Both N6,O2′-dibutyryl adenosine-3′,5′-cyclic monophosphate (DBcAMP) and prostaglandin E1 (PGE1) stimulate maturation and differentiation of neuroblastoma cells in tissue culture. This effect is potentiated by several phosphodiesterase inhibitors. DBcAMP and adenosine-3′,5′-cyclic monophosphate (cAMP) have also been reported to mimic the effects of nerve growth factor (NGF) on dorsal root ganglia but not on sympathetic ganglia in stimulating neurite outgrowth.We found that prostaglandins E1 and E2 as well as cAMP and DBcAMP elicit neurite outgrowth from chick embryo sympathetic ganglia incubated in microtest tissue culture plates with a liquid medium. The effects of DBcAMP were also evoked by the addition of sodium butyrate to the culture medium. When these compounds were used in the presence of 4 mM theophylline the neurite growth barely exceeded that observed in control cultures. Theophylline also reduced the amount of nerve fiber growth obtained in the presence of NGF. Thus it seems likely that theophylline acts on nerve fiber growth in a manner different from its known action on intracellular cAMP levels.The amount of neurite outgrowth caused by all compounds tested was always significantly less than that in response to NGF. The morphology of the neurite growth in response to PGE1, PGE2, cAMP, DBcAMP, and sodium butyrate was different than that observed with neurites growing in the presence of NGF. It is possible that the former compounds act on some non-neuronal components of the sympathetic explants, whereas NGF acts on the neuronal cells directly.