Existing reports of tolerance to the behavioral effects of d-amphetamine are most parsimoniously interpreted as reflecting behavioral adaptation to the disruptive effects of the drug rather than physiological tolerance. The present study shows that physiological tolerance does develop to the facilitation of self-stimulation behavior which the drug produces. Rats were trained to bar-press for electrical stimulation of the medial forebrain bundle and tested for facilitation of responding following the administration of 0.25 or 0.50 mg/kg d-amphetamine. Testing was terminated for 4 days during which increasing doses (1.0-12.0 mg/kg) of the drug were given. 16 h after the last injection, the test doses (0.25 or 0.50 mg/kg) no longer produced facilitation of self-stimulation. In addition, testing on the following day with no further drug administration showed a depression of responding indicating depression of the sensitivity of the reward system of the brain.