Critical roles for NO in regulating cell and tissue physiology are broadly appreciated, but aspects remain to be explored. In the mollusc Pleurobranchaea, NO synthase activity is high in CNS ganglia containing motor networks for feeding and locomotion, where a cAMP-gated cation current (I_Na,cAMP) is also prominent in many neurons. We examined effects of NO on I_Na,cAMP using voltage clamp methods developed to analyze cAMP signaling in the live neuron, focusing on the identified metacerebral giant neuron of the feeding network. NO donors enhanced the I_Na,cAMP response to injected cAMP by an averaged 85%. In dose-response measures, NO increased the current stimulated by cAMP injection without altering either apparent cAMP binding affinity or cooperativity of current activation. NO did not detectably alter levels of native cAMP or synthesis or degradation rates, as observable in both current saturation and decay rate of I_Na,cAMP responses to cAMP injection. NO actions were not exerted by cGMP signaling, as they were not mimicked by cGMP analog nor blocked by inhibitors of guanylate cyclase and protein kinase G. NO potentiation of I_Na,cAMP was broadly distributed among many other neurons of the feeding motor network in the buccal ganglion. However, NO did not affect a second type of I_Na,cAMP found in locomotor neurons of the pedal ganglia. These results suggest that NO acts through a novel mechanism to regulate the gain of cAMP-dependent neuromodulatory pathways that activate I_Na,cAMP, and may thereby affect the set-points of feeding network excitability and reactivity to exogenous input.