The functional properties of neuronal networks can be reconfigured by a variety of modulatory neurotransmitters, which may alter the excitable properties of neurons or the strengths of synaptic connections. Many of these neuromodulators act via the intracellular second messenger cyclic AMP, but their effects on the spatial distribution of cAMP concentration have never been examined in an intact neural circuit. We therefore used the cAMP-indicator dye FICRhR (refs 1, 2) to investigate the effect of several neuromodulators (octopamine, dopamine, acetylcholine, serotonin and proctolin) on cAMP distribution in identified neurons of the lobster stomatogastric ganglion (STG). When added to the bath solution, each of these neuromodulators produced a unique pattern of cAMP transients among the different neurons of the STG. Electrical stimulation of neurons innervating the STG causes synaptic release of endogenous modulators, leading within a few seconds to local increases of cAMP in fine neurite branches, the site where many modulators are thought to act. After prolonged stimulation, cAMP diffuses from the site of production to throughout the neuritic tree and eventually to the cell body. Diffusion of cAMP may explain how transient localized inputs to a neuron can produce long-range effects such as long-term changes in gene expression.