Repeated Administration of 3,4-Methylenedioxymethamphetamine (MDMA) Elevates the Levels of Neuronal Nitric Oxide Synthase in the Nigrostriatal System: Possible Relevance to Neurotoxicity

  • Giulia Costa
  • Micaela Morelli
  • Nicola Simola
Short Communication


Previous studies have consistently demonstrated that the amphetamine-related drug 3,4-methylenedioxymethamphetamine (MDMA) induces dopaminergic damage in the mouse brain, and that this effect is most marked in the nigrostriatal system. Moreover, it has been suggested that the overproduction of nitric oxide (NO) may participate in the dopaminergic damage induced by MDMA. To further elucidate this issue, we evaluated the levels of the enzyme nitric oxide synthase (nNOS), which catalyzes the production of NO, in mice treated with regimens of MDMA that induce progressive and persistent neurotoxicity in the dopaminergic nigrostriatal system. Mice received 14, 28, or 36 administrations of MDMA (10 mg/kg i.p.), twice a day/twice a week, and were sacrificed at different time-points after treatment discontinuation. Thereafter, the number of nNOS-positive neurons was quantified by immunohistochemistry in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc). MDMA elevated the numbers of nNOS-positive neurons in the CPu of mice that received 28 or 36 drug administrations. This effect was still detectable at 3 months after treatment discontinuation. Moreover, MDMA elevated the numbers of nNOS-positive neurons in the SNc. However, this effect occurred only in mice that received 28 drug administrations and were sacrificed 3 days after treatment discontinuation. These results are in line with the hypothesis that activation of the NO cascade participates in the toxic effects induced by MDMA in the dopaminergic nigrostriatal system. Moreover, they suggest that activation of the NO cascade induces toxic effects that are more marked in striatal terminals, compared with nigral neurons.


Amphetamine-related drugs Substantia nigra pars compacta Caudate-putamen Neurotoxicity 



The authors are grateful to Prof. Antonio Plumitallo for the synthesis of MDMA.

Funding Information

This study was supported by funds from Regione Autonoma della Sardegna (Legge Regionale 7 Agosto 2007, N.7, annualità 2008 and 2010). Dr. Giulia Costa received financial support from the University of Cagliari (D.R. n.159 del 18.11.2016) and the Fondazione di Sardegna (project 2016.0845). Dr. Nicola Simola and Dr. Giulia Costa received financial support from the Autonomous Region of Sardinia (L.R. n 7/2007-2015) and from Fondazione di Sardegna (Esercizio Finanziario 2017).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biomedical Sciences, Section of NeuropsychopharmacologyUniversity of Cagliari, Building A, Monserrato University CampusMonserratoItaly
  2. 2.National Research Council of Italy (CNR)Neuroscience InstituteCagliariItaly
  3. 3.National Institute of Neuroscience (INN)University of CagliariCagliariItaly

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