Cytidylate cyclase is a membrane-bound enzyme which catalyzes the biosynthesis of cytidine 3',5'-cyclic monophosphate (cCMP) from CTP. To date little is known about the factors activating this enzyme, although extensive studies have clarified the physiological and pharmacological activities of cCMP. In this study, we found by using a sensitive and specific enzyme immunoassay method that cytidylate cyclase activity is prominently high in the neonatal rat (2-8 days old) brain and additionally that the nerve growth factor (NGF) activates the cytidylate cyclase activity of the neonatal rat brain in a dose-dependent manner. However, cytidylate cyclase in the adult rat brain and other tissues including the liver and kidney was insensitive to stimulation by NGF. NGF had no effect on the adenylate cyclase in various tissues including the brain. Cytidylate cyclase activity in the solubilized fractions of the neonatal rat brain was not stimulated by NGF. These findings suggest that NGF activates cytidylate cyclase through the receptor/ligand-protein and that the cytidylate cyclase-cCMP system plays an important role in the signal transduction of neuropeptides and neural development of the neonatal rat brain.