Role of alpha 1- and beta 3-adrenoceptors in the modulation by SR59230A of the effects of MDMA on body temperature in the mouse

Background and purpose: We have investigated the ability of the beta(3)-adrenoceptor antagonist 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4,-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol hydrochloride (SR59230A) to affect the hyperthermia produced by methylenedioxymethamphetamine (MDMA) in conscious mice and whether alpha(1)-adrenoceptor antagonist actions are involved.

Experimental approach: Mice were implanted with temperature probes under anaesthesia, and allowed 2 week recovery. MDMA (20 mg x kg(-1)) was administered subcutaneously 30 min after vehicle or test antagonist and effects on body temperature monitored by telemetry.

Key results: Following vehicle, MDMA produced a slowly developing hyperthermia, reaching a maximum increase of 1.8 degrees C at 130 min post injection. A low concentration of SR59230A (0.5 mg x kg(-1)) produced a small but significant attenuation of the slowly developing hyperthermia to MDMA. A high concentration of SR59230A (5 mg x kg(-1)) revealed a significant and marked early hypothermic reaction to MDMA, an effect that was mimicked by the alpha(1)-adrenoceptor antagonist prazosin. Functional and ligand binding studies revealed actions of SR59230A at alpha(1)-adrenoceptors.

Conclusions and implications: 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4,-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol hydrochloride in high concentrations modulates the hyperthermic actions of MDMA in mice in two ways: by blocking an early alpha(1)-adrenoceptor-mediated component to reveal a hypothermia, and by a small attenuation of the later hyperthermic component which may possibly be beta(3)-adrenoceptor-mediated (this seen with the low concentration of SR59230A). Hence, the major actions of SR59230A in modulating the actions of MDMA on temperature involve alpha(1)-adrenoceptor antagonism.