Nerve growth factor (NGF) is a neurotrophic agent for sympathetic and embryonic sensory neurons both in vivo and in vitro. We report here that the membrane-permeant cAMP analogs, 8-(4-chlorophenylthio)-cAMP and 8-bromo-cAMP, can replace NGF in promoting long-term survival and neurite outgrowth in cultures of rat neonatal sympathetic and embryonic sensory neurons. N6-substituted analogs, including the more commonly used N6,O2'-dibutyryl-cAMP, are less efficacious. Additivity and switching experiments indicate that the cAMP analogs affect the same neuronal population as that maintained by NGF. However, unlike NGF, the cAMP analogs do not evoke somatic hypertrophy. Moreover, studies with sympathetic neurons reveal that the neurotrophic actions of the cAMP analogs, but not of NGF, are blocked by the axial diastereoisomer of adenosine 3',5'-phosphorothioate, a competitive cAMP antagonist. Thus, the mechanism by which cAMP analogs promote neuronal survival and differentiation appears to involve activation of cAMP-dependent protein kinases, whereas, in contrast, the same effects of NGF neither require nor are mediated by such a pathway. Furthermore, the different efficacies observed with N6- and C8-substituted cAMP analogs suggest that this neurotrophic pathway may involve differential activation of the regulatory subunits of cAMP-dependent protein kinases. The presence of this parallel, cAMP-responsive, neurotrophic pathway in at least two types of NGF-responsive neurons may be developmentally important and has the potential to be exploited for the treatment of injuries or diseases affecting these and possibly other nerve cells.