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The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons

Capela, Joao Paulo ; Araujo, Silvana da Costa ; Costa, Vera Marisa ; Ruscher, Karsten LU ; Fernandes, Eduarda ; Bastos, Maria de Lourdes ; Dirnagl, Ulrich ; Meisel, Andreas and Carvalho, Felix (2013) In NeuroToxicology 34. p.254-263
Abstract
3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) are hallucinogenic amphetamines with addictive properties. The hippocampus is involved in learning and memory and seems particularly vulnerable to amphetamine's neurotoxicity. We evaluated the neurotoxicity of DOI and MDMA in primary neuronal cultures of hippocampus obtained from Wistar rat embryos (E-17 to E-19). Mature neurons after 10 days in culture were exposed for 24 or 48 h either to MDMA (100-800 mu M) or DOI (10-100 mu M). Both the lactate dehydrogenase (LDH) release and the tetrazolium-based (MTT) assays revealed a concentration- and time-dependent neuronal death and mitochondrial dysfunction after exposure to both drugs.... (More)
3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) are hallucinogenic amphetamines with addictive properties. The hippocampus is involved in learning and memory and seems particularly vulnerable to amphetamine's neurotoxicity. We evaluated the neurotoxicity of DOI and MDMA in primary neuronal cultures of hippocampus obtained from Wistar rat embryos (E-17 to E-19). Mature neurons after 10 days in culture were exposed for 24 or 48 h either to MDMA (100-800 mu M) or DOI (10-100 mu M). Both the lactate dehydrogenase (LDH) release and the tetrazolium-based (MTT) assays revealed a concentration- and time-dependent neuronal death and mitochondrial dysfunction after exposure to both drugs. Both drugs promoted a significant increase in caspase-8 and caspase-3 activities. At concentrations that produced similar levels of neuronal death, DOI promoted a higher increase in the activity of both caspases than MDMA. In the mitochondrial fraction of neurons exposed 24 h to DOI or MDMA, we found a significant increase in the 67 kDa band of apoptosis inducing factor (AIF) by Western blot. Moreover, 24 h exposure to DOI promoted an increase in cytochrome c in the cytoplasmatic fraction of neurons. Pre-treatment with an antibody raised against the 5-HT2A-receptor (an irreversible antagonist) greatly attenuated neuronal death promoted by 48 h exposure to DOI or MDMA. In conclusion, hallucinogenic amphetamines promoted programmed neuronal death involving both the mitochondria machinery and the extrinsic cell death key regulators. Death was dependent, at least in part, on the stimulation of the 5-HT2A-receptors. (C) 2012 Elsevier Inc. All rights reserved. (Less)
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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Hippocampus, Hallucinogens, Amphetamines, MDMA, DOI, 5-HT2A-receptors, Apoptosis, AIF, Caspases
in
NeuroToxicology
volume
34
pages
254 - 263
publisher
Elsevier
external identifiers
  • wos:000314626100027
  • scopus:84872677219
  • pmid:22983118
ISSN
1872-9711
DOI
10.1016/j.neuro.2012.09.005
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Laboratory for Experimental Brain Research (013041000)
id
0e6edba0-e90d-4047-ad80-29434f57a232 (old id 3590078)
date added to LUP
2016-04-01 13:04:04
date last changed
2022-05-19 17:26:36
@article{0e6edba0-e90d-4047-ad80-29434f57a232,
  abstract     = {{3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) are hallucinogenic amphetamines with addictive properties. The hippocampus is involved in learning and memory and seems particularly vulnerable to amphetamine's neurotoxicity. We evaluated the neurotoxicity of DOI and MDMA in primary neuronal cultures of hippocampus obtained from Wistar rat embryos (E-17 to E-19). Mature neurons after 10 days in culture were exposed for 24 or 48 h either to MDMA (100-800 mu M) or DOI (10-100 mu M). Both the lactate dehydrogenase (LDH) release and the tetrazolium-based (MTT) assays revealed a concentration- and time-dependent neuronal death and mitochondrial dysfunction after exposure to both drugs. Both drugs promoted a significant increase in caspase-8 and caspase-3 activities. At concentrations that produced similar levels of neuronal death, DOI promoted a higher increase in the activity of both caspases than MDMA. In the mitochondrial fraction of neurons exposed 24 h to DOI or MDMA, we found a significant increase in the 67 kDa band of apoptosis inducing factor (AIF) by Western blot. Moreover, 24 h exposure to DOI promoted an increase in cytochrome c in the cytoplasmatic fraction of neurons. Pre-treatment with an antibody raised against the 5-HT2A-receptor (an irreversible antagonist) greatly attenuated neuronal death promoted by 48 h exposure to DOI or MDMA. In conclusion, hallucinogenic amphetamines promoted programmed neuronal death involving both the mitochondria machinery and the extrinsic cell death key regulators. Death was dependent, at least in part, on the stimulation of the 5-HT2A-receptors. (C) 2012 Elsevier Inc. All rights reserved.}},
  author       = {{Capela, Joao Paulo and Araujo, Silvana da Costa and Costa, Vera Marisa and Ruscher, Karsten and Fernandes, Eduarda and Bastos, Maria de Lourdes and Dirnagl, Ulrich and Meisel, Andreas and Carvalho, Felix}},
  issn         = {{1872-9711}},
  keywords     = {{Hippocampus; Hallucinogens; Amphetamines; MDMA; DOI; 5-HT2A-receptors; Apoptosis; AIF; Caspases}},
  language     = {{eng}},
  pages        = {{254--263}},
  publisher    = {{Elsevier}},
  series       = {{NeuroToxicology}},
  title        = {{The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons}},
  url          = {{http://dx.doi.org/10.1016/j.neuro.2012.09.005}},
  doi          = {{10.1016/j.neuro.2012.09.005}},
  volume       = {{34}},
  year         = {{2013}},
}