2009 mol neurobiol

Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview João Paulo Capela & Helena Carmo & Fernando Remião & Maria Lourdes Bastos & Andrea s Meisel & Félix Carvalho Received: 1 Decem ber 2008 / Accep ted: 27 Febru ary 2009 / Published online: 17 Apri l 2009 # Humana Pres s Inc. 2009 Abstract “Ecstasy” [(±)-3,4-methylenedioxymethamphet- amine, MDMA, XTC, X, E] is a psych oactive recrea tiona l hallucinogenic substance and a major worldwide drug of abuse. Several reports raised the concern that MDMA has the ability to induce neurotoxic effects both in laboratory animals and humans. Despite more than two decades of research, the mechanisms by which MDMA is neurotoxic are still to be fully elucidated. MDMA induces serotonergic terminal loss in rats and also in some mice strai ns, but also a broader neuronal degeneration throughout several brain areas such as the cor tex , hi ppo campus , and st ria tum. Meanwh ile, in human “ecstasy” abusers, there are eviden- ces for deficits in seronergic biochemical markers, which cor rel ate with lon g-t erm impai rme nts in memory and learni ng. There are seve ral factors tha t contri but e to MDMA-induced neurotoxi city , namel y, hyper thermia, monoamine oxidase metabolism of dopamine and serotonin, dopamine oxidation, the serotonin transporter action, nitric oxide, and the formation of peroxinitrite, glutamate excitotoxicity, serotonin 2A receptor agonism, and, impor- tant ly, the formation of MDMA neurotoxic metaboli tes. The present review covered the following topics: history and epidemiology, pharmacological mechanisms, metabolic pathways and the influence of isoenzyme genetic poly- mo rphisms, as we ll as the acut e ef fects of MDMA in laboratory animals and humans, with a special focus on MDMA-in duce d neur otoxic effe cts at the cell ular and mo lecular le vel. The main ai m of th is review wa s to contribute to the understanding of the cellular and molecular mechanisms involved in MDMA neurotoxicity, which can help in the development of therapeutic approaches to prevent or treat the long-term neuropsychiatric complica- tions of MDMA abuse in humans. Keywords Ecstasy . MDMA . Dru g abuse . Hallucinogen . Neurotoxicity . Mecha nism of neurod egener atio n Abbreviations Amph Amphetamine AMPT α -Methyl- p-tyrosine A TP Adenosine triphos ph a te AUC Area under the curve C max Maximum concentration CNS Central nervous system COMT Catechol-O-methyltransferase CSF Cerebrospinal fluid CTX Cortex CYP Cytochrome P450 DA Dopamine DA T Dopam ine transporter DHT Dihydroxytri ptamine Mol Neurobiol (2009) 39:210 – 271 DOI 10.1007/s12035-009-8064-1 J. P. Capela : H. Carmo : F. Remião : M. L. Bastos : F. Carvalho (*) REQUIMTE (Rede de Química e Tecnologia), Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha 164, 4099-030 Porto, Portugal e-mail: [email protected] J. P. Capela (*) Faculty of Health Sciences, University Fernando Pessoa, Rua Carlos da Maia 296, 4200-150 Porto, Portugal e-mail: [email protected] A. Meisel Department of Experimental Neurology and Center for Stroke Research, Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany

2009 mol neurobiol

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