Vascular actions of MDMA involve α 1 and α 2 ‐adrenoceptors in the anaesthetized rat

We have investigated the effects of methylenedioxymethamphetamine (MDMA, ‘ecstasy’), i.v., on diastolic blood pressure (DBP) in pithed and pentobarbitone anaesthetized rats. In pithed rats, the non‐selective 5‐HT receptor antagonist methiothepin (0.1 mg kg −1 ) and the α 2 ‐adrenoceptor antagonists methoxyidazoxan and yohimbine (1 mg kg −1 ) showed significant α 1 ‐adrenoceptor antagonist potency, but methiothepin did not show α 2 ‐adrenoceptor antagonist potency. MDMA (1 and 5 mg kg −1 ) produced pressor responses which were significantly reduced by the α 1 ‐adrenoceptor antagonist prazosin (0.1 mg kg −1 ), yohimbine (1 mg kg −1 ) or methiothepin (0.1 mg kg −1 ), but not by the 5‐HT 2 receptor antagonist ritanserin (1 mg kg −1 ). In anaesthetized rats, antagonists revealed two phases with three components to the effects of MDMA (5 mg kg −1 ) on DBP: an initial pressor response, a later pressor component at 1 min, the sustained depressor response. Methoxyidazoxan, methiothepin or the combination ritanserin/prazosin significantly reduced the initial pressor response, although neither of the latter compounds alone had any effect. The pressor response to MDMA (5 mg kg −1 ) at 1 min was converted to a depressor response by prazosin and to a lesser extent methiothepin and methoxyidazoxan. The depressor response to MDMA (5 mg kg −1 ) was significantly reduced by methoxyidazoxan (0.1 mg kg −1 ), and by the noradrenaline re‐uptake blocker cocaine 10 mg kg −1 but not 1 mg kg −1 . However, the most marked reduction in the depressor response was produced by the combination of methoxyidazoxan and cocaine. It is concluded that the initial pressor response to MDMA (5 mg kg −1 ) in anaesthetized rats involves α 2 ‐ and possibly α 1 ‐adrenoceptors and 5‐HT 2 receptors, the pressor component at 1 min is largely α 1 ‐adrenoceptor mediated, and the sustained depressor response involves α 2 ‐adrenoceptors.British Journal of Pharmacology (2001) 133 , 429–437; doi: 10.1038/sj.bjp.0704094