Dose and Time-Dependent Selective Neurotoxicity Induced by Mephedrone in Mice

Martínez-Clemente, José; López-Arnau, Raúl; Abad, Sònia; Piccoli, David A.; Escubedo, Elena; Camarasa, Jorge

doi:10.1371/journal.pone.0099002

Cited by 64 publications

(63 citation statements)

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“…To this end, the bath salt MEPH can be particularly useful in studying METH toxicity. Although DA depletion when MEPH is given at elevated ambient temperatures has been reported, as well as a potentially toxic in vitro effect (den Hollander et al, 2014;Martínez-Clemente et al, 2014), numerous studies conducted in this laboratory and others under ambient conditions known to produce METH toxicity have reported no significant longterm in vivo dopaminergic neurotoxicity when MEPH is administered in a binge regimen (Angoa-Pérez et al, 2012Baumann et al, 2012;den Hollander et al, 2013;Motbey et al, 2013;Anneken et al, 2015). As shown in Fig.…”

mentioning

confidence: 90%

“…The synthetic cathinones found in bath salts are less apt to produce lasting neurotoxicity compared with 3,4-methylenedioxymethamphetmine (MDMA) and methamphetamine (METH) (Angoa-Pérez et al, 2012;Baumann et al, 2012;den Hollander et al, 2013;Motbey et al, 2013;Anneken et al, 2015). This is despite a striking similarity in acute neurochemical and behavioral effects, including the aforementioned monoamine release, thermoregulation (Baumann et al, 2012;Fantegrossi et al, 2013;López-Arnau et al, 2014;Martínez-Clemente et al, 2014;Aarde et al, 2015;Kiyatkin et al, 2015;Shortall et al, 2016), hyperlocomotion (Baumann et al, 2012;López-Arnau et al, 2012;Marusich et al, 2012;Motbey et al, 2012;Wright et al, 2012;Aarde et al, 2013Aarde et al, , 2015Fantegrossi et al, 2013;Gatch et al, 2013), and measures of abuse potential (Hadlock et al, 2011;Lisek et al, 2012;Watterson et al, 2012;Aarde et al, 2013;Motbey et al, 2013;Karlsson et al, 2014).…”

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confidence: 99%

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Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone

Anneken

Angoa‐Pérez

Sati

et al. 2016

J Pharmacol Exp Ther

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Mephedrone (MEPH) is a b-ketoamphetamine stimulant drug of abuse that is often a constituent of illicit bath salts formulations. Although MEPH bears remarkable similarities to methamphetamine (METH) in terms of chemical structure, as well as its neurochemical and behavioral effects, it has been shown to have a reduced neurotoxic profile compared with METH. The addition of a b-keto moiety and a 4-methyl ring substituent to METH yields MEPH, and a loss of direct neurotoxic potential. In the present study, two analogs of METH, methcathinone (MeCa) and 4-methylmethamphetamine (4MM), were assessed for their effects on mouse dopamine (DA) nerve endings to determine the relative contribution of each individual moiety to the loss of direct neurotoxicity in MEPH. Both MeCa and 4MM caused significant alterations in core body temperature as well as locomotor activity and stereotypy, but 4MM was found to elicit minimal dopaminergic toxicity only at the highest dose. By contrast, MeCa caused significant reductions in all markers of DA nerve-ending damage over a range of doses. These results lead to the conclusion that ring substitution at the 4-position profoundly reduces the neurotoxicity of METH, whereas the b-keto group has much less influence on this property. Although the mechanism(s) by which the 4-methyl substituent reduces METH-induced neurotoxicity remains unclear, it is speculated that this effect is mediated by a loss of DA-releasing action in MEPH and 4MM at the synaptic vesicle monoamine transporter, an effect that is thought to be critical for METH-induced neurotoxicity.

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confidence: 90%

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confidence: 99%

Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone

Anneken

Angoa‐Pérez

Sati

et al. 2016

J Pharmacol Exp Ther

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“…With regard to mephedrone, in vivo studies reported that there were no signs of striatal [17] or cortical [25] astroglial activation after administration of mephedrone in a binge paradigm. Similarly, no signs of microglial activation were observed in the striatum at 2 or 7 days after administration of mephedrone [17].…”

Section: Neuroinflammationmentioning

confidence: 99%

“…In these animals, no increase in the density of [ 3 H]PK11195 binding sites was detected, indicating a lack of microglial activation [20]. However, Martinez-Clemente reported an increase in reactive astrocytes in the dentate gyrus of the hippocampus of mice treated with mephedrone at 7 days after a binge of 3 doses of 25 mg/kg for 2 days [25]. …”

Section: Neuroinflammationmentioning

confidence: 99%

Neurotoxicology of Synthetic Cathinone Analogs

Angoa‐Pérez

Anneken

Kuhn

2016

Current Topics in Behavioral Neurosciences

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The present review briefly explores the neurotoxic properties of methcathinone, mephedrone, methylone, and methylenedioxypyrovalerone (MDPV), four synthetic cathinones most commonly found in “bath salts.” Cathinones are β-keto analogs of the commonly abused amphetamines and display pharmacological effects resembling cocaine and amphetamines, but despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce unique effects. Among the similarities of synthetic cathinones with their non-keto analogs are their targeting of monoamine systems, the release of neurotransmitters, and their stimulant properties. Most of the literature on synthetic cathinones has focused on describing their properties as psychostimulants, their behavioral effects on locomotion, memory, and potential for abuse, whereas descriptions of their neurotoxic properties are not abundant. The biochemical gauges of neurotoxicity induced by non-keto analogs are well studied in humans and experimental animals and include their ability to induce neuroinflammation, oxidative stress, excitotoxicity, temperature alterations as well as dysregulation of neurotransmitter systems and induce changes in monoamine transporters and receptors. These neurotoxicity gauges will serve as parameters to discuss the effects of the four previously mentioned synthetic cathinones alone or in combination with either another cathinone or with some of their non-keto analogs. Bath salts are not a defined combination of drugs and may consist of one synthetic cathinone compound or combinations of more cathinones. Furthermore, this review also presents some of the mechanisms that are thought to underlie this toxicity. A better understanding of the cellular and molecular mechanisms involved in the synthetic cathinones-induced neurotoxicity should contribute to generate modern therapeutic approaches to prevent or attenuate the adverse consequences of use of these drugs in humans.

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“…Stimulant drugs, which have been approved for weight loss, include methamphetamine, fenfluramine, diethylpropion and bupropion (amfebutamone) (Weintraub et al, 1984;Bray, 1993). Of the legal highs thus far examined, a number have been shown to evoked weight loss in rodents (Martínez-Clemente et al, 2014). User reports from mephedrone abusers also suggest that this drug is anorectic as is methiopropamine (Winstock et al, 2010).…”

Section: Accepted Manuscriptmentioning

confidence: 99%