Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion.
T Chu, Y Kumagai, E W DiStefano, A K Cho
Biochemical Pharmacology March 1, 1996 DOI: 10.1016/0006-2952(95)02397-6 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational animal study Peer reviewed |
|---|---|
| Population | Male Sprague-Dawley rats, plus male and female Sprague-Dawley and female Dark Agouti rats |
| Interventions | 3 4-Methylenedioxymethamphetamine (MDMA) |
| Duration | 6 hr monitoring period |
| Topics | Serotonin MDMA |
| Keywords | Brain Animals Rats, inbred strains Rats, sprague-dawley N-methyl-3,4-methylenedioxyamphetamine Hallucinogens Sex factors Species specificity Methylation Dose-response relationship, drug Stereoisomerism Female |
| Key findings | Brain MDMA and MDA levels did not correlate with the extent of acute 5-HT depletion, and Dark Agouti rats accumulated more MDMA yet showed somewhat attenuated depletion. The authors conclude that MDMA is apparently not the single causative agent for acute 5-HT depletion and propose that a metabolite formed by CYP2D may also be involved. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 63
- Human Pharmacology of MDMA Therapeutic Drug Monitoring March 19, 2004
- 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings Psychopharmacology March 15, 2006
- Toxicokinetics of Amphetamines: Metabolism and Toxicokinetic Data of Designer Drugs, Amphetamine, Methamphetamine, and Their N-Alkyl Derivatives Therapeutic Drug Monitoring April 1, 2002
- The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity Therapeutic Drug Monitoring March 19, 2004
- Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine ACS Chemical Neuroscience July 12, 2018
and 58 more in the library
Cites 13
- The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proceedings of the National Academy of Sciences March 1, 1992
- Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Journal of Pharmacology and Experimental Therapeutics 1987
- Enzymic and chemical demethylenation of (methylenedioxy)amphetamine and (methylenedioxy)methamphetamine by rat brain microsomes Chemical Research in Toxicology May 1, 1992
- Drug effects on distribution of [3H]3,4-methylenedioxymethamphetamine in mice. European Journal of Pharmacology April 1, 1993
- Effects of 3,4-dihydroxymethamphetamine and 2,4,5-trihydroxymethamphetamine, two metabolites of 3,4-methylenedioxymethamphetamine, on central serotonergic and dopaminergic systems. Journal of Pharmacology and Experimental Therapeutics May 1, 1992
and 8 more in the library