The sensorimotor synapse of Aplysia exhibits long-term facilitation (LTF) and long-term depression (LTD) elicited by the neuromodulator serotonin (5-HT) and the peptide Phe-Met-Arg-Phe-NH(2), respectively. 5-HT-induced LTF engages extracellular-regulated kinase (Erk) and CREB1, whereas FMRFa-induced LTD engages p38 MAPK (mitogen-activated protein kinase) and CREB2. The interaction of the 5-HT and FMRFa pathways was recently investigated in Aplysia at the level of gene expression. However, little is known about crosstalk of these pathways at the level of the second messenger cascades. We investigated the potential interaction of the 5-HT and FMRFa pathways at the level of the Erk cascade. We found that FMRFa inhibited basal Erk activity through p38 MAPK. FMRFa also inhibited 5-HT-induced phosphorylation of Erk and nuclear accumulation of phospho-ERK, suggesting that FMRFa may place inhibitory constraints on memory formation through regulation of the Erk MAPK cascade.