title: Persistent MDMA-induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice.
abstract: Acute administration of repeated doses of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) dramatically reduces striatal dopamine (DA) content, tyrosine hydroxylase (TH), and DA transporter-immunoreactivity in mice. In this study, we show for the first time the spatiotemporal pattern of dopaminergic damage and related molecular events produced by MDMA administration in mice. Our results include the novel finding that MDMA produces a significant decrease in the number of TH-immunoreactive neurons in the substantia nigra (SN). This decrease appears 1 day after injection, remains stable for at least 30 days, and is accompanied by a dose-dependent long-lasting decrease in TH- and DA transporter-immunoreactivity in the striatum, which peaked 1 day after treatment and persisted for at least 30 days, however, some recovery was evident from day 3 onwards, evidencing sprouting of TH fibers. No change is observed in the NAc indicating that MDMA causes selective destruction of DA-containing neurons in the nigrostriatal pathway, sparing the mesolimbic pathway. The expression of Mac-1 increased 1 day after MDMA treatment and glial fibrillary acidic protein increased 3 days post-treatment in the striatum and SN but not in the NAc, in strict anatomical correlation with dopaminergic damage. These data provide the first evidence that MDMA causes persistent loss of dopaminergic cell bodies in the SN.
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Granado
authors.forename: Esther
authors.initials: E
authors.lastname: O'Shea
authors.forename: Jordi
authors.initials: J
authors.lastname: Bove
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
authors.forename: Ma Isabel
authors.initials: MI
authors.lastname: Colado
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D013238:Stereotaxic Techniques; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D016177:Macrophage-1 Antigen; D009498:Neurotoxins; D019001:Nitric Oxide Synthase; D014446:Tyrosine 3-Monooxygenase; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine