Further studies on the mechanism of 3,4-methylenedioxymethamphetamine-induced serotonergic neurotoxicity

Xuemei Huang, Purdue University

Abstract

Several lines of evidence suggest that both serotonin (5-HT) and dopamine (DA) releasing effects of 3,4-methylenedioxymethamphetamine (MDMA) are responsible for its long-term neurotoxicity effect. This project was designed to gain further insight into the mechanism of MDMA-induced serotonergic neurotoxicity. Because a great deal of pharmacological similarity exists between p-chloroamphetamine (PCA) and MDMA, PCA was used in several studies in the project. The project had two phases. The results from the first phase exclude the role of corticosteroids in PCA-induced serotonergic neurotoxicity. In addition, no evidence was found to implicate Ca$\sp{2+}$ as the final mediator of serotonergic terminal degeneration, since preliminary experiments were performed showing that regional $\sp{45}$Ca accumulation was not altered after PCA treatment. The second phase of this project involved studies of the role of 5-HT and DA in MDMA and/or PCA-induced serotonergic neurotoxicity. This phase of the project had five parts. In the first part, a 5-HT$\rm\sb{1A}$ agonist and a 5-HT$\sb3$ antagonist failed to provide protection against PCA-induced toxicity. In the second part, it was shown that simply increasing DA synthesis rate or administration of a DA agonist, were ineffective in inducing serotonergic neurotoxicity. In the third part, p-methylthioamphetamine (MTA), a highly selective indirect serotonergic amphetamine was shown to lack neurotoxic effects. In part four, $\alpha$-ethyltryptamine (Monase), a drug that releases both DA and 5-HT, was shown to induce long-term serotonergic deficits. In the fifth part, synaptosomes prepared from rats treated acutely with the 5-HT releasing agent MMAI were found not to accumulate significantly more DA or NE than synaptosomes from control rats. In addition, increased DA synthesis and release in animals whose brain 5-HT had previously been depleted did not lead to serotonergic deficits. These results lead to several conclusions regarding the mechanism of the serotonergic neurotoxic effect of MDMA and PCA. First, simply increasing the rate of DA biosynthesis or stimulating DA receptors with a DA-mimic does not lead to toxic events. It appears that the actual neuronal release of DA per se, in high concentrations, is necessary. It also appears that active 5-HT release and/or depletion are necessary for induction of toxicity. No evidence could be found from these experiments that the combination of these two events leads to excess DA uptake into 5-HT neuron terminals. Hence, it is not clear that DA itself is the ultimate toxicant. In addition, there was no evidence from these experiments to implicate either calcium or corticosteroids in the sequence of neurotoxic events.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Neurology

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