The Monitoring the Future Study reported that 2.7% of high school students reported a non-therapeutic use of MPH while 1.9% of college students reported a similar non-medicinal usage In both diagnosed ADHD and non-ADHD populations, MPH has been shown to increase scores on standardized tests, as well as increase working memory and thus, there have been calls for making it available as an ‘‘over the counter’’ drug. Despite the extensive use of this stimulant in ADHD and as well as for ‘‘off-label’’ use, few papers have been published regarding the long-term neurological consequences of MPH exposure in the CNS. MPH is a Schedule II CNS stimulant that exerts its Glycitin pharmacological effects via preferential blockade of the dopamine transporter and norepinephrine transporter, similar to that of cocaine. This blockade results in a reduction of dopamine/norepinephrine uptake, leading to an increase in postsynaptic dopamine/norepinephrine levels. Thus, MPH usage leads to an acute increase in striatal dopamine levels. In terms of neurological effects, dopamine has been shown to have a major modulatory effect in the developing brain on both neostriatal and cortical neurogenesis. Additionally, excess dopamine has been shown to be toxic both in vitro and in vivo due to the production of superoxide, hydrogen peroxide, and the dopamine quinone. In fact, both acute and chronic treatment with MPH has been shown to result in superoxide production in the brain. Free dopamine has also been shown to induce an inflammatory response in the brain characterized by an increase in cytokines and chemokines that lead to an induction of microgliosis. Specifically, we examined if acute or chronic administration of MPH altered SNpc dopamine neuron number and catecholamine levels in the striatum. Since excessive dopamine can induce oxidative stress and inflammation, we examined if MPH rendered the basal ganglia more sensitive to MPTP, an agent that has previously been shown to induce neuron damage in the SNpc. The present study investigated the pathological effects of acute and chronic MPH in the basal ganglia using two different doses that Dimethyl-lithospermate-B the therapeutic window of MPH use for ADHD and narcolepsy in humans. We demonstrate that chronic administration of 10 mg/kg MPH induces a small but significant loss of SNpc dopaminergic neurons. We also find that chronic exposure to both 1 mg/kg and 10 mg/kg MPH can sensitize SNpc dopamine neurons to a further oxidative stress. Though the complete mechanism for this sensitization of dopamine neurons is not well understood, our experiments suggest a combined effect of an increased inflammatory response with reduced levels of several trophic factors, including BDNF and GDNF. Despite the extensive use of MPH in school aged and adult populations with ADHD as well its use in general cognitive enhancement in non-ADHD individuals, only a few studies have investigated the neuropathological consequences of long-term MPH exposure. In this study, we used a 12-week MPH administration schedule that spans the developmental period in rodents and corresponds to the pre-adolescent through young adult period in humans, during which MPH is typically used. MPH’s mechanism of action is to increase the availability of extracellular DA and NE in the synaptic cleft through blockade of the dopamine transporter and norepinephrine transporter. In this study, we observed a significant increase in total dopamine levels in the striatum at 1 mg/kg MPH, a change that was not observed at 10 mg/kg MPH. Previous studies have also reported a similar increase in striatal dopamine levels at similar lower doses of MPH.