Prejunctional actions of methylenedioxymethamphetamine in vas deferens from wild-type and alpha(2A/D)-adrenoceptor knockout mice.
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.
Rajamani
K
K
Department of Physiology, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
Leong
S
S
Lavelle
A
A
Docherty
J R
JR
D018663:Adrenergic Agents / Q000494:pharmacology*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D005838:Genotype; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010109:Oxymetazoline / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D014316:Tritium / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014991:Xylazine / Q000494:pharmacology
C547769:Adra2a protein, mouse; C547770:Adra2a protein, rat; D018663:Adrenergic Agents; D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D014665:Vasodilator Agents; D014316:Tritium; D014991:Xylazine; D010109:Oxymetazoline; D009543:Nifedipine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D003891:Desipramine; D009638:Norepinephrine