1. Serotonin (5-HT), small cardioactive peptide B (SCPB) and FMRFamide have well-established facilitatory and inhibitory effects on sensory neurons and their connections with motor neurons mediating withdrawal reflexes in Aplysia. Little is known, however, about their effects on interneurons contributing to those reflexes. As a first step, we examined the effects of these three transmitters on the identified inhibitory interneuron RP14 in isolated pleural-pedal ganglia. 2. Bath application of 5-HT hyperpolarized RP14, inhibited its spontaneous activity and decreased its excitability. In addition, 5-HT decreased the amplitude of inhibitory postsynaptic potentials produced by RP14 in tail sensory and motor neurons. 3. In contrast, bath application of SCPB increased spontaneous activity in RP14. Subsequent application of 5-HT to the bath, which still contained SCPB, inhibited RP14. Therefore, the effects of SCPB were essentially opposite to those of 5-HT on this inhibitory interneuron. 4. FMRFamide had little effect on RP14. It did not produce an obvious change in its resting membrane potential and produced only a transient increase in its spontaneous activity. 5. These results suggest that various neuromodulators have differential effects on elements of the neuronal circuit underlying the tail-withdrawal reflex of Aplysia. Differential modulation may determine the overall behavioral manifestations associated with sensitization.