Synthesis, in vitro formation, and behavioural effects of glutathione regioisomers of alpha-methyldopamine with relevance to MDA and MDMA (ecstasy).
Neil Easton, Jeff Fry, Esther O'Shea, Adam Watkins, Shaun Kingston, Charles A Marsden
Brain Research October 17, 2003 DOI: 10.1016/s0006-8993(03)03319-5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Dark Agouti and Sprague-Dawley rats |
| Interventions | 5-(glutathion-S-yl)-alpha-MeDA 6-(glutathion-S-yl)-alpha-MeDA haloperidol |
| Dose | 180 nmol (glutathione adducts); 0.25 mg/kg (haloperidol) |
| Topics | MDMA |
| Key points | MDA is converted by human liver microsomes into two glutathione regioisomers, 5-(glutathion-S-yl)-alpha-MeDA and 6-(glutathion-S-yl)-alpha-MeDA, in a process related to cytochrome P450 2D6 activity. After intracerebroventricular administration in rats, only the 5-(glutathion-S-yl)-alpha-MeDA adduct produced behavioral effects including hyperactivity, teeth chattering, tremor, head weaving, splayed posture, clonus, and wet dog shakes. Haloperidol pretreatment attenuated several of these behaviors but potentiated splayed posture. |
Abstract
Administration of 3,4-methylenedioxymethamphetamine (MDMA) or 3,4-methylenedioxyamphetamine (MDA) to rats produces serotonergic nerve terminal degeneration. However, they are not neurotoxic when injected directly into the brain, suggesting the requirement for peripheral metabolism of MDMA to a neurotoxic metabolite. Alpha-methyldopamine (alpha-MeDA) is a major metabolite of MDA. There are indications that a glutathione metabolite of alpha-MeDA and/or 3,4-dihydroxymethamphetamine may be responsible for the neurotoxicity and some of the behavioural effects produced by MDMA and/or MDA. The present study details the synthesis, purification and separation of the 5-(glutathion-S-yl)-alpha-MeDA and 6-(glutathion-S-yl)-alpha-MeDA regioisomers of alpha-MeDA. Incubation of MDA with human liver microsomes demonstrated that production of both glutathione adducts are related to cytochrome P450 2D6 isoform activity. Following intracerebroventricular administration (180 nmol) of either GSH adduct into Dark Agouti or Sprague-Dawley rats only 5-(glutathion-S-yl)-alpha-MeDA produced behavioural effects characterised by hyperactivity, teeth chattering, tremor/trembling, head weaving, splayed posture, clonus and wet dog shakes. Pre-treatment with a dopamine receptor antagonist (haloperidol, 0.25 mg/kg; i.p.) attenuated hyperactivity, teeth chattering, low posture and clonus and potentiated splayed postural effects. These results indicate that MDA can be converted into two glutathione regioisomers by human liver microsomes, but only the 5-(glutathion-S-yl)-alpha-MeDA adduct is behaviourally active in the rat.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 10
- Psychedelic Therapy: A Primer for Primary Care Clinicians-3,4-Methylenedioxy-methamphetamine (MDMA). American Journal of Therapeutics
- Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms. Progress in Neurobiology August 2017
- Mixtures of 3,4‐methylenedioxymethamphetamine (ecstasy) and its major human metabolites act additively to induce significant toxicity to liver cells when combined at low, non‐cytotoxic concentrations Journal of Applied Toxicology June 1, 2014
- Neurotoxicity of "ecstasy" and its metabolites in human dopaminergic differentiated SH-SY5Y cells. Toxicology Letters February 4, 2013
- Lost in translation: preclinical studies on 3,4‐methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans British Journal of Pharmacology July 1, 2012
and 5 more in the library
Cites 24
- Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Journal of Neuroscience August 1, 1988
- In vivo evidence for free radical involvement in the degeneration of rat brain 5‐HT following administration of MDMA (‘ecstasy’) and p‐chloroamphetamine but not the degeneration following fenfluramine British Journal of Pharmacology July 1, 1997
- The hyperthermic and neurotoxic effects of ‘Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype British Journal of Pharmacology August 1, 1995
- In vivo detection of short- and long-term MDMA neurotoxicity?a positron emission tomography study in the living baboon brain Synapse June 1, 1998
- 5‐HT loss in rat brain following 3, 4‐methylenedioxymethamphetamine (MDMA), p‐chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine British Journal of Pharmacology March 1, 1993
and 19 more in the library