title: Effect of 3,4-methylenedioxyamphetamine on dendritic spine dynamics in rat neocortical neurons--involvement of heat shock protein 27.
abstract: Along with chronic neurotoxic effects, the long-term consumption of amphetamines has been associated to psychiatric symptoms and memory disturbances. Dendritic spine dynamics have been discussed as a possible morphological correlate. However, the underlying mechanisms are still elusive. 3,4-Methylenedioxyamphetamine (MDA), a major drug of abuse and a main metabolite after 3,4-methylenedioxymethamphetamine (MDMA) intake, provokes a loss of dendritic spine-like protrusions in primary cultures of rat cortical neurons. 3,4-Methylenedioxyamphetamine also induced a rapid activation of the p38 mitogen activated protein kinase (p38 MAPK) pathway and phosphorylation of heat shock protein 27 (hsp27) indicative for its decreased chaperone activity. Concurrent pharmacological inhibition of the p38 MAPK by SB203580 abolished hsp27 phosphorylation and diminished the loss of dendritic spine-like protrusions. Moreover, upon MDA treatment dendritic spine-like protrusions were stabilized in neurons constitutively expressing hsp27. In parallel experiments we observed a robust activation of the heat shock transcription factor 1 (HSF-1) and a subsequent increase of hsp27 and hsp70. The regulation of small heat shock proteins corroborates the existence of a neuronal stress response after MDA treatment. Pharmacological targeting of small heat shock protein phosphorylation may provide a new strategy to preserve spine integrity after amphetamine exposure.
authors.affiliation: Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University, BMC A13, S-22184 Lund, Sweden. karsten.ruscher@med.lu.se
authors.forename: Karsten
authors.initials: K
authors.lastname: Ruscher
authors.forename: Eduarda
authors.initials: E
authors.lastname: Fernandes
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Capela
authors.forename: Maria de Lourdes
authors.initials: Mde L
authors.lastname: Bastos
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wieloch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006213:Hallucinogens / Q000633:toxicity; D056004:Molecular Dynamics Simulation; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism / Q000633:toxicity; D019579:Neocortex / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
chemical_list: D055551:HSP27 Heat-Shock Proteins; D006213:Hallucinogens; D009498:Neurotoxins; D015104:3,4-Methylenedioxyamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine