Glutathione and N-Acetylcysteine Conjugates of α-Methyldopamine Produce Serotonergic Neurotoxicity: Possible Role in Methylenedioxyamphetamine-Mediated Neurotoxicity
Fengju Bai, Serrine S. Lau, Terrence J. Monks
Chemical Research in Toxicology November 19, 1999 DOI: 10.1021/tx990084t (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rat brain (striatum, cortex, hippocampus, midbrain/diencephalon/telencephalon, pons/medulla) |
| Interventions | 5-(glutathion-S-yl)-alpha-methyldopamine 5-(N-acetylcystein-S-yl)-alpha-methyldopamine 2 5-bis(glutathion-S-yl)-alpha-methyldopamine |
| Dose | 4 x 200 or 4 x 400 nmol for 5-(glutathion-S-yl)-alpha-MeDA; 4 x 7 or 4 x 20 nmol for 5-(N-acetylcystein-S-yl)-alpha-MeDA; 4 x 150 or 4 x 300 nmol for 2,5-bis(glutathion-S-yl)-alpha-MeDA |
| Duration | 7 days after the last injection |
| Measures | serotonin (5-HT) concentrations, dopamine concentrations, norepinephrine concentrations |
| Topics | MDMA Serotonin |
| Keywords | Neurotoxicity Pharmacology Glutathione Dopamine Striatum Metabolite |
| Citations | 109 |
| Key findings | Thioether conjugates of alpha-MeDA, particularly 5-(glutathion-S-yl)-alpha-MeDA, 5-(N-acetylcystein-S-yl)-alpha-MeDA, and 2,5-bis(glutathion-S-yl)-alpha-MeDA, cause selective long-term decreases in serotonin concentrations in rat striatum and cortex when injected directly, without affecting dopamine or norepinephrine levels. |
Abstract
Direct injection of either 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) or 3,4-(+/-)-methylenedioxyamphetamine (MDA) into the brain fails to reproduce the serotonergic neurotoxicity seen following peripheral administration. The serotonergic neurotoxicity of MDA and MDMA therefore appears to be dependent upon the generation of a neurotoxic metabolite, or metabolites, the identity of which remains unclear. alpha-Methyldopamine (alpha-MeDA) is a major metabolite of both MDA and MDMA. We have shown that intracerebroventricular (icv) injection of 2,5-bis(glutathion-S-yl)-alpha-methyldopamine [2, 5-bis(glutathion-S-yl)-alpha-MeDA] causes decreases in serotonin concentrations in the striatum, cortex, and hippocampus, and neurobehavioral effects similar to those seen following MDA and MDMA administration. In contrast, although 5-(glutathion-S-yl)-alpha-methyldopamine [5-(glutathion-S-yl)-alpha-MeDA] and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine [5-(N-acetylcystein-S-yl)-alpha-MeDA] produce neurobehavioral changes similar to those seen with MDA and MDMA, and acute changes in brain 5-HT and dopamine concentrations, neither conjugate caused long-term decreases in 5-HT concentrations. We now report that direct intrastriatal or intracortical administration of 5-(glutathion-S-yl)-alpha-MeDA (4 x 200 or 4 x 400 nmol), 5-(N-acetylcystein-S-yl)-alpha-MeDA (4 x 7 or 4 x 20 nmol), and 2, 5-bis(glutathion-S-yl)-alpha-MeDA (4 x 150 or 4 x 300 nmol) causes significant decreases in striatal and cortical 5-HT concentrations (7 days following the last injection). Interestingly, intrastriatal injection of 5-(glutathion-S-yl)-alpha-MeDA or 2, 5-bis(glutathion-S-yl)-alpha-MeDA, but not 5-(N-acetylcystein-S-yl)-alpha-methyldopamine, also caused decreases in 5-HT concentrations in the ipsilateral cortex. The same pattern of changes was seen when the conjugates were injected into the cortex. The effects of the thioether conjugates of alpha-MeDA were confined to 5-HT nerve terminal fields, since no significant changes in monoamine neurotransmitter levels were detected in brain regions enriched with 5-HT cell bodies (midbrain/diencephalon/telencephalon and pons/medulla). In addition, the effects of the conjugates were selective with respect to the serotonergic system, as no significant changes were seen in dopamine or norepinephrine concentrations. The results indicate that thioether conjugates of alpha-MeDA are selective serotonergic neurotoxicants. Nonetheless, a role for these conjugates in the toxicity observed following systemic administration of MDA and MDMA remains to be demonstrated, and requires further experimentation.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 45
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- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity Therapeutic Drug Monitoring March 19, 2004
- The mechanisms involved in the long‐lasting neuroprotective effect of fluoxetine against MDMA (‘ecstasy’)‐induced degeneration of 5‐HT nerve endings in rat brain British Journal of Pharmacology September 1, 2001
- Metabolism Is Required for the Expression of Ecstasy-Induced Cardiotoxicity in Vitro Chemical Research in Toxicology April 27, 2004
and 40 more in the library
Cites 18
- Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Journal of Neuroscience August 1, 1988
- 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Journal of Pharmacology and Experimental Therapeutics September 1, 1987
- Hallucinogenic Amphetamine Selectively Destroys Brain Serotonin Nerve Terminals Science September 6, 1985
- Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors Brain Research October 1, 1990
- Increasing Use of “Ecstasy“ (MDMA) and other Hallucinogens on a College Campus Journal of American College Health May 1, 1994
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