In rats trained to discriminate 0.8 mg/kg IP d-amphetamine from 1 ml/kg saline, 4 x 10(6) U/kg of recombinant human interferon-alpha (rIFN-alpha) given intramuscularly 1 h prior to tests potentiated responses elicited by 0.4 mg/kg d-amphetamine. Coadministration of the opioid receptor antagonist naloxone (1 mg/kg IP) with rIFN-alpha suppressed the potentiation of d-amphetamine by the cytokine. Opioid-dopaminergic mechanisms are proposed to explain the action of rIFN-alpha.