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Mice lacking multidrug resistance protein 1a show altered dopaminergic responses to methylenedioxymethamphetamine
Karl B Scheidweiler1, Bruce Ladenheim, Jean Lud Cadet
1Chemistry 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.
Abstract:
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.
Insights
Multidrug resistance protein 1a (MDR1a) influences methylenedioxymethamphetamine (MDMA) effects on mouse dopamine systems. MDR1a knockout mice show altered dopamine turnover after MDMA, suggesting a role in neurotoxicity.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Multidrug resistance protein 1a (MDR1a) is implicated in the neurotoxic effects of methylenedioxymethamphetamine (MDMA).
- Previous studies suggest MDR1a influences dopamine (DA) and dopamine transporter levels post-MDMA exposure.
Purpose of the Study:
- To investigate the acute effects of MDMA on the nigrostriatal dopamine system in MDR1a wild-type and knockout mice.
- To determine the role of MDR1a in the immediate handling of MDMA and its impact on dopamine turnover within 0-24 hours.
Main Methods:
- Acute MDMA administration to mdr1a wild-type (mdr1a +/+) and knockout (mdr1a -/-) mice at varying doses.
- Measurement of 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratios in striatal tissue over 0-24 hours.
- Quantification of striatal MDMA and metabolite concentrations using gas chromatography-mass spectrometry.
Main Results:
- Significant interactions between mouse strain, time, and dose were observed for DOPAC/DA ratios.
- MDMA increased DOPAC/DA ratios in mdr1a +/+ mice but decreased them in mdr1a -/- mice within the first 3 hours.
- Twenty-four hours post-MDMA, mdr1a +/+ mice exhibited a 600% increase in DOPAC/DA ratios, while mdr1a -/- mice showed no change.
- Striatal MDMA and metabolite levels were similar between strains, ruling out altered drug transport.
Conclusions:
- MDR1a significantly modulates the acute effects of MDMA on dopamine turnover in the nigrostriatal system.
- The observed differences in dopamine turnover suggest MDR1a influences MDMA neurotoxicity, potentially via increased reactive oxygen species production.
- MDR1a knockout protects against acute MDMA-induced changes in dopamine turnover.
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