The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (
MDMA; "Ecstasy") is influenced by temperature and varies according to species. The mechanisms underlying these two features of
MDMA neurotoxicity are unknown, but differences in
MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of
hypothermia on
MDMA metabolism, 2) determine whether the
neuroprotective effect of
hypothermia is related to inhibition of
MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in
MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of
MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured.
Hypothermia did not alter
MDMA metabolism in rats and only modestly inhibited
MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized
MDMA in a similar pattern, with
3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between
MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of
MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of
MDMA metabolism is not responsible for the
neuroprotective effect of
hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in
MDMA metabolism or disposition.