Mice lacking multidrug resistance protein 1a show altered dopaminergic responses to methylenedioxymethamphetamine (MDMA) in striatum.
Multidrug resistance protein 1a (MDR1a) potentiated methylenedioxymethamphetamine (MDMA)-induced decreases of dopamine (DA) and dopamine transport protein in mouse brain one week after MDMA administration. In the present study, we examined if mdr1a wild-type (mdr1a +/+) and knock-out (mdr1a -/-) mice differentially handle the acute effects of MDMA on the nigrostriatal DA system 0-24 h following a single drug injection. 3-way ANOVA revealed significant 2-way interactions of strain x time (F (5,152) = 32.4, P < 0.001) and strain x dose (F (3,152) = 25.8, P < 0.001) on 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratios in mdr1a +/+ and -/- mice. 0.3-3 h after 10 mg/kg MDMA, DOPAC/DA ratios were increased in mdr1a +/+ mice, but decreased 0.3-1 h after MDMA in mdr1a -/- mice. Twenty-four hours after 10 mg/kg MDMA, DOPAC/DA ratios were increased 600% in mdr1a +/+ mice compared to saline-treated control mice, while in mdr1a -/- mice DOPAC/DA ratios were unchanged. Striatal MDMA and its metabolite, methylenedioxyamphetamine, concentrations by gas chromatography-mass spectrometry were similar in both strains 0.3-4 h after MDMA, discounting the role of MDR1a-facilitated MDMA transport in observed inter-strain differences. Increased DOPAC/DA turnover in mdr1a +/+ mice following MDMA is consistent with the previous report that MDMA neurotoxicity is increased in mdr1a +/+ mice. Increased DA turnover via monoamine oxidase in mdr1a +/+ vs -/- mice might increase exposure to neurotoxic reactive oxygen species.
Chemistry and Drug Metabolism, Intramural Research Program, National Institutes of Health, Biomedical Research Center, 251 Bayview Boulevard Suite 200, Room 05A-721, Baltimore, MD 21224, USA.
Karl B
KB
Scheidweiler
Bruce
B
Ladenheim
Jean Lud
JL
Cadet
Marilyn A
MA
Huestis
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D015104:3,4-Methylenedioxyamphetamine / Q000493:pharmacokinetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D006719:Homovanillic Acid