Chronic Methylphenidate Induces Increased Quinone Production and Subsequent Depletion of the Antioxidant Glutathione in the Striatum
Document Type
Article
Publication Date
12-1-2019
Description
Background: Methylphenidate (Ritalin®) is a psychostimulant used chronically to treat attention deficit hyperactivity disorder. Methylphenidate acts by preventing the reuptake of dopamine and norepinephrine, resulting in an increase in these neurotransmitters in the synaptic cleft. Excess dopamine can be autoxidized to a quinone that may lead to oxidative stress. The antioxidant, glutathione helps to protect the cell against quinones via conjugation reactions; however, depletion of glutathione may result from excess quinone formation. Chronic exposure to methylphenidate appears to sensitize dopaminergic neurons to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We hypothesized that oxidative stress caused by the autooxidation of the excess dopamine renders dopaminergic neurons within the nigrostriatal pathway to be more sensitive to MPTP. Methods: To test this hypothesis, male mice received chronic low or high doses of MPH and were exposed to saline or MPTP following a 1-week washout. Quinone formation in the striatum was examined via dot blot, and striatal GSH was quantified using a glutathione assay. Results: Indeed, quinone formation increased with increasing doses of methylphenidate. Additionally, methylphenidate dose-dependently resulted in a depletion of glutathione, which was further depleted following MPTP treatment. Conclusions: Thus, the increased sensitivity of dopamine neurons to MPTP toxicity following chronic methylphenidate exposure may be due to quinone production and subsequent depletion of glutathione.
Citation Information
Oakes, Hannah V.; Ketchem, Shannon; Hall, Alexis N.; Ensley, Tucker; Archibald, Kristen M.; and Pond, Brooks B.. 2019. Chronic Methylphenidate Induces Increased Quinone Production and Subsequent Depletion of the Antioxidant Glutathione in the Striatum. Pharmacological Reports. Vol.71(6). 1289-1292. https://doi.org/10.1016/j.pharep.2019.08.003 PMID: 31693968 ISSN: 1734-1140