Tolerance to Discriminative Stimulus Effects of d-Amphetamine

Chronic administration of high doses of d-amphetamine produced time-limited, surmountable tolerance to stimulus effects of d-amphetamine. Sprague-Dawley rats (Rattus norvegicus, N = 23) discriminated saline and 0.80 mg/kg d-amphetamine under fixed-ratio schedules of food delivery. Suspending training and administering saline did not alter sensitivity to d-amphetamine, indicating that neither tolerance nor sensitization developed during regular training. Acute pretreatment with 3.2 mg/kg d-amphetamine did not alter the ED50 for stimulus effects of d-amphetamine. In contrast, administration of 3.2 or 6.4 mg/kg d-amphetamine, b.i.d., for 3 days or 2 weeks increased the ED50 for stimulus effects 3- to 4-fold but did not produce consistent tolerance to rate-altering effects. Tolerance to stimulus effects was surmountable, as higher doses of d-amphetamine produced full drug-lever selection in tolerant rats. Sensitivity recovered after chronic administration ended.