The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes

Rationale  3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans. Objectives  The purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR). Materials and methods  Sprague–Dawley rats with telemetry implants were administered 40 μmol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (T _A) (HOT; 30 ± 1°C) or an area at room temperature (ROOM; 21.5 ± 1.5°C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation. Results  HOT rats showed higher core temperature (T _C), HR, and locomotor activity than ROOM rats during confinement to a set T _A (P < 0.001). HR responses to MDMA over 6 weeks at both T _As progressively decreased with repeated dosing (P < 0.05). T _C was significantly higher in both 6-week groups compared to the 1-week groups (P < 0.05) at the end of time in the gradient. Cortical concentrations of dihydroxyphenylacetic acid (DOPAC; P < 0.05) and 5-hydroxyindole acetic acid (5-HIAA; P < 0.001) decreased significantly irrespective of T _A, while concentrations of dopamine and 5-HT did not change. Conclusion  Long-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of T _C in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.