Synaptic facilitation at sensory-to-motor neuron synapses in Aplysia is a mechanism contributing to a simple form of learning called behavioral sensitization. Previous work has shown that facilitation is mediated in part by the neurotransmitter 5-HT acting through cAMP to broaden presynaptic action potentials and thus increase transmitter release from the sensory neuron terminals. Other studies have indicated that 5- HT causes facilitation by more than one mechanism, depending on whether the synapse has first been depressed by prior stimulation. The present study examines the involvement of cAMP in facilitation at depressed synapses by utilizing the adenylyl cyclase activator 7 beta-desacetyl-7 beta-[gamma-(N-methylpiperazino)-butyryl] forskolin (7B-forskolin) and 5-HT separately and in combination. Facilitation at relatively rested synapses can be mimicked with application of 7B-forskolin, whereas transmission at synapses that have been subjected to repeated stimulation is not affected. The forskolin derivative by itself increases cAMP levels in sensory neurons and potentiates 5-HT-induced stimulation of cAMP 2–10-fold. Nonetheless, joint application of 7B- forskolin and 5-HT at submaximal concentrations to depressed synapses causes the same amount of facilitation as 5-HT alone. This finding implies that facilitation by 5-HT at repeatedly stimulated synapses is not mediated by cAMP alone. In addition, facilitation by 7B-forskolin at relatively rested synapses can occur without prolongation of action potentials, suggesting that cAMP can act in more than one way to enhance transmission. Taken together with earlier findings, the present results suggest that at least three distinct processes participate in facilitation by 5-HT.