Evidence in laboratory animals indicates that exposure to stimulants produces sensitization to their rewarding effects, a process that in humans would be expected to increase the risk of substance abuse. However, therapeutic administration of stimulants such as methylphenidate (MPH) in children with attention deficit hyperactivity disorder reportedly reduces the risk of substance abuse. Here we show in rats that exposure to MPH during pre-adolescence causes behavioral and neurobiological adaptations that endure into adulthood, and that are consistent with increased sensitivity to the aversive effects of cocaine.