Vascular actions of MDMA involve α1 and α2‐adrenoceptors in the anaesthetized rat

MDMA (ecstasy) raises diastolic blood pressure in rats through multiple adrenoceptor mechanisms. In pithed rats, MDMA's pressor effects were blocked by α₁-adrenoceptor antagonist prazosin, α₂-antagonists yohimbine and methoxyidazoxan, and the non-selective 5-HT antagonist methiothepin, but not by the 5-HT₂ antagonist ritanserin. In anesthetized rats, MDMA produced a triphasic blood pressure response: an initial pressor phase involving α₂- and possibly α₁-adrenoceptors and 5-HT₂ receptors; a pressor component at 1 minute mediated largely by α₁-adrenoceptors; and a sustained depressor phase involving α₂-adrenoceptors and noradrenaline reuptake. The depressor response was most reduced by combining methoxyidazoxan and cocaine.

Study at a glance

Abstract

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