Assessment of the mechanism of neurotoxicity of 3,4-methylenedioxy methamphetamine (MDMA)
Abstract
3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug with psychotherapeutic potential. In several animal species the drug induces profound neurotoxic alterations in neurons that contain the neurotransmitter 5-hydroxytryptamine (5-HT). The present studies were aimed at assessing potential mechanisms that underly the neurotoxicity. In contrast to reported effects in rats, MDMA did not persistently deplete mouse brain 5-HT, suggesting a species difference in susceptibility to MDMA neurotoxicity. Transient alterations in levels of brain biogenic amines and metabolites and cardiac norepinephrine were the only marked changes induced by acute or subacute MDMA treatment. Therefore, the mouse is not a suitable model for mechanistic studies. To assess possible factors involved in the mechanism of MDMA neurotoxicity, a series of drug interaction studies was conducted in rats. No substantial evidence to support the involvement of endogenous 5-HT stores or a reactive electrophilic intermediate in the neurotoxic pathway was obtained. However, from studies with affectors of cytochrome P-450 metabolism, it was concluded that a centrally formed MDMA metabolite may mediate the toxicity. To evaluate possible relations between metabolism and neurotoxicity, studies were conducted to characterize the in vitro conversion of MDMA to the catechol $\alpha$-methylepinine. Microsomes from rat brain and liver appeared to differ in susceptibility to manipulation by the metabolic affectors, which may account for the unexpected results in the drug interaction studies. In contrast to known differences in the neurotoxicity of the stereoisomers of MDMA, no stereochemical differences in metabolism were apparent. To directly test the neurotoxicity of $\alpha$-methylepinine, the compound was administered intracerebroventricularly to rats. No significant depletion of brain biogenic amines or metabolites was produced by this treatment. These data suggest metabolic activation to $\alpha$-methylepinine is not responsible for the neurotoxicity of MDMA. The possibility remains that other metabolic pathways, particularly involving brain monoamine oxidase, play a role in the neurotoxic mechanism.
Degree
Ph.D.
Advisors
Yim, Purdue University.
Subject Area
Pharmacology
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