Interaction of mephedrone with dopamine and serotonin targets in rats

Martínez-Clemente, José; Escubedo, Elena; Piccoli, David A.; Camarasa, Jorge

doi:10.1016/j.euroneuro.2011.07.009

Cited by 113 publications

(91 citation statements)

References 18 publications

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“…3,4-Methylenedioxypyrovalerone and monoamine transporters MH Baumann et al there are conflicting reports in the literature regarding the precise interactions of designer cathinones with monoamine transporters (Baumann et al, 2012;Cozzi et al, 1999;Hadlock et al, 2011;Martinez-Clemente et al, 2011;Nagai et al, 2007;Sogawa et al, 2011). Our results from in vitro experiments in synaptosomes confirm that uptake inhibition assays can identify drugs which interact with transporter proteins.…”

Section: Discussionsupporting

confidence: 73%

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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Section: Discussionsupporting

confidence: 73%

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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“…Mephedrone has a high affinity for rat dopamine and 5-HT transporters as well as the 5-HT 2A and 5-HT 2C receptors, and α 1A -and α 2A -adrenoceptors (Eshleman et al, 2013;Martinez-Clemente et al, 2012;Simmler et al, 2013). It increases extracellular dopamine and to an even greater extent 5-HT in the nucleus accumbens (Baumann et al, 2012;Eshleman et al, 2013;Kehr et al, 2011;Wright et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Contribution of serotonin and dopamine to changes in core body temperature and locomotor activity in rats following repeated administration of mephedrone

et al. 2015

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. (2015) Contribution of serotonin and dopamine to changes in core body temperature and locomotor activity in rats following repeated administration of mephedrone. Addiction Biology . ISSN 1355-6215Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/30185/1/Shortall%202015%20AddictionBio.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the University of Nottingham End User licence and may be reused according to the conditions of the licence. For more details see: http://eprints.nottingham.ac.uk/end_user_agreement.pdf A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.

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“…The highest barrier for rotation between two conformers is 7.07 kcal/mol (rotation c↔e). The [26] lowest rotational barrier is 3.64 kcal/mol for transition a↔b.…”

Section: Results and Discussion 3-mmcmentioning

confidence: 96%

“…Calculation shows that for this reaction, enzyme is necessary to decrease barrier, which is 142 kcal/mol high for this reaction. Experiment shows that mephedrone reacts with dopamine and serotonine [26]. Dopamine is one of the neurotransmitters, a chemical messenger heavily active in the mesolimbic and mesocortical reward pathways.…”

Section: -Mmcmentioning

confidence: 99%

Conformational analysis, energy profile, and structural-electronic properties evaluation of mephedrone derivatives employing quantum-mechanical models

2016

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Mephedrone (4-methyl-meth-cathinone) or 4-MMC and its derivative 3-MMC are analogs of cathinone which act as non-selective substrates for monoamine transporters, facilitating a neurotransmitter release via the reversal of normal transporter fluxes. The pharmacological effects like paranoia, hallucinations, euphoria, aggressiveness, and psychosis make these molecules Babusive designer drugs.^In the present study, conformations of all isomers of 3-and 4-MMC have been studied at the quantum-chemical level. Calculations have been performed using Møller-Plesset second-order (MP2) methods with 6-31G(d, p) basis sets. Present study shows that there are lowenergy conformers for the meta (3-MMC) and para (4-MMC) isomers that are connected by way of low-barrier transition states. Natural bond orbital (NBO) analyses have been also performed to corroborate the results as estimated from the MP2 calculations. The molecular electrostatic potential surface data for each molecule has been calculated, revealing likely that reaction sites and probable metabolism pathway for both derivatives have been proposed. IR spectra for MMC derivatives have been compared with experimental data, and rotational transition states connecting all conformers have been reported.

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Interaction of mephedrone with dopamine and serotonin targets in rats

Cited by 113 publications

References 18 publications

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

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

Contribution of serotonin and dopamine to changes in core body temperature and locomotor activity in rats following repeated administration of mephedrone

Conformational analysis, energy profile, and structural-electronic properties evaluation of mephedrone derivatives employing quantum-mechanical models

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