Investigation of the prejunctional α2‐adrenoceptor mediated actions of MDMA in rat atrium and vas deferens

MDMA (ecstasy) acts as an agonist at alpha-2 adrenoceptors in the rat peripheral nervous system, inhibiting noradrenaline release and nerve-stimulated contractions. In atrial slices, MDMA (10 µM) reduced tritium release evoked by electrical stimulation, an effect blocked by the alpha-2 antagonist yohimbine. In the epididymal vas deferens, MDMA inhibited contractions with a pD2 of 5.88, antagonized by yohimbine but not by a serotonin receptor antagonist. In the prostatic vas deferens, yohimbine converted MDMA's inhibition into potentiation of contractions. Radioligand binding showed MDMA had similar affinities for alpha-2B, alpha-2C, and alpha-2D adrenoceptor subtypes, with pKi values around 5.1–5.3.

Study at a glance

Abstract

We have investigated the effects of methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on peripheral noradrenergic neurotransmission in the rat. In rat atrial slices pre‐incubated with [ 3 H]‐noradrenaline and in the presence of desipramine (1 μ M ) to prevent effects of MDMA on basal outflow of tritium, MDMA (10 μ M ) significantly inhibited the release of tritium evoked by short trains of six pulses at 100 Hz every 10 s for 3 min. This effect did not occur in the presence of the α 2 ‐adrenoceptor antagonist yohimbine (1 μ M ). In epididymal portions of rat vas deferens in the presence of nifedipine (10 μ M ), MDMA produced a concentration‐dependent inhibition of single pulse nerve stimulation‐evoked contractions with a pD 2 of 5.88±0.16 ( n =4). Inhibitory effects of MDMA were antagonized by the α 2 ‐adrenoceptor antagonist yohimbine (0.3 μ M ), but not by the 5‐hydroxytryptamine receptor antagonist cyanopindolol in a concentration (1 μ M ) which markedly antagonized the inhibitory actions of the 5‐HT‐1 receptor agonist 5‐carboxamidotryptamine. In prostatic portions of rat vas deferens in the presence of cocaine (3 μ M ), MDMA produced a concentration‐dependent inhibition of single pulse nerve stimulation‐evoked contractions with a pD 2 of 5.12±0.21 ( n =4). In the absence of cocaine, only the highest concentration of MDMA (30 μ M ) produced an inhibition, but the α 2 ‐adrenoceptor antagonist yohimbine (0.3 μ M ) converted the response to MDMA from inhibition to potentiation of the stimulation‐evoked contraction. In radioligand binding studies, MDMA showed similar affinities for α 2B , α 2C and α 2D ‐adrenoceptor sites, with pK i values of 5.14±0.16, 5.11±0.05 and 5.31±0.14, respectively. It is concluded that MDMA has significant α 2 ‐adrenoceptor agonist actions. British Journal of Pharmacology (1999) 128 , 975–980; doi: 10.1038/sj.bjp.0702875