Release of serotonin induced by 3,4-methylenedioxymethamphetamine (MDMA) and other substituted amphetamines in cultured fetal raphe neurons: further evidence for calcium-independent mechanisms of release

Wichems, Christine H.; Hollingsworth, Charlotte; Bennett, Barbara A.

doi:10.1016/0006-8993(95)00774-k

Cited by 46 publications

(33 citation statements)

References 37 publications

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“…The data reported here for MDC differ somewhat from findings with 3,4-methylenedioxyamphetamine (MDA), the analogous N-demethylated metabolite of MDMA. We and others have shown that MDA and MDMA display nearly identical potency and selectivity as substrate-type releasers at monoamine transporters in vitro (McKenna et al, 1991;Sandtner et al, 2016;Wichems et al, 1995). Interestingly, HHMC was found to be a potent and selective substrate for DAT and NET, with a DAT/SERT ratio of 155 in vitro.…”

Section: Discussionmentioning

confidence: 80%

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: 80%

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

Elmore

Dillon‐Carter

Partilla

et al. 2016

Neuropsychopharmacol

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“…This leads to other intriguing structure-activity findings, namely the transporter interaction of the compounds 12 and 13 containing two 3,4-methylenedioxyphenyl groups compared with that of 3,4-methylenedioxyamphetamine (not functionally different from MDMA; see Wichems et al, 1995), and 8 containing only one of them: the 3,4-methylenedioxy substitution increased the affinity of phenylethylamines to the SERT and decreased it to the NET and DAT (Wall et al, 1995;Rothman et al, 2001). This can explain our finding that 13, containing two 3,4-methylenedioxyphenyl groups, was equipotent with MDMA at the SERT, whereas it displayed less affinity to NET and DAT than MDMA.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Characterization of Ecstasy Synthesis Byproducts with Recombinant Human Monoamine Transporters

Pifl

Nagy²,

Berényi³

et al. 2005

J Pharmacol Exp Ther

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Ecstasy samples often contain byproducts of the illegal, uncontrolled synthesis of N-methyl-3,4-methylenedioxy-amphetamine or 3,4-methylenedioxy-methamphetamine (MDMA). MDMA and eight chemically defined byproducts of MDMA synthesis were investigated for their interaction with the primary sites of action of MDMA, namely the human plasmalemmal monamine transporters for norepinephrine, serotonin, and dopamine [(norepinephrine transporter (NET), serotonin transporter (SERT), and dopamine transporter (DAT)]. SK-N-MC neuroblastoma and human embryonic kidney cells stably transfected with the transporter cDNA were used for uptake and release experiments. Two of the eight compounds, 1,3-bis (3,4-methylenedioxyphenyl)-2-propanamine (12) and N-formyl-1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine (13) had uptake inhibitory potencies with IC 50 values in the low micromolar range similar to MDMA. Compounds with nitro instead of amino groups and a phenylethenyl instead of a phenylethyl structure or a formamide or acetamide modification had IC 50 values beyond 100 M. MDMA, 12, and 13 were examined for induction of carrier-mediated release by superfusion of transporter expressing cells preloaded with the metabolically inert transporter substrate [3 H]1-methyl-4-phenylpyridinium. MDMA induced release mediated by NET, SERT, or DAT with EC 50 values of 0.64, 1.12, and 3.24 M, respectively. 12 weakly released from NET-and SERT-expressing cells with maximum effects less than one-tenth of that of MDMA and did not release from DAT cells. 13 had no releasing activity. 12 and 13 inhibited release induced by MDMA, and the concentration dependence of this effect correlated with their uptake inhibitory potency at the various transporters. These results do not support a neurotoxic potential of the examined ecstasy synthesis byproducts and provide interesting structure-activity relationships on the transporters.

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“…Next, we investigated the contribution of exocytotic 5-HT release in the augmented 5-HT release, although it is considered to play a limited part in acute 5-HT release by MDMA (9). When vehicle-exposed slice cultures were challenged with MDMA, MDMA-induced 5-HT release was significantly inhibited by co-treatment with an SSRI, citalopram (0.3 μ M), but not by TTX (1 μ M) ( F 2,6 = 8.868, P < 0.05).…”

mentioning

confidence: 99%

Sustained Exposure to 3,4-Methylenedioxymethamphetamine Induces the Augmentation of Exocytotic Serotonin Release in Rat Organotypic Raphe Slice Cultures

et al. 2010

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Abstract. 3,4-Methylenedioxymethamphetamine (MDMA) causes serotonin efflux via serotonin transporter. Recently, we have reported that sustained exposure to MDMA induced an augmentation of serotonin release in rat raphe serotonergic slice cultures. Here we investigated the mechanism of augmented serotonin release from the slice cultures. Sustained MDMA exposure had no effect on MDMA-induced serotonin efflux in the synaptosomal fraction, whereas either tetrodotoxin, calcium channel inhibitors, or AMPA-receptor antagonists significantly attenuated the augmented serotonin release. These results suggest that the increase in Ca 2+ -dependent exocytotic serotonin release is mediated through activation of AMPA receptors and responsible for the sustained MDMA-induced augmentation of serotonin release.

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Release of serotonin induced by 3,4-methylenedioxymethamphetamine (MDMA) and other substituted amphetamines in cultured fetal raphe neurons: further evidence for calcium-independent mechanisms of release

Cited by 46 publications

References 37 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

Pharmacological Characterization of Ecstasy Synthesis Byproducts with Recombinant Human Monoamine Transporters

Sustained Exposure to 3,4-Methylenedioxymethamphetamine Induces the Augmentation of Exocytotic Serotonin Release in Rat Organotypic Raphe Slice Cultures

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