This research examined the effects of several cyclic nucleotides on in vivo cat soleus nerves and muscles. The reagents were administered by rapid close intra-arterial injection while electrical activity in single motor axons and contractile activity in the whole muscle were monitored. Cyclic N6-2'-O-dibutyryl adenosine 3',5'-monophosphate (dibutyryl cAMP) initiated bursts of action potentials in unstimulated axons. It also caused the occurrence of stimulus bound repetitive potentials in stimulated axons. It caused the muscle to undergo a series of rapid asynchronous contractions and potentiated the strength of stimulus-evoked contractions. Monobutyryl cAMP produced similar responses, but was less potent than dibutyryl cAMP. cAMP produced only a small, transient depression of neuromuscular transmission. There was no response to dibutyryl cyclic 3',5' guanosine monophosphate or sodium butyrate. None of these reagents affected denervated muscle. The results suggest that cAMP-like materials that can penetrate nerve membranes cause depolarization of motor nerve terminals, prolongation of the depolarization of the terminal initiated by an action potential and release of transmitter.