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.