Hyperthermia induced by 3,4-methylenedioxymethamphetamine in unrestrained rhesus monkeys

Abstract

Background: Exposure to (+/-)3,4-methylenedioxymethamphetamine ((+/-)MDMA) results in lasting reductions of many markers for serotonin terminals in a range of species. In rodents, the severity of insult depends in large part on the generation of hyperthermia in the subject. (+/-)MDMA can produce either hyperthermia or hypothermia in rodents depending on the ambient temperature and these effects may be limited to the S(+) enantiomer. Limited prior evidence suggests (+/-)MDMA does not produce hyperthermia in chair-restrained monkeys [Bowyer, J.F., Young, J.F., Slikker, W., Itzak, Y., Mayorga, A.J., Newport, G.D., Ali, S.F., Frederick, D.L., Paule, M.G., 2003. Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations. Neurotoxicology 24, 379-390]. This study was therefore conducted to determine if racemic MDMA and its enantiomers induce hyperthermia and increase spontaneous locomotor activity in unrestrained rhesus monkeys.

Methods: Body temperature and spontaneous home cage activity were monitored continuously in four monkeys via radiotelemetric devices. The subjects were challenged with 1.7 mg/kg, i.m., (+/-)MDMA, S(+)MDMA and R(-)MDMA in pseudorandomized order.

Results: Maximum and average temperature in the 4h interval post-dosing was elevated 0.7-0.9 degrees C by (+/-)MDMA and each enantiomer. Reductions in locomotor activity following dosing did not reliably differ from vehicle effects.

Conclusions: MDMA produces an acute hyperthermia in unrestrained rhesus monkeys, much as it does with rats, mice, pigs, rabbits and humans. Hyperthermia occurs despite no increase in locomotor activity thus the effect does not depend on motor activation. Each enantiomer appears to be equivalently active thus primates may differ from rodents in thermoregulatory sensitivity to the R(-) enantiomer. Significant differences in outcome between this and a prior study in monkeys indicate a need for additional study of the thermoregulatory impact of MDMA in nonhuman primates.

Figure 1

The mean (N=4, bars indicate SEM) subcutaneous temperature and activity values following A) racemic MDMA, B) S(+)MDMA and C) R(−)MDMA, as well as the respective vehicle challenges, are presented. Temperature values are an average of three sequential 10-min interval samples and activity data represent the average of summed activity counts across three sequential 10-min intervals. Injections were made at 1030 for all conditions, thus the data represent the interval from midnight prior to injection to 1030 the following day. Shaded regions indicate the night period during which the room lights are off and arrows indicate the time of injection. A significant increase from both the 30-min timepoint preceding injection and the corresponding vehicle timepoint is indicated by *. Additional differences of significance are detailed in the Results.