3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings

Baumann, Michael H.; Wang, Xiaoying; Rothman, Richard B.

doi:10.1007/s00213-006-0322-6

Cited by 241 publications

(283 citation statements)

References 132 publications

(202 reference statements)

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“…Administration of MDC increased dopamine and 5-HT as well, but weakly compared with methylone. The microdialysis data with MDC are generally consistent with its lower potency at DAT and SERT but differ from results obtained with MDA (Baumann et al, 2007;Kankaanpaa et al, 1998;Nash and Nichols, 1991). For example, Kankaanpaa et al (1998) showed that MDA administration to rats induced elevations in extracellular dopamine and 5-HT in the nucleus accumbens that were greater than those produced by MDMA.…”

Section: Discussionmentioning

confidence: 61%

Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats

Elmore

Dillon‐Carter

Partilla

et al. 2016

Neuropsychopharmacol

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3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the β-keto analog of 3,4-methylenedioxy-Nmethylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-Nmethylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (T max = 15-45 min) and were short lived (t 1/2 = 60-90 min), while HHMC and HMMC peaked later (T max = 60-120 min) and persisted (t 1/2 = 120-180 min). Areaunder-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo.

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Section: Discussionmentioning

confidence: 61%

Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats

Elmore

Dillon‐Carter

Partilla

et al. 2016

Neuropsychopharmacol

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“…By contrast, MDPV is a catecholamine-selective uptake blocker. The presence of a 3,4-methylenedioxy ring-substitution in MDPV does not confer serotonergic activity as observed with MDMA and methylone (Baumann et al, 2012;Baumann et al, 2007). Indeed, MDPV displays more than 100-fold greater potency at DAT and NET when compared with SERT.…”

Section: Discussionmentioning

confidence: 88%

“…This distinction in molecular mechanism is essential to determine for at least three reasons: (1) transporter substrates, but not blockers, are translocated into cells and evoke non-exocytotic release of transmitters via reverse transport (Rothman and Baumann, 2003a;Sitte, Freissmuth, 2010); (2) transporter substrates, but not blockers, are known to produce long-term deficits in monoamine neurons that are often viewed as neurotoxicity (Baumann et al, 2007;Fleckenstein et al, 2007); and (3) Figure 4 Effects of MDPV and cocaine on extracellular dopamine in nucleus accumbens, locomotor activity and cardiovascular parameters in conscious rats. For microdialysis studies (a, b), rats received i.v.…”

Section: Discussionmentioning

confidence: 99%

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

Baumann

Partilla

Lehner

et al. 2012

Neuropsychopharmacol

374

453

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The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods. In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats. We found that MDPV blocks uptake of [ 3 H]dopamine (IC 50 ¼ 4.1 nM) and [ 3 H]norepinephrine (IC 50 ¼ 26 nM) with high potency but has weak effects on uptake of [ 3 H]serotonin (IC 50 ¼ 3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats. Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations.

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“…Methamphetamine is a substrate for MAT and can more potently affect DAT than SERT (Rothman et al, 2001;Baumann et al, 2007). Co-administration of methamphetamine with MDMA caused additive dopamine release at the striatum in rats, indicating that each drug might independently diffuse into the brain and affect dopamine levels in neurons.…”

Section: Pharmacodynamic Effects Of Mdma On Dopamine and 5-ht Levels mentioning

confidence: 99%

Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain

Ikeda

Igari

Fuchigami

et al. 2011

European Journal of Pharmacology

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Baseline levels of dopamine and 5-HT in the striatum were 16.5±7.7 and 3.5±1.7 nM (mean ± standard deviation), respectively. After a single administration of MDMA (10 mg/kg, i.p.), a dramatic increase in extracellular dopamine (C max : 36.1-fold vs. baseline) and 5-HT levels (C max : 9.3-fold vs. baseline) was observed. When rats were co-administered with methamphetamine (1, 5 or 10 mg/kg) with MDMA, the dopamine levels induced by MDMA increased in a methamphetamine-dose-dependent manner (C max : 2.5-, 3.5-, and 3.8-fold vs. MDMA). A similar trend was observed in 5-HT levels (C max : 1.1-, 1.3-, and 1.8-fold vs. MDMA). In contrast, ketamine and caffeine showed synergistic effects on the monoamine levels induced by MDMA, whereas the individual administration of either of these compounds did not affect monoamine levels. Ketamine (1, 5 mg/kg) decreased the dopamine levels induced by MDMA (C max : 0.9-and 0.7-fold vs. MDMA) and increased the 5-HT levels induced by MDMA (C max : 1.4-and 1.6-fold vs. MDMA), and co-administration of caffeine (20 2 mg/kg) with MDMA increased dopamine levels (C max : 1.7-fold vs. MDMA). These results suggest that exposure to multiple drugs in addition to MDMA can have neurotoxic effects. 249 words

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3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings

Cited by 241 publications

References 132 publications

Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats

Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain

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