Rats were implanted with stimulating electrodes aimed at the medial forebrain bundle-lateral hypothalamus (MFB-LH) and were trained to lever-press for brain self-stimulation on a fixed interval: 60 s schedule of reinforcement. The effects of graded doses of naloxone (0.1-30 mg/kg), morphine (0.3-5.6 mg/kg), naloxone plus morphine, d-amphetamine (0.03-1.0 mg/kg), naloxone plus d-amphetamine, phencyclidine (0.3-5.6 mg/kg), and naloxone plus phencyclidine were tested. Naloxone produced a significant decrease in rates at 30 mg/kg. Naloxone (0.1-1.0 mg/kg) plus morphine blocked the dose-dependent decrease produced by morphine alone. In contrast, naloxone (1.0-10 mg/kg) plus d-amphetamine attenuated the graded increase in response rates produced by d-amphetamine. Naloxone (1.0-10 mg/kg) plus phencyclidine did not reliably change the increase in response rates produced by phencyclidine alone. The use of the fixed interval schedule of brain self-stimulation to study these drug interactions is novel, and further demonstrates that the highly reinforcing aspects of brain stimulation, known to be influenced by dopamine, may also be modulated by the endogenous opiate system.