Mild footshock stress selectively activates ventral tegmental area dopamine neurons innervating the prefrontal cortex. The same stressor rapidly dissociates ventral tegmental substance P from its preprotachykinin-derived co-transmitter substance K, and preproenkephalin B-derived dynorphin B from preproenkephalin A-derived Met-enkephalin-Arg-Gly-Leu and Leu-enkephalin. Mild footshock stress may provide a paradigm for studying both peptidergic modulation of brain dopaminergic neurons and the dynamic regulation of tachykinin and opioid peptide transcription, processing and utilization.