PMID- 14673567
OWN - NLM
STAT- MEDLINE
DCOM- 20041122
LR  - 20181113
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 173
IP  - 3-4
DP  - 2004 May
TI  - DNA damage and ubiquitinated neuronal inclusions in the substantia nigra and 
      striatum of mice following MDMA (ecstasy).
PG  - 353-63
AB  - RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, 
      which is neurotoxic to both serotonin (5HT) and dopamine (DA) nerve terminals. 
      Previous reports, carried out in rodents and non-human primates, demonstrated 
      neurotoxicity to monoamine axon terminals, although no study has analyzed nigral 
      and striatal cell bodies at the sub-cellular level. OBJECTIVE: In this study, we 
      examined intrinsic nigral and striatal cells, and PC12 cell cultures to evaluate 
      whether, in mice, MDMA might affect nigral and striatal cell bodies. METHODS: 
      After administering MDMA, we analyzed effects induced in vivo and in vitro using 
      high-performance liquid chromatography (HPLC) analysis, light- and electron 
      microscopy with immunocytochemistry, and DNA comet assay. RESULTS: We found that 
      MDMA (5 mg/kg x4, 2 h apart), besides a decrease of nigrostriatal DA innervation 
      and 5HT loss, produces neuronal inclusions within nigral and intrinsic striatal 
      neurons consisting of multi-layer ubiquitin-positive whorls extending to the 
      nucleus of the cell. These fine morphological changes are associated with 
      clustering of heat shock protein (HSP)-70 in the nucleus, very close to chromatin 
      filaments. In the same experimental conditions, we could detect oxidation of DNA 
      bases followed by DNA damage. The nature of inclusions was further investigated 
      using PC12 cell cultures. CONCLUSIONS: The present findings lead to 
      re-consideration of the neurotoxic consequences of MDMA administration. In fact, 
      occurrence of ubiquitin-positive neuronal inclusions and DNA damage both in 
      nigral and striatal cells sheds new light into the fine alterations induced by 
      MDMA, also suggesting the involvement of nuclear and cytoplasmic components of 
      the ubiquitin-proteasome pathway in MDMA toxicity.
FAU - Fornai, F
AU  - Fornai F
AD  - Department of Human Morphology and Applied Biology, University of Pisa, 56126 
      Pisa, Italy. f.fornai@med.unipi.it
FAU - Lenzi, P
AU  - Lenzi P
FAU - Frenzilli, G
AU  - Frenzilli G
FAU - Gesi, M
AU  - Gesi M
FAU - Ferrucci, M
AU  - Ferrucci M
FAU - Lazzeri, G
AU  - Lazzeri G
FAU - Biagioni, F
AU  - Biagioni F
FAU - Nigro, M
AU  - Nigro M
FAU - Falleni, A
AU  - Falleni A
FAU - Giusiani, M
AU  - Giusiani M
FAU - Pellegrini, A
AU  - Pellegrini A
FAU - Blandini, F
AU  - Blandini F
FAU - Ruggieri, S
AU  - Ruggieri S
FAU - Paparelli, A
AU  - Paparelli A
LA  - eng
PT  - Journal Article
DEP - 20031213
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Serotonin Agents)
RN  - 0 (Ubiquitin)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Corpus Striatum/*drug effects/metabolism/pathology
MH  - *DNA Damage
MH  - Dopamine/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Neurons/*metabolism/ultrastructure
MH  - PC12 Cells
MH  - Rats
MH  - Serotonin Agents/*toxicity
MH  - Substantia Nigra/*drug effects/metabolism/pathology
MH  - Ubiquitin/*metabolism
EDAT- 2003/12/16 05:00
MHDA- 2004/12/16 09:00
CRDT- 2003/12/16 05:00
PHST- 2003/08/26 00:00 [received]
PHST- 2003/11/04 00:00 [accepted]
PHST- 2003/12/16 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2003/12/16 05:00 [entrez]
AID - 10.1007/s00213-003-1708-3 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2004 May;173(3-4):353-63. doi: 
      10.1007/s00213-003-1708-3. Epub 2003 Dec 13.