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Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits

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Abstract

(±)3,4-Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. This study was designed to evaluate whether MDMA exposure affects their recognition memory and hippocampal expression of plasticity markers. Mice were administered with increasing doses of MDMA once per week for 8 weeks (three times in 1 day, every 3 h) and killed 2 weeks (2w) or 3 months (3m) later. The treatment did not modify hippocampal tryptophan hydroxylase 2, a serotonergic indicator, but induced an initial reduction in dopaminergic markers in substantia nigra, which remained stable for at least 3 months. In parallel, MDMA produced a decrease in dopamine (DA) levels in the striatum at 2w, which were restored 3 months later, suggesting dopaminergic terminal regeneration (sprouting phenomenon). Moreover, recognition memory was assessed using the object recognition test. Young (2w) and mature (3m) adult mice exhibited impaired memory after 24-h but not after just 1-h retention interval. Two weeks after the treatment, animals showed constant levels of CREB but an increase in its phosphorylated form and in c-Fos expression. Brain-derived neurotrophic factor (BDNF) and especially Arc overexpression was sustained and long-lasting. We cannot rule out the absence of MDMA injury in the hippocampus being due to the generation of BDNF. The levels of NMDAR2B, PSD-95, and synaptophysin were unaffected. In conclusion, the young mice exposed to MDMA showed increased expression of early key markers of plasticity, which sometimes remained for 3 months, and suggests hippocampal maladaptive plasticity that could explain memory deficits evidenced here.

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Acknowledgments

The authors thank J.A. Paulsen-Medalen for technical assistance, and they also acknowledge the Language Advisory Service of the University of Barcelona for editing the language of the manuscript. Sonia Abad received a fellowship from the Institut de Biomedicina (IBUB, University of Barcelona). Funding for this study was provided by the Plan Nacional sobre Drogas (2012I102) and the Ministerio de Economía y Competitividad (SAF 2013-46135-P) and by the Generalitat de Catalunya (2014SGR525). AC belongs to 2014SGR525, and JC, DP, and EE to 2014SGR1081.

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  1. Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona, Avda. Joan XXIII s/n., Barcelona, 08028, Spain

    S. Abad, J. Camarasa, D. Pubill, A. Camins & E. Escubedo

  2. Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    A. Camins

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  1. S. Abad
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  2. J. Camarasa
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  3. D. Pubill
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Correspondence to E. Escubedo.

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Abad, S., Camarasa, J., Pubill, D. et al. Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits. Mol Neurobiol 53, 7271–7283 (2016). https://doi.org/10.1007/s12035-015-9618-z

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