Response to O'Shea and Colado: the MDMA neurotoxicity profile might provide clues to mechanisms

We commend O'Shea and Colado for their thoughtful commentary [1xIs frequent dosing with ecstasy a risky business for dopamine-containing neurons?. O'Shea, E. and Colado, M.I. Trends Pharmacol. Sci. 2003; 24Abstract | Full Text | Full Text PDF | PubMed | Scopus (7)See all References[1] on our recent study [2xSevere dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (‘ecstasy’). Ricaurte, G.A. et al. Science. 2002; 297: 2260–2263Crossref | PubMed | Scopus (122)See all References[2]. They raise the interesting possibility that very small increments in temperature, even if within the typical range routinely used to house non-human primates, could be responsible for the emergence of neurotoxicity to dopamine (DA)-containing neurons in animals treated with a sequential dose regimen of 3,4-methylenedioxymethamphetamine (MDMA). Previous studies in non-human primates housed at various different temperatures have not demonstrated graded increases of toxicity to DA-containing neurons [3x(+/−) 3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. Ricaurte, G.A. et al. J. Am. Med. Assoc. 1988; 260: 51–55Crossref | Scopus (235)See all References, 4x3,4-Methylenedioxymethamphetamine (‘ecstasy’) selectively destroys brain serotonin terminals in rhesus monkeys. Insel, T.R. et al. J. Pharmacol. Exp. Ther. 1989; 249: 713–720PubMedSee all References, 5xEvidence that both intragastric and subcutaneous administration of methylenedioxymethylamphetamine (MDMA) produce serotonin neurotoxicity in rhesus monkeys. Kleven, M.S. et al. Brain Res. 1989; 488: 121–125Crossref | PubMed | Scopus (33)See all References, 6xAltered serotonin innervation patterns in the forebrain of monkeys treated with (+/−)3,4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery. Hatzidimitriou, G. et al. J. Neurosci. 1999; 19: 5096–5107PubMedSee all References, 7xAltered prolactin response to M-chlorophenylpiperazine in monkeys previously treated with 3,4-methylenedioxymethamphetamine (MDMA) or fenfluramine. Hatzidimitriou, G. et al. Synapse. 2002; 44: 51–57Crossref | PubMed | Scopus (11)See all References] but, rather, selective toxicity to serotonin (5-HT)-containing neurons. However, as noted in our study [2xSevere dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (‘ecstasy’). Ricaurte, G.A. et al. Science. 2002; 297: 2260–2263Crossref | PubMed | Scopus (122)See all References[2], it is possible that DA-containing neurons, once affected by sequential dosing, are more sensitive to temperature-related increases in neurotoxicity than are 5-HT-containing neurons. This possibility was raised by previous findings in rodents [8xEffects of 2-deoxy-D-glucose on methamphetamine-induced dopamine and serotonin neurotoxicity. Callahan, B. et al. J. Neurochem. 1998; 70: 190–197Crossref | PubMedSee all References[8] suggesting that DA-containing neurons, when compared with 5-HT-containing neurons, were more sensitive to temperature increases following treatment with methamphetamine. Studies are currently underway to evaluate this possibility in primates. If it is determined that small temperature changes within typical ambient ranges can profoundly influence the effects of MDMA on DA-containing neurons in non-human primates, this would have significant implications for humans who employ a repeated-dosing regimen in settings where temperatures can vary widely.It is important to clarify a point made by O'Shea and Colado [1xIs frequent dosing with ecstasy a risky business for dopamine-containing neurons?. O'Shea, E. and Colado, M.I. Trends Pharmacol. Sci. 2003; 24Abstract | Full Text | Full Text PDF | PubMed | Scopus (7)See all References[1], who apparently thought that we employed interspecies dose scaling in our study [2xSevere dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (‘ecstasy’). Ricaurte, G.A. et al. Science. 2002; 297: 2260–2263Crossref | PubMed | Scopus (122)See all References[2]. Although it is appropriate to make interspecies drug dose adjustments to account for differences in body mass between species, this was not done in our study. If such adjustments had been made, the doses given to monkeys and baboons in our study would have been several-fold higher. Along these lines, O'Shea and Colado note that when dosage intervals are shortened in rats, neurotoxicity to DA-containing neurons is not observed, which led O'Shea and Colado to posit that dosing intervals might not account entirely for the toxic effect of MDMA on DA-containing neurons. However, when sequential dosages of a drug are administered, adjustments to dosing intervals, in addition to dose, must be made, again to adjust for species differences. Thus, smaller rodents require higher dosages (on a mg per kg basis) and more frequent dosing than larger primates to achieve comparable plasma levels, pharmacological effects and toxic effects [9xThe use of interspecies scaling in toxicokinetics. Mordenti, J. and Chappell, W. : 42–96See all References[9].Finally, as noted by O'Shea and Colado, it is well documented that MDMA leads to an increase of markers of oxidative stress, which has led some to postulate that reactive oxygen species (ROS) might have a primary causative role in MDMA-mediated neurotoxicity. However, as noted by O'Shea and Colado, nonspecific neuronal injury is also associated with the production of oxidative stress; thus, ROS might be related to the downstream effects of MDMA but not to the initial processes that lead to selective injury to monoamine-containing neurons. Additional research focusing on early events in the neurotoxic process, events that are transporter-dependent and influenced by temperature, might help unravel what have proved to be elusive mechanisms underlying the neurotoxicity of MDMA and related drugs.