Role of α1‐ and β3‐adrenoceptors in the modulation by SR59230A of the effects of MDMA on body temperature in the mouse

In conscious mice, the drug MDMA (20 mg/kg) caused a slow rise in body temperature peaking at 1.8°C above baseline about 130 minutes after injection. A low dose of the β3-adrenoceptor antagonist SR59230A (0.5 mg/kg) slightly reduced this hyperthermia. A high dose of SR59230A (5 mg/kg) instead triggered an early drop in temperature, an effect also produced by the α1-adrenoceptor blocker prazosin. Further tests showed that SR59230A also blocks α1-adrenoceptors. Thus, SR59230A alters MDMA's temperature effects mainly by blocking α1-adrenoceptors, which unmasks a hypothermic response, and to a lesser extent by possibly blocking β3-adrenoceptors to slightly reduce later hyperthermia.

Study at a glance

Abstract

Background and purpose: We have investigated the ability of the β 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 α 1 ‐adrenoceptor antagonist actions are involved. Experimental approach: Mice were implanted with temperature probes under anaesthesia, and allowed 2 week recovery. MDMA (20 mg·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°C at 130 min post injection. A low concentration of SR59230A (0.5 mg·kg −1 ) produced a small but significant attenuation of the slowly developing hyperthermia to MDMA. A high concentration of SR59230A (5 mg·kg −1 ) revealed a significant and marked early hypothermic reaction to MDMA, an effect that was mimicked by the α 1 ‐adrenoceptor antagonist prazosin. Functional and ligand binding studies revealed actions of SR59230A at α 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 α 1 ‐adrenoceptor‐mediated component to reveal a hypothermia, and by a small attenuation of the later hyperthermic component which may possibly be β 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 α 1 ‐adrenoceptor antagonism.