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The Journal of Neuroscience, March 19, 2008, 28(12):3234-3245; doi:10.1523/JNEUROSCI.0159-08.2008
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Neurobiology of Disease
Enhanced Tau Phosphorylation in the Hippocampus of Mice Treated with 3,4-Methylenedioxymethamphetamine ("Ecstasy")
Carla L. Busceti,1 * Francesca Biagioni,1 * Barbara Riozzi,1 Giuseppe Battaglia,1 Marianna Storto,1 Carlo Cinque,2 Gemma Molinaro,1 Roberto Gradini,3 Andrea Caricasole,4 Anna Maria Canudas,5 Valeria Bruno,1,2 Ferdinando Nicoletti,1,2 andFrancesco Fornai1,6 1Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy, 2Departments of Human Physiology and Pharmacology and 3Experimental Medicine, University "La Sapienza," 00185 Rome, Italy, 4Siena Biotech, 53100 Siena, Italy, 5Unit of Pharmacology and Pharmacognosy, School of Pharmacy, University of Barcelona, 08028 Barcelona, Spain, and 6Department of Human Morphology and Applied Biology, University of Pisa, 56126 Pisa, Italy
Correspondence should be addressed to Dr. Ferdinando Nicoletti, Department of Human Physiology and Pharmacology, Piazzale Aldo Moro, 5, 00185 Rome, Italy. Email: ferdinandonicoletti{at}hotmail.com
3,4-Methylenedioxymethamphetamine (MDMA) ("Ecstasy") produces neurotoxic effects, which result into an impairment of learning and memory and other neurological dysfunctions. We examined whether MDMA induces increases in tau protein phosphorylation, which are typically associated with Alzheimer's disease and other chronic neurodegenerative disorders. We injected mice with MDMA at cumulative doses of 10–50 mg/kg intraperitoneally, which are approximately equivalent to doses generally consumed by humans. MDMA enhanced the formation of reactive oxygen species and induced reactive gliosis in the hippocampus, without histological evidence of neuronal loss. An acute or 6 d treatment with MDMA increased tau protein phosphorylation in the hippocampus, revealed by both anti-phospho(Ser404)-tau and paired helical filament-1 antibodies. This increase was restricted to the CA2/CA3 subfields and lasted 1 and 7 d after acute and repeated MDMA treatment, respectively. Tau protein was phosphorylated as a result of two nonredundant mechanisms: (1) inhibition of the canonical Wnt (wingless-type MMTV integration site family) pathway, with ensuing activation of glycogen synthase kinase-3β; and (2) activation of type-5 cyclin-dependent kinase (Cdk5). MDMA induced the expression of the Wnt antagonist, Dickkopf-1, and the expression of the Cdk5-activating protein, p25. In addition, the increase in tau phosphorylation was attenuated by strategies that rescued the Wnt pathway or inhibited Cdk5. Finally, an impairment in hippocampus-dependent spatial learning was induced by doses of MDMA that increased tau phosphorylation, although the impairment outlasted this biochemical event. We conclude that tau hyperphosphorylation in the hippocampus may contribute to the impairment of learning and memory associated with MDMA abuse.
Key words: MDMA; tau phosphorylation; dickkopf-1; Cdk5; hippocampus; neurotoxicity
Received Aug. 9, 2007; revised Feb. 6, 2008; accepted Feb. 7, 2008.
Correspondence should be addressed to Dr. Ferdinando Nicoletti, Department of Human Physiology and Pharmacology, Piazzale Aldo Moro, 5, 00185 Rome, Italy. Email: ferdinandonicoletti{at}hotmail.com
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