The efficacy of the synapses between the sensory and motor cells of Aplysia, as well as the number of presynaptic sensory cell varicosities in vitro, can undergo long-term increases and decreases, respectively, following application of the facilitatory modulator serotonin or the inhibitory modulator FMRFamide. We here report that cAMP and arachidonic acid, two second messenger systems mediating some of the short-term actions of serotonin and FMRFamide on sensory cells, reproduce some of the long-term changes in the structure of the sensory cells, and these structural changes in turn parallel the long-term changes in the functional effectiveness of the synapses. cAMP enhances the strength of the connections between the sensory and motor cells and increases the number of sensory varicosities. Conversely, arachidonic acid decreases the strength of the connections and decreases the number of sensory varicosities. Thus, each of the modulatory neurotransmitters may activate the same intracellular second messenger system to establish both short and long lasting functional changes in synaptic efficacy, as well as to produce enduring structural changes in neuron connectivity.