Rats were trained to discriminate the opiold receptor agonist ethylketocyclazocine (EKC) (0.3 mg/kg body weight, intraperitoneally) from saline. Interferon-alpha (IFN-α), when substituted for EKC, ellcited a dose-related increase in EKC-like responses. This generalization of EKC responses was blocked by the oploid antagonist naloxone (1 mg/kg). Potentiation of responses to a low dose (0.1 mg/kg) of EKC by IFN-α (1 x 106 U/kg or 0.22 nmol/kg) was also observed. Data thus indicate the involvement of opiold neurons on the action of IFN-α. d-Amphetamine (0.8 mg/kg) was shown to potentiate both EKC (0.1 mg/kg) and IFN-α (1 x 106 U/kg). The present study confirms our previously proposed opioid mediated dopaminergic mechanism of IFN-α.