Role of α1‐ and β3‐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 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.