Whole cell voltage clamp recordings from Aplysia mechanosensory neurons obtained from the pleural ganglion were used to investigate the actions on membrane currents of the neuropeptides SCP_B and FMRFamide. At the start of whole cell recording, SCP_B typically evoked an inward current at a holding potential of -40 mV, due to the cAMP mediated closure of the S-type K⁺ channel, whereas FMRFamide evoked an outward current, due to the opening of the S-type K⁺ channels mediated by 12-lipoxygenase metabolites of arachidonic acid. However, after several minutes of whole cell recording with a high concentration of chloride in the whole cell patch pipette solution, the responses to SCPB and FMRFamide at -40 mV were inverted; SCP_B evoked an outward current whereas FMRFamide and YGGFMRFamide evoked inward currents. Ion substitution experiments and reversal potential measurements revealed that these responses were due to the opposing regulation of a Cl^- current, whose magnitude was greatly enhanced by dialysis with the high Cl^-containing pipette solution. SCP_B inhibited this Cl^- current through production of cAMP and activation of PKA. YGGFMRFamide activated this Cl^- current by stimulating a cGMP-activated phosphodiesterase that hydrolyzed cAMP. Thus, a cAMP-dependent Cl^- current undergoes antagonistic modulation by two neuropeptides in Aplysia sensory neurons.