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
This is a preview of subscription content, log in to check access.
The authors are grateful to Prof. Antonio Plumitallo for the synthesis of MDMA.
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.
Adriani W, Granstrem O, Macri S, Izykenova G, Dambinova S, Laviola G (2004) Behavioral and neurochemical vulnerability during adolescence in mice: studies with nicotine. Neuropsychopharmacology 29:869–878CrossRefPubMedGoogle Scholar
Anneken JH, Cunningham JI, Collins SA, Yamamoto BK, Gudelsky GA (2013) MDMA increases glutamate release and reduces parvalbumin-positive GABAergic cells in the dorsal hippocampus of the rat: role of cyclooxygenase. J NeuroImmune Pharmacol 8:58–65CrossRefPubMedGoogle Scholar
Cadet, JL (1999) Neurotoxicity of drugs of abuse. In: Koliatsos, Vassilis E. (ed) Cell Death and Diseases of the Nervous System, pp 521–526, Humana Press, ISBN 978-1-4612-1602-5Google Scholar
Cadet JL, Krasnova IN, Jayanthi S, Lyles J (2007) Neurotoxicity of substituted amphetamines: molecular and cellular mechanisms. Neurotox Res 11:183–202CrossRefPubMedGoogle Scholar
Cadoni C, Pisanu A, Simola N, Frau L, Porceddu PF, Corongiu S, Dessì C, Sil A, Plumitallo A, Wardas J, Di Chiara G (2017) Widespread reduction of dopamine cell bodies and terminals in adult rats exposed to a low dose regimen of MDMA during adolescence. Neuropharmacology 123:385–394CrossRefPubMedGoogle Scholar
Castelli MP, Madeddu C, Casti A, Casu A, Casti P, Scherma M, Fattore L, Fadda P, Ennas MG (2014) Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity. PLoS One 9:e98079CrossRefPubMedPubMedCentralGoogle Scholar
Colado MI, Camarero J, Mechan AO, Sanchez V, Esteban B, Elliott JM, Green AR (2001) A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurones in mouse brain. Br J Pharmacol 134:1711–1723CrossRefPubMedPubMedCentralGoogle Scholar
Costa G, Frau L, Wardas J, Pinna A, Plumitallo A, Morelli M (2013) MPTP-induced dopamine neuron degeneration and glia activation is potentiated in MDMA-pretreated mice. Mov Disord 28:1957–1965CrossRefPubMedGoogle Scholar
Costa G, Simola N, Morelli M (2014) MDMA administration during adolescence exacerbates MPTP-induced cognitive impairment and neuroinflammation in the hippocampus and prefrontal cortex. Psychopharmacology 231:4007–4018CrossRefPubMedGoogle Scholar
Costa G, Morelli M, Simola N (2017) Progression and persistence of neurotoxicity induced by MDMA in dopaminergic regions of the mouse brain and association with noradrenergic, GABAergic, and serotonergic damage. Neurotox Res 32:563–574CrossRefPubMedGoogle Scholar
Deng X, Cadet JL (1999) Methamphetamine administration causes overexpression of nNOS in the mouse CPu. Brain Res 851:254–257CrossRefPubMedGoogle Scholar
Fox J, Barthold S, Davisson M, Newcomer C, Quimby F, Smith A (2006) The Mouse in Biomedical Research, vol Volume 3. Academic Press, AmsterdamGoogle Scholar
Frau L, Costa G, Porceddu PF, Khairnar A, Castelli MP, Ennas MG, Madeddu C, Wardas J, Morelli M (2016a) Influence of caffeine on 3,4-methylenedioxymethamphetamine-induced dopaminergic neuron degeneration and neuroinflammation is age-dependent. J Neurochem 136:148–162CrossRefPubMedGoogle Scholar
Frau L, Simola N, Porceddu PF, Morelli M (2016b) Effect of crowding, temperature and age on glia activation and dopaminergic neurotoxicity induced by MDMA in the mouse brain. Neurotoxicology 56:127–138CrossRefPubMedGoogle Scholar
Friend DM, Son JH, Keefe KA, Fricks-Gleason AN (2013) Expression and activity of nitric oxide synthase isoforms in methamphetamine-induced striatal dopamine toxicity. J Pharmacol Exp Ther 344:511–521CrossRefPubMedPubMedCentralGoogle Scholar
García-Pardo MP, Rodríguez-Arias M, Miñarro J, Aguilar MA (2017) Role of nitric oxide pathway in the conditioned rewarding effects of MDMA in mice. Behav Brain Res. 330:75–77Google Scholar
Granado N, O'Shea E, Bove J, Vila M, Colado MI, Moratalla R (2008) Persistent MDMA-induced dopaminergic neurotoxicity in the CPu and substantia nigra of mice. J Neurochem 107:1102–1112PubMedGoogle Scholar
Halpin LE, Collins SA, Yamamoto BK (2014) Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine. Life Sci 97:37–44CrossRefPubMedGoogle Scholar
Itzhak Y, Anderson KL, Ali SF (2004) Differential response of nNOS knockout mice to MDMA (“ecstasy”)- and methamphetamine-induced psychomotor sensitization and neurotoxicity. Ann N Y Acad Sci 1025:119–128CrossRefPubMedGoogle Scholar
Itzhak Y, Ali SF (2006) Role of nitrergic system in behavioral and neurotoxic effects of amphetamine analogs. Pharmacol Ther 109:246–262CrossRefPubMedGoogle Scholar
Kiedrowski L, Costa E, Wroblewski JT (1992) Glutamate receptor agonists stimulate nitric oxide synthase in primary cultures of cerebellar granule cells. J Neurochem 58:335–341CrossRefPubMedGoogle Scholar
Moratalla R, Khairnar A, Simola N, Granado N, García-Montes JR, Porceddu PF, Tizabi Y, Costa G, Morelli M (2017) Amphetamine-related drugs neurotoxicity in humans and in experimental animals: main mechanisms. Prog Neurobiol 155:149–170CrossRefPubMedGoogle Scholar
O'Shea E, Urrutia A, Green AR, Colado MI (2014) Current preclinical studies on neuroinflammation and changes in blood-brain barrier integrity by MDMA and methamphetamine. Neuropharmacology 87:125–134CrossRefPubMedGoogle Scholar
Palamar JJ, Acosta P, Ompad DC, Cleland CM (2017) Self-reported ecstasy/“MDMA/Molly” use in a sample of nightclub and dance festival attendees in New York City. Subst Use Misuse 52:82–91CrossRefPubMedGoogle Scholar
Parrott AC (2013a) MDMA, serotonergic neurotoxicity, and the diverse functional deficits of recreational ‘Ecstasy’ users. Neurosci Biobehav Rev 37:1466–1484CrossRefPubMedGoogle Scholar
Parrott AC (2013b) Human psychobiology of MDMA or ‘Ecstasy’: an overview of 25 years of empirical research. Hum Psychopharmacol 28:289–307CrossRefPubMedGoogle Scholar
Paxinos G, Franklin KBJ (2008) The mouse brain in stereotaxic coordinates, Third edn. Academic Press, San DiegoGoogle Scholar
Smirnov A, Najman JM, Hayatbakhsh R, Plotnikova M, Wells H, Legosz M, Kemp R (2013) Young adults’ trajectories of Ecstasy use: a population based study. Addict Behav 38:2667–2674CrossRefPubMedGoogle Scholar