MODULATION OF THE TEMPERATURE EFFECTS OF MDMA BY THE BETA3-ADRENOCEPTOR ANTAGONIST SR59230A IN THE MOUSE

Sotiria Bexis, Jim Docherty
RCSI, Dublin, Ireland

We have reported that combined alpha1A- and alpha1D-adrenoceptor blockade alters the temperature response to MDMA from monophasic hyperthermia to biphasic hypothermia followed by hyperthermia (Bexis & Docherty, 2006, 2007). In rats, the hyperthermia to MDMA 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). In this study, we wished to investigate the actions of SR59230A at alpha1-adrenoceptors and on temperature responses to MDMA in mice.

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 (s.c.). Alpha1-adrenoceptor ligand binding studies were carried out using 3H-prazosin in membranes from rat submandibular gland (alpha1A) and spleen (alpha1B). Potency against isometric contractions to phenylephrine in rat spleen (alpha1B) and noradrenaline in rat aortic rings (alpha1D) was expressed as a pKB.

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. However, SR59230A has relevant potency as an antagonist at alpha1A-, alpha1B- and alpha1D-adrenoceptors in functional and ligand binding studies in vitro (see Table 1). Although SR59230A is more than 100 times less potent than prazosin at alpha1-adrenoceptor subtypes, it was used in our telemetry studies at a 50 times higher concentration than prazosin. Hence, alpha1-adrenoceptor actions of SR59230A may contribute to its ability to decrease the hyperthermic response to MDMA.

In conclusion, the beta3-adrenoceptor antagonist SR59230A reduced hyperthermic actions of MDMA in mice, but this action may at least partly involve alpha1-adrenoceptor antagonism.

Supported by the Health Research Board (Ireland).

Bexis, S. & Docherty, J.R. (2006). pA2online.org/Vo13Issue4abst 095P.hmtl.
Bexis, S. & Docherty, J.R. (2007). pA2online Oxford Meeting (in press).
Sprague, J.E. et al. (2004). Br. J. Pharmacol. 142, 667-670