Effects of Intracerebroventricular Administration of 5-(Glutathion-S-yl)-α-methyldopamine on Brain Dopamine, Serotonin, and Norepinephrine Concentrations in Male Sprague-Dawley Rats
R. Timothy Miller, Serrine S. Lau, Terrence J. Monks
Chemical Research in Toxicology 1996 DOI: 10.1021/tx9501546 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male Sprague-Dawley rats |
| Intervention | 5-(glutathion-S-yl)-alpha-methyldopamine |
| Dose | 720 nmol |
| Topics | MDMA Serotonin |
| Keywords | Neurochemical Dopaminergic Glutathione Pharmacology Norepinephrine Methamphetamine Endocrinology |
| Citations | 63 |
| Key findings | A single intracerebroventricular injection of 5-(glutathion-S-yl)-alpha-methyldopamine in rats produced acute behavioral and neurochemical changes similar to MDA but did not cause long-term serotonergic toxicity. |
Abstract
alpha-Methyldopamine (alpha-MeDA) is a metabolite of the serotonergic neurotoxicants 3,4-(+/-)-(methylenedioxy)amphetamine (MDA) and 3,4-(+/-)-(methylenedioxy)methamphetamine (MDMA). alpha-MeDA readily oxidizes, and in the presence of glutathione (GSH) it forms 5-(glutathion-S-yl)-alpha-methyldopamine [5-(glutathion-S-yl)-alpha-MeDA]. Since GSH conjugates of many polyphenols are biologically (re)active, we investigated the role of 5-(glutathion-S-yl)-alpha-MeDA in the acute and long-term neurochemical changes observed after administration of MDA. Intracerebroventricular (icv) administration of 5-(glutathion-S-yl)-alpha-MeDA (720 nmol) to male Sprague-Dawley rats produced behavioral changes similar to those reported after subcutaneous administration of MDA. Thus, animals became hyperactive and aggressive and displayed forepaw treading and Straub tails, behaviors usually seen after administration of serotonin (5-HT) releasers, and consistent with a role for 5-(glutathion-S-yl)-alpha-MeDA in some of the behavioral alterations seen after administration of MDA and MDMA. In addition to the behavioral changes, 5-(glutathion-S-yl)-alpha-MeDA also caused short-term alterations in the dopaminergic, serotonergic, and noradrenergic systems. An increase in dopamine synthesis appears to be a prerequisite for the long-term depletion of brain 5-HT following MDMA administration. However, although 5-(glutathion-S-yl)-alpha-MeDA reproduced some of the effects of MDA on the dopaminergic system and was capable of causing acute increases in 5-HT turnover, a single icv injection of 5-(glutathion-S-yl)-alpha-MeDA did not result in long-term serotonergic toxicity. Thus, although acute stimulation of dopamine turnover may be necessary for long-term serotonergic toxicity, such changes are not sufficient to produce these effects. The effects of a multiple dosing schedule of 5-(glutathion-S-yl)-alpha-MeDA will therefore require investigation before we can define a role for this metabolite in MDA and MDMA mediated neurotoxicity. MDA also produces a pressor response that is related to its ability to release neuronal norepinephrine stores, and 5-(glutathion-S-yl)-alpha-MeDA caused comparable depletions of brain norepinephrine concentrations, indicating that both compounds produce similar effects on the noradrenergic system.
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Citations in the library
Cited by 26
- 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
- Glutathione and N-Acetylcysteine Conjugates of α-Methyldopamine Produce Serotonergic Neurotoxicity: Possible Role in Methylenedioxyamphetamine-Mediated Neurotoxicity Chemical Research in Toxicology November 19, 1999
- Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT Synapse 2001
- Metabolism Is Required for the Expression of Ecstasy-Induced Cardiotoxicity in Vitro Chemical Research in Toxicology April 27, 2004
and 21 more in the library
Cites 11
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- The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine European Journal of Pharmacology May 1, 1992
- Enzymic and chemical demethylenation of (methylenedioxy)amphetamine and (methylenedioxy)methamphetamine by rat brain microsomes Chemical Research in Toxicology May 1, 1992
- Effect of acute monoamine depletion on 3,4-methylenedioxymethamphetamine-induced neurotoxicity. Pharmacology, Biochemistry, and Behavior July 1, 1993
- Effects of benzylpiperazine derivatives on the neurotoxicity of 3,4-methylenedioxymethamphetamine in rat brain. Brain Research September 1, 1992
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