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 mgkg MDMA, DOPACDA ratios were increased in mdr1a mice, but decreased 0.3-1 h after MDMA in mdr1a -- mice. Twenty-four hours after 10 mgkg MDMA, DOPACDA ratios were increased 600% in mdr1a mice compared to saline-treated control mice, while in mdr1a -- mice DOPACDA 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 DOPACDA 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.