Involvement of adrenoceptors in the temperature effects of MDMA in the mouse

Bexis & J.R. Docherty. Department of Physiology, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland.

In our recent studies of MDMA on body temperature in wild-type (WT) and alpha2A-knockout (KO) mice, we found that the loss of the alpha2A-adrenoceptor altered the response to MDMA from monophasic hyperthermia to biphasic hypothermia followed by hyperthermia (Bexis & Docherty, 2005). In rats, the hyperthermia to MDMA (40 mg kg-1) was significantly attenuated by pretreatment with the alpha1-adrenoceptor antagonist prazosin (0.1mg kg-1) plus the beta3-adrenoceptor antagonist SR59230A (5 mg kg-1) in combination (Sprague et al., 2004), and the alpha1- and beta-adrenoceptor antagonist carvedilol reversed the hyperthermia to a hypothermia (Sprague et al., 2005). In this study, we wished to investigate the actions of prazosin and SR59230A on temperature responses to MDMA in WT and alpha2A-KO mice.

Alpha2A-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 for 300 min after drug injection. The antagonists or vehicle were administered 30 min before MDMA and recording continued for a further 300 min. Drugs were injected subcutaneously. Statistical comparisons were carried out using ANOVA with post tests, as appropriate.

In WT mice, MDMA (20 mg kg-1) produced a significant hyperthermia beginning at approximately 100 min after injection. In WT mice, prazosin (0.1mg kg-1) or SR59230A (5 mg kg-1), or the combination of prazosin and SR59230A, produced essentially similar effects: the response to MDMA was altered from a monophasic hyperthermia to a biphasic hypothermia followed by hyperthermia (e.g. in the presence of the combination of antagonists, MDMA produced an initial decreases of 2.15 ± 0.45 ° C, n=9). In alpha2A-KO mice, MDMA produced biphasic responses, and following the combination of prazosin (0.1mg kg-1) and SR59230A (5 mg kg-1), MDMA produced a significantly greater initial hypothermia (2.76±0.30 ° C, n=7) than MDMA in the absence of antagonist (1.45±0.27 ° C, n=7 ).

In conclusion, alpha1-, alpha2-, and beta3-adrenoceptors may be involved in hyperthermic actions of MDMA in mice, and blocking any one of these receptors reveals a hypothermic component to the response to MDMA.

Bexis, S. & Docherty, J.R. (2005). Br. J. Pharmacol. 146, 1-6.
Sprague, J.E. et al. (2004). Br. J. Pharmacol. 142, 667-670.
Sprague, J.E. et al. (2005). Crit. Care 33, 1311-1316.

Supported by the Health Research Board ( Ireland).