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

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. 24 h 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 to 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.

( )-3,4-Methylenedioxymethamphetamine and Metabolite Disposition in Plasma and Striatum of Wild-Type and Multidrug Resistance Protein 1a Knock-Out Mice

“…Our previous research demonstrated that deletion of mdr1a affords protection from MDMA-induced decreases in dopamine and DAT binding in mouse striatum suggesting that individuals with elevated MDR1a expression would be at higher risk of neurotoxicity (9). We also demonstrated that MDR1a does not alter striatal MDMA and MDA concentrations (8). The current research investigated the role of MDR1a-mediated MDMA metabolism and distribution in mdr1a +/+ and −/− mice and whether altered MDMA metabolism in mdr1a −/− mice confounded our previous results.…”

“…Upreti and Eddington (10) reported that MDR1a does not alter whole brain concentrations of MDMA and its metabolite methylenedioxyamphetamine (MDA) (10); however, MDMA effects are region specific. In a previous preliminary study, we found that MDR1a did not alter MDMA and MDA striatal distribution after MDMA (8); however, we were unable to collect plasma to evaluate potentially altered MDMA metabolism in mdr1a −/− mice. The primary objective of this study was to evaluate whether MDR1a alters MDMA metabolism and whether altered metabolism may have confounded interpretation of striatal MDMA and MDA concentrations during our preliminary studies.…”

“…Our previously reported studies in mice lacking MDR1a protein (mdr1a −/−) versus wild-type mice expressing MDR1a protein (mdr1a +/+), suggest that MDR1a plays a role in neurotoxicity caused by MDMA and that individuals with elevated MDR1a expression could be at increased risk of neurotoxicity (8,9). After 20 mg/kg MDMA, mdr1a −/− mice were protected from MDMA-induced decreases in dopamine uptake sites (DAT) in striatum compared to mdr1a +/+ mice (9).…”

Mice in Ecstasy: Advanced Animal Models in the Study of MDMA

“…injection of MDMA [42]. Finally, Scheidweiler and colleagues, administering 10 to 40 mg/kg to mdr1a wt or -/-mice found differences in dihydroxyphenyl acetic acid (DOPAC) / dopamine ratios in striatal specimens from treated mice, which depended on the time point of evaluation and the dosage applied [43]. Also here, striatal concentrations of MDMA and its metabolite MDA were not higher in wt than in mdr1a -/-mice, suggesting that altered MDR1a-mediated transport of MDMA does not account for the observed differences of MDMA's effects on DOPAC/dopamine ratios between mdr1a +/+ and -/-mice.…”

Effects of 3,4‐methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats

“…Hydroxyl‐containing metabolites of MDMA are conjugated to sulfate or glutathione and excreted. It is noteworthy that the metabolic pathways for MDMA biotransformation in rodents are similar to those described for humans (Baumann et al ., ; Scheidweiler et al ., ), although there are species differences in hepatic enzymes involved and time intervals for drug clearance (de la Torre and Farre, ).…”