP) content and on NGF content in neonatal astrocytes but not in adult astrocytes. In neonatal striatal astrocytes, serotonin increases both cAMP and NGF, whereas, in neonatal cerebellar astrocytes, serotonin decreases both. The increase in neonatal cortical astrocyte cAMP appeared to be too small (45%) to increase NGF significantly. The beta-adrenergic agonist isoproterenol increased cAMP and NGF in both cortical and striatal astrocytes derived from neonatal rats. In contrast, there was a dissociation between cAMP changes and NGF changes in astrocytes derived from adult rats. Both serotonin and isoproterenol increased cAMP in adult cortical astrocytes, without any effect on NGF content. However, adult striatal astrocytes responded to serotonin with an elevation of both cAMP and NGF, whereas isoproterenol could only enhance cAMP, without affecting NGF. Thus, in neonatal astrocytes, a change of sufficient magnitude in cAMP was correlated with a comparable change in NGF, in response to activation of either serotonergic or beta-adrenergic receptors; in cerebellar astrocytes, the decrease in cAMP was accompanied by a decrease in NGF. In contrast, adult astrocytes were not responsive: Although cAMP changes were large, NGF synthesis was increased only in striatal astrocytes and only in response to serotonin. J. Neurosci. Res. 64:261-267, 2001. Published 2001 Wiley-Liss, Inc.