Serotonergic Neurotoxicity of 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylendioxymethamphetamine (Ecstasy) Is Potentiated by Inhibition of γ-Glutamyl Transpeptidase
Fengju Bai, Douglas C. Jones, Serrine S. Lau, Terrence J. Monks
Chemical Research in Toxicology May 31, 2001 DOI: 10.1021/tx010011l (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | acivicin MDA MDMA |
| Dose | 18 mg/kg acivicin, 10 mg/kg MDA |
| Topics | Serotonin MDMA |
| Keywords | Glutathione Neurotoxicity Pharmacology Biochemistry Endocrinology |
| Citations | 56 |
| Key findings | Inhibiting gamma-glutamyl transpeptidase at the blood-brain barrier potentiates MDA- and MDMA-mediated depletions of serotonin and 5-HIAA in brain regions, indicating that thioether metabolites contribute to serotonergic neurotoxicity. |
Abstract
Reactive metabolites play an important role in 3,4-(+/-)-methylenedioxyamphetamine (MDA) and 3,4-(+/-)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of such metabolites remains unclear. 5-(Glutathion-S-yl)-alpha-methyldopamine (5-GSyl-alpha-MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-alpha-MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of gamma-glutamyl transpeptidase (gamma-GT) suggesting competition between intact 5-GSyl-alpha-MeDA and GSH for the putative GSH transporter. gamma-GT is enriched in blood-brain barrier endothelial cells and is the only enzyme known to cleave the gamma-glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial gamma-GT activity by 60%, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid (5-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell gamma-GT at the blood-brain barrier likely enhances the uptake into brain of thioether metabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-alpha-MeDA and 2,5-bis-(glutathion-S-yl)-alpha-MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 26
- 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings Psychopharmacology March 15, 2006
- The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity Therapeutic Drug Monitoring March 19, 2004
- 3,4‐methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein Synapse July 14, 2004
- Metabolism Is Required for the Expression of Ecstasy-Induced Cardiotoxicity in Vitro Chemical Research in Toxicology April 27, 2004
- Mechanisms of MDMA (Ecstasy)-Induced Oxidative Stress, Mitochondrial Dysfunction, and Organ Damage Current Pharmaceutical Biotechnology June 27, 2010
and 21 more in the library
Cites 6
- Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings The Lancet October 1, 1998
- Memory impairment in abstinent MDMA ("Ecstasy") users Neurology December 1, 1998
- Human Research on MDMA (3,4-Methylene- dioxymethamphetamine) Neurotoxicity: Cognitive and Behavioural Indices of Change Neuropsychobiology 2000
- Glutathione and N-Acetylcysteine Conjugates of α-Methyldopamine Produce Serotonergic Neurotoxicity: Possible Role in Methylenedioxyamphetamine-Mediated Neurotoxicity Chemical Research in Toxicology November 19, 1999
- Effects of Intracerebroventricular Administration of 5-(Glutathion-S-yl)-α-methyldopamine on Brain Dopamine, Serotonin, and Norepinephrine Concentrations in Male Sprague-Dawley Rats Chemical Research in Toxicology 1996
and 1 more in the library