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

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Abstract

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.

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Acknowledgments

This work was supported by grants from Ministerio de Ciencia e Innovación, Ministerio de Sanidad y Política Social, ISCIII, and Universidad Complutense-Comunidad de Madrid: SAF2006-07045, SAF2010-21529, PI070892, PNSD 3SI/04/01, Retics RTA RD06/0001/0006 and RD06/0001/1011, CIBERNED CB06/05/0055, and UCM-CAM 910258. IP and ET received predoctoral grants from Universidad Complutense de Madrid and Ministerio de Educación y Ciencia. NG was funded by a Juan de la Cierva postdoctoral contract from Ministerio de Ciencia e Innovación.

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Authors and Affiliations

  1. Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, 28040, Spain

    Ines Peraile, Noelia Granado, Elisa Torres, M. Dolores Gutiérrez-López, M. Isabel Colado & Esther O’Shea

  2. Instituto Cajal, Consejo Superior de Investigaciones Científicas, Avda Doctor Arce 37, 28002, Madrid, Spain

    Rosario Moratalla

  3. CIBERNED, Madrid, Spain

    Rosario Moratalla

Authors
  1. Ines Peraile
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  2. Noelia Granado
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  3. Elisa Torres
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  4. M. Dolores Gutiérrez-López
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  5. Rosario Moratalla
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  6. M. Isabel Colado
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  7. Esther O’Shea
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Correspondence to Esther O’Shea.

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Peraile, I., Granado, N., Torres, E. et al. Cocaine potentiates MDMA-induced oxidative stress but not dopaminergic neurotoxicity in mice: implications for the pathogenesis of free radical-induced neurodegenerative disorders. Psychopharmacology 230, 125–135 (2013). https://doi.org/10.1007/s00213-013-3142-5

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  • DOI: https://doi.org/10.1007/s00213-013-3142-5

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