The existence of tolerance to and cross-tolerance between d-amphetamine and methylphenidate for their effects on milk consumption and on differential-reinforcement-of-low-rate performance in the rat.

Administration of d-amphetamine (2.5 mg/kg) or methylphenidate (20 mg/kg) decreased milk consumption in rats. When these drugs were administered daily, tolerance developed to this effect over the course of 20 days. Cross-tolerance to the effects on milk consumption occurred between d-amphetamine and methylphenidate over a 4-fold range of dose of both drugs. Administration of d-amphetamine (1.5 mg/kg) or methylphenidate (10 mg/kg) disrupted responding under differential-reinforcement-or-low-rate (DRL) contingencies. Both drugs increased response rate, decreased frequency of reinforcement and shifted the mode of the inter-response time distribution to the left. When the drugs were administered daily, tolerance developed to all these effects over the course of 20 days. Cross-tolerance to the effects on DRL behavior occurred between d-amphetamine and methylphenidate over a 4-fold range of dose of both drugs. Daily administration of d-amphetamine (2.5 mg/kg) but not of methylphenidate (20 mg/kg) resulted in decreased norepinephrine (NE) levels in brain; the decreased norepinephrine levels, which occur with repeated d-amphetamine administration, are believed to result from the storage in noradrenergic neurons of p-hydroxynorephedrine, a metabolite of d-amphetamine. Radioactivity was not detectable in brain 24 hours after the last of 15 daily doses of radiolabeled methylphenidate. These results suggest that d-amphetamine, but not methylphenidate, is metabolized to a compound which is stored in noradrenergic neurons. The existence of behavioral cross-tolerance between d-amphetamine and methylphenidate is therefore inconsistent with the hypothesis that tolerance to the behavioral effects of d-amphetamine is due to the metabolism of d-amphetamine to p-hydroxynorephedrine, a false transmitter in noradrenergic neurons.