Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat

Small changes in ambient temperature alter core body temperature in rats given MDMA, and those temperature shifts influence the drug's neurotoxicity. Rats treated with MDMA at 20 or 22°C showed a drop in core temperature and no detectable damage to serotonin nerve endings in brain regions examined. At 26–30°C, core temperature rose and neurotoxicity appeared in the frontal cortex, somatosensory cortex, hippocampus, and striatum, with damage severity linked to core temperature. Saline-treated rats showed no temperature changes across the same ambient conditions. These findings suggest ambient temperature strongly affects MDMA's toxicity and thermoregulation, with implications for human use where fatal hyperthermia occurs.

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Abstract

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) is a drug of abuse and has been shown to be neurotoxic to 5-HT terminals in many species. MDMA-engendered neurotoxicity has been shown to be affected by both ambient temperature and core body temperature. We now report that small (2°C) changes in ambient temperature produce changes in core temperature in MDMA-treated rats, but the same changes in ambient temperature do not affect core temperature of saline-treated animals. Furthermore, increases in core temperature of MDMA-treated animals increase neurotoxicity. Rats were given MDMA (20 or 40 mg/kg) or saline and placed in an ambient temperature of 20, 22, 24, 26, 28, or 30°C using a novel temperature measurement apparatus that controls ambient temperature ±0.5°C. Two weeks after MDMA treatment, the rats were killed, and regional 5-HT and 5-hydroxyindole acetic acid levels were analyzed as a measure of neurotoxicity. Rats treated with MDMA at 20 and 22°C showed a hypothermic core temperature response. Treatment with MDMA at 28 and 30°C produced a hyperthermic response. At ambient temperatures of 20–24°C, neurotoxicity was not observed in the frontal cortex, somatosensory cortex, hippocampus, or striatum. At ambient temperatures of 26–30°C, neurotoxicity was seen and correlated with core temperature in all regions examined. These data indicate that ambient temperature has a significant affect on MDMA neurotoxicity, core temperature, and thermoregulation in rats. This finding has implications on both the temperature dependence of the mechanism of MDMA neurotoxicity and human use because fatal hyperthermia is associated with MDMA use in humans.