5-HT or FMRFamide evoke long-lasting changes in the efficacy of sensorimotor (SN-L7) synapses of Aplysia, structural alterations of the presynaptic sensory cell, and cell-specific downregulation in the distribution of the adhesion molecule apCAM. We examined how the cell- specific changes in apCAM might contribute to the formation of new presynaptic varicosities by 5-HT or the elimination of existing presynaptic varicosities by FMRFamide. We report that the formation of new sensory varicosities is directed by the presence of preexisting zones on the motor axon that are enriched for apCAM. Moreover, there was a further enrichment of apCAM levels at existing sensory varicosities contacting the motor axon beginning at 1 hr and lasting 24 hr after treatment with 5-HT. As was found for synapse formation during the early stages of cell-cell interaction, incubation with anti-apCAM mAb blocked the 5-HT-induced long-term changes in synaptic efficacy and the accompanying changes in sensory neuron structure. Long-term synaptic depression with FMRFamide was accompanied by an overall decline of apCAM levels. Treatment with FMRFamide evoked an even greater decline in apCAM levels at sites of sensory varicosities that preceded the structural changes and persisted especially at sites where sensory varicosities are eliminated. These results suggest that neurotransmitters evoke both cell- and site-specific changes in the levels of adhesion molecules that can influence either the formation or the elimination of presynaptic varicosities that accompany long-term heterosynaptic modulation of a behaviorally relevant synaptic connection.