Methylenedioxymethamphetamine (MDMA) produces complex effects on body temperature, including hypo- and hyperthermic components which vary with ambient temperature and strain of rat (Malberg et al., 1988; Malpass et al., 1999). MDMA has alpha₂-adrenoceptor agonist actions (Lavelle et al., 1999), and alpha2-adrenoceptor agonists such as clonidine produce hypothermia (Zarrindast et al., 2003). The purpose of this study was to investigate the effects of MDMA on body temperature in wild-type (WT) and alpha_2A/D-knockout (KO) mice.

Alpha_2A/D-KO (Jackson laboratories, USA) and C57-BL/6 WT mice (22-30g male) were implanted under ether anaesthesia with temperature probes (DSI) in the abdomen. After 14 days, temperature was recorded in freely moving mice by telemetry for 90 min before and 300 min after drug injection subcutaneously. In interaction studies, BRL 44408 was administered 30 min before test agonist and recording continued for a further 300 min. Room temperature was 22 °C. Statistical test (two way ANOVA followed by Bonferroni Test).

In WT mice, the alpha₂-adrenoceptor agonist clonidine (0.1 mgkg^-1) produced a hypothermic response which reached a peak fall of 1.73 ± 0.40 ° C n=6 mean ± S.E.M. at 50 min and temperature recovered to not significantly different from the effects of vehicle by 100 min. In KO mice, clonidine (0.1 mgkg^-1) did not significantly affect temperature as compared with vehicle.

In WT mice, MDMA (20 mgkg^-1) produced a significant hyperthermia beginning at approximately 100 min after injection, with a maximum rise of 1.56 ± 0.22 ° C. The response recovered to not significantly different from vehicle by 300 min. In KO mice, MDMA (20 mgkg^-1) produced a significant hypothermia by 20 min which reached a maximum fall at 40 min of 1.45 ± 0.27 ° C which returned to vehicle levels by 90 min, and changed to a hyperthermic response by 170 min. Maximum hyperthermic response of 1.86 ± 0.07 ° C was similar to that to MDMA in WT, and response recovered to baseline by 300 min. In WT mice, following the alpha_2D-adrenoceptor antagonist BRL 44408 (1 mgkg^-1), MDMA (20 mgkg^-1) produced an initial hypothermia ( fall of 1.10 ± 0.27) followed by hyperthermia (increase of 1.23 ± 0.10).

In conclusion, alpha 2-adrenoceptor agonist actions of MDMA contribute to its effects on body temperature, but in a surprising way. Although alpha₂-adrenoceptor agonists produce hypothermia, the alpha_2D-adrenoceptor mediated action of MDMA prevents an initial hypothermia. Alpha_2D-adrenoceptor actions modulate other actions of MDMA, altering the temperature response from biphasic (hypothermia then hyperthermia) to monophasic hyperthemia.

Lavelle, A. et al. (1999). Br. J. Pharmacol. 128, 975-980.
Malberg, J.E. et al. (1988) J. Neurosci. 18, 5086-5094.
Malpass, A. et al. (1999) Pharmacol. Biochem. Behav. 64, 29-34.
Zarrindast, M. (2003) Pharmacol Toxicol. 93, 48-53.