Investigation of the prejunctional alpha2-adrenoceptor mediated actions of MDMA in rat atrium and vas deferens.

1. We have investigated the effects of methylenedioxymethamphetamine (MDMA, 'ecstasy') on peripheral noradrenergic neurotransmission in the rat. 2. In rat atrial slices pre-incubated with [3H]-noradrenaline and in the presence of desipramine (1 micronM) to prevent effects of MDMA on basal outflow of tritium, MDMA (10 micronM) 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 alpha2-adrenoceptor antagonist yohimbine (1 micronM). 3. In epididymal portions of rat vas deferens in the presence of nifedipine (10 micronM), MDMA produced a concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions with a pD2 of 5.88+/-0.16 (n=4). Inhibitory effects of MDMA were antagonized by the alpha2-adrenoceptor antagonist yohimbine (0.3 micronM), but not by the 5-hydroxytryptamine receptor antagonist cyanopindolol in a concentration (1 micronM) which markedly antagonized the inhibitory actions of the 5-HT-1 receptor agonist 5-carboxamidotryptamine. 4. In prostatic portions of rat vas deferens in the presence of cocaine (3 micronM), MDMA produced a concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions with a pD2 of 5. 12+/-0.21 (n=4). In the absence of cocaine, only the highest concentration of MDMA (30 micronM) produced an inhibition, but the alpha2-adrenoceptor antagonist yohimbine (0.3 micronM) converted the response to MDMA from inhibition to potentiation of the stimulation-evoked contraction. 5. In radioligand binding studies, MDMA showed similar affinities for alpha2B, alpha2C and alpha2D-adrenoceptor sites, with pKi values of 5.14+/-0.16, 5.11+/-0. 05 and 5.31+/-0.14, respectively. 6 It is concluded that MDMA has significant alpha2-adrenoceptor agonist actions.