The newly discovered peptide substance K (SK) is an aliphatic tachykinin structurally related to the aromatic tachykinin substance P (SP). Immunohistochemical examination showed a close association between SK afferents and dopamine (DA) cell bodies. Examination of the possible role of SK in modulating midbrain DA systems revealed that SP, but not SK, is associated with the stress response of the mesocortical system. Ventral tegmental area injections of SK effected locomotor hyperactivity, a mesolimbic-mediated behavior. Ventral tegmental injections of SP, but not SK, activated DA metabolism in the prefrontal cortex, while SK injections altered DA metabolism in the nucleus accumbens, but not the cortical site. These data suggest that SK and SP may differentially modulate the mesolimbic and mesocortical systems.