Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity.
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Hansen JP, Riddle EL, Sandoval V, Brown JM, Gibb JW, Hanson GR, Fleckenstein AE
Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity.
J Pharmacol Exp Ther. 2002 Mar;300(3):1093-100.
- PubMed ID
- 11861820 [ View in PubMed]
- Abstract
Administration of a high-dose regimen of methamphetamine (METH) rapidly and profoundly decreases plasmalemmal and vesicular dopamine (DA) transport in the striatum, as assessed in synaptosomes and purified vesicles, respectively. To determine whether these responses were common to other amphetamines of abuse, effects of methylenedioxymethamphetamine (MDMA) on the plasmalemmal DA transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) were assessed. Similar to effects of METH reported previously, multiple high-dose MDMA administrations rapidly (within 1 h) decreased plasmalemmal DA uptake, as assessed ex vivo in synaptosomes prepared from treated rats. Unlike effects of multiple METH injections, this deficit was reversed completely 24 h after drug treatment. Also in contrast to effects of multiple METH injections, 1) MDMA caused little or no decrease in binding of the DAT ligand WIN35428, and 2) neither prevention of hyperthermia nor prior depletion of DA prevented the MDMA-induced reduction in plasmalemmal DA transport. However, a role for phosphorylation was suggested because pretreatment with protein kinase C inhibitors attenuated the deficit caused by MDMA in an in vitro model system. In addition to affecting DAT function, MDMA rapidly decreased vesicular DA transport as assessed in striatal vesicles prepared from treated rats. Unlike effects of multiple METH injections reported previously, this decrease partially recovered by 24 h after drug treatment. Taken together, these results reveal several differences between effects of MDMA and previously reported METH on DAT and VMAT-2; differences that may underlie the dissimilar neurotoxic profile of these agents.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions 4-Methoxyamphetamine Sodium-dependent dopamine transporter Protein Humans YesInhibitorDetails 4-Methoxyamphetamine Synaptic vesicular amine transporter Protein Humans YesInhibitorDetails Midomafetamine Sodium-dependent dopamine transporter Protein Humans UnknownNegative modulatorDetails Midomafetamine Synaptic vesicular amine transporter Protein Humans YesInhibitorDetails