Amphetamine cumulation and tolerance development: concurrent and opposing phenomena.

Abstract

Whether diminished or augmented behavioral effects are observed after repeated amphetamine administration may reflect the relative balance between tolerance and drug cumulation. To investigate this, we measured the distribution of d-amphetamine in various tissues and its effects on performance of a conditioned behavior after acute or chronic treatment. Rats trained to lever press under a fixed ratio 5 schedule for food-reinforcement were tested daily for 4 min epochs in each of 6 consecutive hours. After responding was stable, animals were injected for 16 days with saline or 1.0, 2.5 or 5.0 mg 3H-d-amphetamine sulfate/kg IP 15 min before the second daily behavioral epoch. On the 17th day, animals which had been receiving 3H-d-amphetamine were given their usual dose and those which had been receiving saline were given one of the doses of 3H-d-amphetamine; all animals were decapitated approximately 2 1/4 hours after this final injection, immediately after the 4th behavioral epoch. Brain, heart, muscle, epididymal fat, and kidney were removed for subsequent analysis of unchanged 3H-d-amphetamine. The experiment was carried out in two phases, 3 1/2 months apart, which inadvertently resulted in shipment of rats from different buildings on the supplier's campus. Acute treatment produced dose-related effects on operant responding, the lowest dose increasing responding and the highest dose suppressing it. Chronic injection of the highest dose of d-amphetamine resulted in significant attenuation of its acute suppressant effect. Additionally, chronic treatment suppressed responding of rats 23 1/4 hours after injection (i.e., before the subsequent daily injection). Tissue levels of d-amphetamine were dose related and d-amphetamine cumulated after chronic treatment with the highest dose. When d-amphetamine was administered acutely, the behavioural effect immediately before decapitation was highly correlated with the concentration of d-amphetamine in brain and in heart. This was not the case after chronic treatment, since rats given the higher doses showed less behavioural effect than would have been predicted from the concentrations of d-amphetamine in their tissues. Besides evidence of tolerance and cumulation of drug in one or more tissues, a significant phase or colony difference emerged, which could have been due to seasonal or other factors. Additional, different experiments, performed concurrently on a new shipment of rats from each colony, allowed us to conclude that the original observations of phase differences were not due to seasonal differences or chance.(ABSTRACT TRUNCATED AT 400 WORDS)