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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.

The acute administration of moderate to high doses (greater than 2 mg/kg) of amphetamine (AMPH) to rats produces a multiphasic behavioral response consisting of an initial period of locomotor activity followed by episodes of intense stereotyped behavior, and a period of post-stereotype locomotion. Repeated administration of the drug results in a sensitization with two components: more rapid onset of stereotypy and enhancement of the post-stereotype locomotor activity. The studies presented below provide converging evidence that the two components of the sensitization are dissociable. 1. Rats from ten different strains or suppliers all exhibited more rapid onset of stereotypy following repeated AMPH pretreatment, whereas only five of these strains or supplier groups exhibited significantly enhanced poststereotypy locomotion. 2. The time course differed for the development of these two components of the sensitization. 3. The recovery from sensitization differed for these two components of the behavioral response. Following withdrawal of the drug, post-stereotypy motor activity diminished within 2 months while the more rapid onset of stereotypy persisted for at least 3 months. These observations have particular relevance to future studies directed at specifying the biochemical substrates of the sensitization.