The observed lack of change in total dopamine concentrations at the higher dose might reflect a ceiling effect achieved due to chronic dosing of the drug, or it may be the result of a compensatory alteration in the production of dopamine that results from the observed 20% loss in dopamine neurons in the SNpc. In order to determine if this compensation is occurring, we measured the ratio of striatal dopamine to SNpc DA neurons. When examined as a ratio, MPH treatment demonstrate a significant increase in the dopamine:SNpc neuron ratios, suggesting that either dose of MPH increases striatal dopamine, not just that of 1 mg/kg MPH. It is well known that increased extracellular DA may be problematic. Oxidation of DA can produce both superoxide and hydrogen peroxide, which may then form hydroxyl radicals in the presence of certain metals. Additionally, previous studies have indicated that DA can become neurotoxic following its oxidation to a DA quinone, which may then react with cellular thiols to form 5-S-glutathionyl DA and 5-S-cysteinyl DA. The subsequent oxidation of 5-S-cysteinyl Danshensu produces a number of neurotoxic compounds. An increase in the free radical content in the basal ganglia has been shown to potentiate neurodegeneration. In addition to a direct effect of MPH on the basal ganglia, we hypothesized that chronic MPH could increase sensitivity of SNpc dopamine neurons to a later oxidative stress exposure. MPH’s mechanism of action- blockade of the DAT- is similar to that of cocaine and results in an increase in extracellular dopamine, which has been shown to quickly form free radical adducts. Similar to our findings, compartmentation of the both ectoenzymes was recently reported for lymph nodes in chronic lymphocytic leukemia patients. In this study, CD39 was widely expressed while CD73 was restricted to proliferation centers suggesting that adenosine generation is locally confined. CD39 and CD73 were found to be unevenly distributed among the different cardiac immune cells. Circulating and resident cardiac lymphoid cells highly expressed CD73 with little abundance on myeloid cells,Tanshinone-I while the opposite was true for CD39. In fact, resident cardiac APCs and monocytes showed no measurable CD73 but were highly positive for CD39. The latter hypothesis is supported by findings in a lymphocyte endothelial coculture model, in which CD73 activity was significantly decreased during adhesion and migration processes. Consistent with data in the literature, we found after I/R profoundly increased numbers of granulocytes and monocytes within the heart. As to the enzymes of the ectonucleotidase cascade, CD73 und CD39 were significantly upregulated on granulocytes under these conditions. While in the unstressed heart coronary endothelial cells contribute to 90% of the cell-associated CD73 in the heart, this fraction dramatically changes after I/R when leukocyte-bound CD73 comprises about 2/3 of the entire CD73 within myocardial tissue. This difference is most likely even more pronounced when considering the local accumulation of immune cells at the site of inflammation. Similarly, we have observed a strong increase in CD73 expression on T-cells while CD39 remained unchanged. Consistent with this finding we recently reported upregulation of CD73 on Treg after antigenic stimulation which was associated with adenosine A2a receptor mediated downregulation of active NFkB and cytokine release. In the context of cardiac function after I/R, the upregulation of CD73 on lymphocytes and granulocytes suggests an adenosinergic axis which becomes functionally relevant when necrosis and apoptosis lead to elevated extracellular nucleotide levels. Since increased free radical production has been shown to increase the sensitivity of SNpc neurons to environmental or administered xenobiotics, it is possible that long-term MPH could be a contributing etiological factor in a multi-hit hypothesis for induction of Parkinson’s disease.