The hypothalamic-pituitary-adrenal/interrenal axis couples serotonergic activity in the brain to the peripheral regulators of energy balance and response to stress. The regulation of peripheral systems occurs largely through the release of peptide hormones, especially the melanocortins (adrenocorticotropic hormone [ACTH] and alpha melanocyte stimulating hormone [alpha-MSH]), and beta-endorphin. Once in circulation, these peptides regulate a wide range of processes; alpha-MSH in particular regulates behaviors and physiologies with sexual and social functions. We investigated the role of the HPI and melanocortin peptides in regulation of electric social signals in the gymnotiform electric fish, Brachyhypopomus pinnicaudatus. We found that corticotropin releasing factor, thyrotropin-releasing hormone, and alpha-MSH, three peptide hormones of the HPI/HPA, increased electric signal waveform amplitude and duration when injected into free-swimming fish. A fourth peptide, a synthetic cyclic-alpha-MSH analog attenuated the normal circadian and socially-induced EOD enhancements in vivo. When applied to the electrogenic cells (electrocytes) in vitro, only alpha-MSH increased the amplitude and duration of the electrocyte discharge similar to the waveform enhancements seen in vivo. The cyclic-alpha-MSH analog had no effect on its own, but blocked or attenuated alpha-MSH-induced enhancements in the single-cell discharge parameters, demonstrating that this compound functions as a silent antagonist at the electrocyte. Overall, these results strongly suggest that the HPI regulates the EOD communication signal, and demonstrate that circulating melanocortin peptides enhance the electrocyte discharge waveform.