Impact of ambient temperature on hyperthermia induced by (+/-)3,4-methylenedioxymethamphetamine in rhesus macaques

Abstract

The ambient temperature (T(A)) under which rodents are exposed to (+/-)3,4-methylenedioxymethamphetamine (MDMA) affects the direction and magnitude of the body temperature response, and the degree of hypo/hyperthermia generated in subjects can modify the severity of lasting brain changes in 'neurotoxicity' models. The thermoregulatory effects of MDMA have not been well described in non-human primates and it is unknown if T(A) has the potential to affect acute hyperthermia and therefore other lasting consequences of MDMA. The objective of this study was to determine if the temperature alteration produced by MDMA in nonhuman primates depends on T(A) as it does in rats and mice. Body temperature and spontaneous home cage activity were monitored continuously in six male rhesus monkeys via radiotelemetry. The subjects were challenged intramuscularly with 0.56-2.4 mg/kg (+/-)MDMA under each of three T(A) conditions (18, 24, and 30 degrees C) in a randomized order. The temperature was significantly elevated following injection with all doses of MDMA under each ambient temperature. The magnitude of mean temperature change was approximately 1 degrees C in most conditions suggesting a closely controlled thermoregulatory response in monkeys across a range of doses and ambient temperatures. Activity levels were generally suppressed by MDMA; however, a 50% increase over vehicle was observed after 0.56 MDMA under the 30 degrees C condition. It is concluded that MDMA produces a similar degree of hyperthermia in rhesus monkeys across a range of T(A) conditions that result in hypothermia or exaggerated hyperthermia in rodents. Monkey temperature responses to MDMA appear to be more similar to humans than to rodents and therefore the monkey may offer an improved model of effects related to MDMA-induced hyperthermia.

Figure 1

The mean (N=6, bars indicate SEM) subcutaneous temperature values following acute challenge with four doses of (±)3,4-methylenedioxymethamphetamine under each of three ambient temperature conditions. The break in the series indicates the time of injection; the slight change at time “0” reflects variation in injecting all 6 subjects relative to the computer sampling schedule and the moving average procedure, see Methods. A significant difference from the timepoint preceding injection is indicated by the open symbols; additional significant differences are detailed in the Results.

Figure 2

The individual subjects’ subcutaneous temperatures following acute challenge with the lowest and highest doses of (±)3,4-methylenedioxymethamphetamine are depicted for each of three ambient temperatures. The data are represented as changes from the individuals’ baseline temperature in degrees Celsius.

Figure 3

The mean (N=6, + SEM) average body temperature (upper panel) and summed activity counts (lower panel) across the 2-hour interval following injection of MDMA or vehicle under each of three ambient temperature conditions. A significant difference from vehicle is indicated by * and a significant difference from the 0.56 mg/kg dose is indicated by §.

Figure 4

The mean subcutaneous temperature values following vehicle injection under three ambient temperature conditions for the experimental group (N=6, bars indicate SEM) are presented in the top panel. A significant difference from the timepoint preceding injection is indicated by the open symbols The lower panel presents mean (N=4, bars indicate SEM) subcutaneous temperature under each ambient temperature for an untreated control group. The control group’s data reflect grand averages of individual data averaged across four sessions for each ambient condition. These data are represented relative to the time of injection of the treatment group within the same housing room.

Figure 5

The mean (N=6, + SEM) activity levels in the vehicle and 2.4 mg/kg MDMA conditions are presented for the experimental group under each of three ambient temperatures. The activity data for the control group are also presented, details are as described in the Figure 4 legend.