PMID- 8602874
OWN - NLM
STAT- MEDLINE
DCOM- 19960509
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 51
IP  - 6
DP  - 1996 Mar 22
TI  - Disposition of methylenedioxymethamphetamine and three metabolites in the brains 
      of different rat strains and their possible roles in acute serotonin depletion.
PG  - 789-96
AB  - 3,4-Methylenedioxymethamphetamine (MDMA) affects both dopamine and serotonin 
      (5-HT) systems. One of its acute actions is to cause a reversible fall in 
      steady-state brain 5-HT concentrations. To investigate the chemical basis of this 
      acute effect, the brain levels of the parent compound and three major 
      metabolites, 3,4- 3,4-methylenedioxyamphetamine (MDA), 
      3,4-dihydroxymethamphetamine (DHMA) and 
      6-hydroxy-3,4-methylenedioxymethamphetamine (6-OHMDMA), were monitored, together 
      with 5-HT levels, over a period of 6 hr in male Sprague-Dawley (SD) rats. The 
      temporal relationships between drug concentrations of both stereoisomers and 
      depletions were evaluated first. There was no correlation between the 
      concentrations of the compounds measured and the extent of 5-HT depletion. Brain 
      levels of MDMA and MDA were higher than plasma levels and exhibited a 
      stereoselectivity in that (-)-MDMA and (+)-MDA levels were higher than those of 
      enantiomers. The relationship between the dose of ((+)-MDMA and reduction in 5-HT 
      levels was next investigated in SD male, SD female, and Dark Agouti (DA) female 
      rats. These animals exhibit different capabilities of MDMA metabolism. There is a 
      lower level of MDA, the N-demethylated metabolite of MDMA, in female SD rats than 
      in males. Female DA rats are deficient in CYP2D isozymes, one of the enzymes 
      responsible for demethylenation of MDMA to DHMA at pharmacological concentrations 
      of substrate. there was a significant accuulation of MDMA in the brain and plasma 
      of DA rats, but their 5-HT depletion was somewhat attenuated. The results 
      indicated that MDMA ++ was apparently not the single, causative agent for the 
      acute 5-HT depletion, which may also involve a metabolite formed by CYP2D.
FAU - Chu, T
AU  - Chu T
AD  - Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los 
      Angeles, CA 90095-1735, USA.
FAU - Kumagai, Y
AU  - Kumagai Y
FAU - DiStefano, E W
AU  - DiStefano EW
FAU - Cho, A K
AU  - Cho AK
LA  - eng
GR  - DA 04206/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Hallucinogens)
RN  - 136706-34-8 (6-hydroxy-N-methyl-3,4-methylenedioxyamphetamine)
RN  - 333DO1RDJY (Serotonin)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/analogs & derivatives/metabolism
MH  - Animals
MH  - Brain/*drug effects/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Hallucinogens/metabolism/*pharmacokinetics/*pharmacology
MH  - Male
MH  - Methylation
MH  - N-Methyl-3,4-methylenedioxyamphetamine/metabolism/*pharmacokinetics/*pharmacology
MH  - Rats
MH  - Rats, Inbred Strains
MH  - Rats, Sprague-Dawley
MH  - Serotonin/*metabolism
MH  - Sex Factors
MH  - Species Specificity
MH  - Stereoisomerism
EDAT- 1996/03/22 00:00
MHDA- 1996/03/22 00:01
CRDT- 1996/03/22 00:00
PHST- 1996/03/22 00:00 [pubmed]
PHST- 1996/03/22 00:01 [medline]
PHST- 1996/03/22 00:00 [entrez]
AID - 0006-2952(95)02397-6 [pii]
AID - 10.1016/0006-2952(95)02397-6 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 1996 Mar 22;51(6):789-96. doi: 10.1016/0006-2952(95)02397-6.