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Mice Lacking Multidrug Resistance Protein 1a Show Altered Dopaminergic Responses to Methylenedioxymethamphetamine (MDMA) in Striatum

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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 × time (F 5,152 = 32.4, P < 0.001) and strain × 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.

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Acknowledgments

We would like to thank David Epstein and Jennifer Bossert from the National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD for assistance with statistical analysis. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health.

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Authors and Affiliations

  1. 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. Scheidweiler & Marilyn A. Huestis

  2. Molecular Neuropsychiatry Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Biomedical Research Center, Baltimore, MD, 21224, USA

    Bruce Ladenheim & Jean Lud Cadet

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  1. Karl B. Scheidweiler
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  2. Bruce Ladenheim
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  3. Jean Lud Cadet
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  4. Marilyn A. Huestis
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Correspondence to Marilyn A. Huestis.

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Scheidweiler, K.B., Ladenheim, B., Cadet, J.L. et al. Mice Lacking Multidrug Resistance Protein 1a Show Altered Dopaminergic Responses to Methylenedioxymethamphetamine (MDMA) in Striatum. Neurotox Res 18, 200–209 (2010). https://doi.org/10.1007/s12640-009-9124-z

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