Cocaine potentiates MDMA-induced oxidative stress but not dopaminergic neurotoxicity in mice: implications for the pathogenesis of free radical-induced neurodegenerative disorders

摘要

RATIONALE:The drugs of abuse 3,4-methylenedioxymethamphetamine (MDMA; >ecstasy>) and cocaine both increase the generation of free radicals, and in the case of MDMA, this increase in oxidative stress is involved in the dopaminergic neurotoxicity produced by the drug in mice. Oxidative stress processes are also involved in the pathogenesis of several neurodegenerative diseases.OBJECTIVES:We aimed to determine the consequences of the combined administration of MDMA and cocaine on oxidative stress and dopaminergic neurotoxicity.METHODS:Mice received MDMA (20 mg/kg, i.p.; two doses separated by 3 h) followed by cocaine 1, 3, 6, or 24 h after the second MDMA dose. Mice were killed between 1 h and 7 days after cocaine injection.RESULTS:MDMA decreased dopamine transporter density and dopamine concentration 7 days later. Cocaine did not alter this neurotoxicity. MDMA produced an increase in the concentration of 2,3-dihydroxybenzoic acid in striatal microdialysis samples and an increase in lipid peroxidation in the striatum which were potentiated by cocaine. MDMA and cocaine given together also increased nitrate and 3-nitrotyrosine levels compared with either drug given alone. On the other hand, MDMA increased superoxide dismutase activity and decreased catalase activity, changes which were prevented by cocaine administration. In addition, cocaine administration produced an increase in glutathione peroxidase (GPx) activity in both saline-treated and MDMA-treated mice.CONCLUSIONS:Cocaine potentiates MDMA-induced oxidative stress but does not produce an increase in the neurotoxicity produced by MDMA, and this lack of potentiation may involve an increase in GPx activity