PMID- 23209329
OWN - NLM
STAT- MEDLINE
DCOM- 20130328
LR  - 20211021
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 344
IP  - 2
DP  - 2013 Feb
TI  - Studies of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) metabolism and 
      disposition in rats and mice: relationship to neuroprotection and neurotoxicity 
      profile.
PG  - 479-88
LID - 10.1124/jpet.112.201699 [doi]
AB  - The neurotoxicity of (+/-)-3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") is 
      influenced by temperature and varies according to species. The mechanisms 
      underlying these two features of MDMA neurotoxicity are unknown, but differences 
      in MDMA metabolism have recently been implicated in both. The present study was 
      designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine 
      whether the neuroprotective effect of hypothermia is related to inhibition of 
      MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and 
      rats are related to differences in MDMA metabolism and/or disposition in the two 
      species. Rats and mice received single neurotoxic oral doses of MDMA at 25 degrees C and 
      4 degrees C, and body temperature, pharmacokinetic parameters, and serotonergic and 
      dopaminergic neuronal markers were measured. Hypothermia did not alter MDMA 
      metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, 
      it afforded complete neuroprotection in both species. Rats and mice metabolized 
      MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major 
      metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 
      3,4-dihydroxymethamphetamine, respectively. Differences between MDMA 
      pharmacokinetics in rats and mice, including faster elimination in mice, did not 
      account for the different profile of MDMA neurotoxicity in the two species. Taken 
      together, the results of these studies indicate that inhibition of MDMA 
      metabolism is not responsible for the neuroprotective effect of hypothermia in 
      rodents, and that different neurotoxicity profiles in rats and mice are not 
      readily explained by differences in MDMA metabolism or disposition.
FAU - Mueller, Melanie
AU  - Mueller M
AD  - Department of Neurology, Johns Hopkins University, 5501 Hopkins Bayview Circle, 
      Baltimore, MD 21224, USA.
FAU - Maldonado-Adrian, Concepcion
AU  - Maldonado-Adrian C
FAU - Yuan, Jie
AU  - Yuan J
FAU - McCann, Una D
AU  - McCann UD
FAU - Ricaurte, George A
AU  - Ricaurte GA
LA  - eng
GR  - R01 DA005707/DA/NIDA NIH HHS/United States
GR  - R01 DA025686/DA/NIDA NIH HHS/United States
GR  - DA05707/DA/NIDA NIH HHS/United States
GR  - DA01796401/DA/NIDA NIH HHS/United States
GR  - F32 DA005707/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20121203
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 333DO1RDJY (Serotonin)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Biotransformation
MH  - Body Temperature
MH  - Brain/drug effects/metabolism
MH  - Dopamine/metabolism
MH  - Dose-Response Relationship, Drug
MH  - *Hypothermia, Induced
MH  - Male
MH  - Mice
MH  - Mice, Inbred Strains
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*metabolism/pharmacokinetics/toxicity
MH  - Neurons/drug effects/metabolism
MH  - Neurotoxicity Syndromes/etiology/*metabolism/*prevention & control
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Serotonin/metabolism
MH  - Species Specificity
MH  - Time Factors
MH  - Tissue Distribution
PMC - PMC3558829
EDAT- 2012/12/05 06:00
MHDA- 2013/03/30 06:00
PMCR- 2014/02/01
CRDT- 2012/12/05 06:00
PHST- 2012/12/05 06:00 [entrez]
PHST- 2012/12/05 06:00 [pubmed]
PHST- 2013/03/30 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - jpet.112.201699 [pii]
AID - JPET_201699 [pii]
AID - 10.1124/jpet.112.201699 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2013 Feb;344(2):479-88. doi: 10.1124/jpet.112.201699. Epub 
      2012 Dec 3.