Prejunctional actions of methylenedioxymethamphetamine in vas deferens from wild-type and alpha(2A/D)-adrenoceptor knockout mice

Abstract

Methylenedioxymethamphetamine (MDMA, 'ecstasy') has major agonist actions at prejunctional alpha(2A/D)-adrenoceptors in the rat. We wished to establish whether MDMA has potency at more than one subtype of alpha(2)-adrenoceptor, in line with affinity in ligand-binding studies. We have investigated the effects of MDMA in vas deferens from wild-type and from knockout mice lacking the alpha(2A/D)-adrenoceptor. The potency of the alpha(2)-adrenoceptor agonist xylazine at inhibiting stimulation-evoked contractions to a single stimulus in the presence of cocaine was significantly reduced in knockout (pD(2) of 8.27+/-0.07, -log M, n=4) as compared with wild-type mice (8.69+/-0.08, n=4, P<0.05), whereas potency of MDMA was unchanged (5.39+/-0.06, n=4 versus 5.38+/-0.06, n=6). Similar differences between xylazine and MDMA were seen for responses to stimulation at 10 Hz for 4 s. In studies of mouse atria pre-incubated with (3)H-noradrenaline, the stimulation-evoked release of tritium was inhibited to a similar extent by MDMA (10 microM) in tissues from wild-type and knockout mice. The prejunctional alpha(2A/D)-adrenoceptor is reported to be replaced by the alpha(2C)-adrenoceptor in this knockout mouse, so that we have evidence that suggests that MDMA has similar potencies at both subtypes in functional studies.