Stress and chronic exposure to drugs of abuse can trigger addictive and depressive disorders. Both stimuli increase activity of dynorphin, a neuropeptide that acts at kappa-opioid receptors (KORs). In humans, KOR agonists cause dysphoria, raising the possibility that dynorphin modulates the depressive-like effects of stress and chronic drug use. We examined if KOR activation alters sensitivity to stimulant drugs by assessing the effects of the selective KOR agonist, salvinorin A (SalvA), on cocaine-induced locomotor activity and c-Fos expression. Acute administration of SalvA blocked the locomotor-stimulant effects of cocaine, whereas repeated SalvA together with concomitant exposure to activity testing chambers potentiated the locomotor response to a cocaine challenge. In contrast, repeated SalvA administered in home cages rather than the activity chambers failed to potentiate the locomotor response to a cocaine challenge. One potential explanation for these findings is that activation of KORs disrupts context conditioning: acute locomotor responses to SalvA alone did not fully habituate with repeated testing in the activity chambers. The effects of SalvA on locomotor activity paralleled its effects on cocaine-induced c-Fos expression in the dorsal striatum: acute SalvA attenuated cocaine-induced c-Fos, whereas repeated SalvA potentiated it when administered in the activity chambers but not the home cage. Acute SalvA also blocked the locomotor stimulant effects of the D1 receptor agonist SKF 82958, whereas repeated SalvA potentiated these effects when administered in the activity chambers. These findings suggest that SalvA regulates the stimulant effects of cocaine through interactions with D1 receptor-mediated signaling in the dorsal striatum.