In accord with previous studies, it was found that vasoactive intestinal peptide (VIP), a powerful activator of adenylate cyclase, and cAMP-active agents (i.e., 8-Br-cAMP, forskolin, and Ro20-1724) increased the firing rate of noradrenergic neurons in the locus coeruleus (LC) by inducing an inward current. The response to VIP was usually more rapid and larger in a subpopulation of LC neurons with subthreshold rhythmic oscillations in membrane potential (oscillatory cells) as compared to nonoscillatory cells. In either case, the inward currents elicited by VIP and cAMP-active agents were found to be nonadditive, suggesting the action of VIP, at least in part, is via the same mechanism as that of cAMP-active agents. Intracellular application of a specific protein (or related peptide) inhibitor of cAMP-dependent protein kinase markedly attenuated the activation induced by either cAMP-active agents or VIP, suggesting that cAMP-dependent protein kinase (protein kinase A), presumably through protein phosphorylation, plays a role in the action of VIP. Taken together, the results provide evidence that cAMP and protein kinase A are involved in mediating the electrophysiological actions of VIP on LC neurons.