Long-term, but not short-term, facilitation induced by 5-HT in Aplysia sensory neurons is blocked by application of inhibitors of protein synthesis or RNA synthesis during the 1.5 hr training period. These findings suggest that genes and proteins not needed for the short-term process are required for long-term facilitation. To identify these proteins, we examined changes in overall and specific protein synthesis in sensory neurons. During the 1.5 hr period of stimulation, 5-HT initiated three temporally distinct changes in total protein synthesis: a small decrease at 0.5 hr, a small increase at 1 hr, and a second and larger increase at 3 hr. 5-HT also produced three temporally distinct changes in the synthesis of individual proteins that could be resolved on 2-D gels. First, there was an increase at 30 min in the rate of synthesis of 10 proteins and a decrease in the synthesis of 5 proteins. These changes in protein expression are rapid and transient, subsiding within 1-3 hr, and are transcription-dependent. Second, at 3 hr, there is a transient increase in 4 different proteins that also is transcription-dependent and lasts ∼5 hr. Finally, at 24 hr, during the retention phase of facilitation, there was a sustained increase in the expression of two proteins.