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Dose and time-dependent selective neurotoxicity induced by mephedrone in mice.

Martínez-Clemente J, López-Arnau R, Abad S, Pubill D, Escubedo E, Camarasa J - PLoS ONE (2014)

Bottom Line: At a lower dose (schedule 2) only a transient dopaminergic injury was found.Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs.In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.

ABSTRACT
Mephedrone is a drug of abuse marketed as 'bath salts". There are discrepancies concerning its long-term effects. We have investigated the neurotoxicity of mephedrone in mice following different exposition schedules. Schedule 1: four doses of 50 mg/kg. Schedule 2: four doses of 25 mg/kg. Schedule 3: three daily doses of 25 mg/kg, for two consecutive days. All schedules induced, in some animals, an aggressive behavior and hyperthermia as well as a decrease in weight gain. Mephedrone (schedule 1) induced dopaminergic and serotoninergic neurotoxicity that persisted 7 days after exposition. At a lower dose (schedule 2) only a transient dopaminergic injury was found. In the weekend consumption pattern (schedule 3), mephedrone induced dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expression one week after exposition. Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs. In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect. Using repeated doses for 2 days in an elevated ambient temperature we evidenced a loss of frontal cortex dopaminergic and hippocampal serotoninergic neuronal markers that suggest injuries at nerve endings.

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Effect of a mephedrone exposure (4 doses of 50 mg/kg, s.c. at 2 h interval) on dopamine transporter density, measured as [3H]WIN35428 binding in mouse striatum (A), or frontal cortex (B) and 5-HT transporter density, measured as [3H]paroxetine binding, in hippocampus (C) and frontal cortex (D).Results are expressed as mean±S.E.M. from 8–10 animals. *p<0.05; **p<0.01 and ***p<0.001 vs. saline.
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pone-0099002-g001: Effect of a mephedrone exposure (4 doses of 50 mg/kg, s.c. at 2 h interval) on dopamine transporter density, measured as [3H]WIN35428 binding in mouse striatum (A), or frontal cortex (B) and 5-HT transporter density, measured as [3H]paroxetine binding, in hippocampus (C) and frontal cortex (D).Results are expressed as mean±S.E.M. from 8–10 animals. *p<0.05; **p<0.01 and ***p<0.001 vs. saline.

Mentions: Schedule 1: At 3 and 7 days post-exposition, mephedrone induced a significant loss in DA reuptake sites of about 50% in mouse striatum and frontal cortex membranes (Fig. 1A and 1B). Additionally, mephedrone-exposed mice showed a transient decrease in [3H]paroxetine binding in the frontal cortex that disappeared four days later (Fig. 1D). By contrast, the decrease of [3H]paroxetine binding in the hippocampus was apparent both 3 and 7 days after exposition (Fig. 1C).


Dose and time-dependent selective neurotoxicity induced by mephedrone in mice.

Martínez-Clemente J, López-Arnau R, Abad S, Pubill D, Escubedo E, Camarasa J - PLoS ONE (2014)

Effect of a mephedrone exposure (4 doses of 50 mg/kg, s.c. at 2 h interval) on dopamine transporter density, measured as [3H]WIN35428 binding in mouse striatum (A), or frontal cortex (B) and 5-HT transporter density, measured as [3H]paroxetine binding, in hippocampus (C) and frontal cortex (D).Results are expressed as mean±S.E.M. from 8–10 animals. *p<0.05; **p<0.01 and ***p<0.001 vs. saline.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043985&req=5

pone-0099002-g001: Effect of a mephedrone exposure (4 doses of 50 mg/kg, s.c. at 2 h interval) on dopamine transporter density, measured as [3H]WIN35428 binding in mouse striatum (A), or frontal cortex (B) and 5-HT transporter density, measured as [3H]paroxetine binding, in hippocampus (C) and frontal cortex (D).Results are expressed as mean±S.E.M. from 8–10 animals. *p<0.05; **p<0.01 and ***p<0.001 vs. saline.
Mentions: Schedule 1: At 3 and 7 days post-exposition, mephedrone induced a significant loss in DA reuptake sites of about 50% in mouse striatum and frontal cortex membranes (Fig. 1A and 1B). Additionally, mephedrone-exposed mice showed a transient decrease in [3H]paroxetine binding in the frontal cortex that disappeared four days later (Fig. 1D). By contrast, the decrease of [3H]paroxetine binding in the hippocampus was apparent both 3 and 7 days after exposition (Fig. 1C).

Bottom Line: At a lower dose (schedule 2) only a transient dopaminergic injury was found.Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs.In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.

ABSTRACT
Mephedrone is a drug of abuse marketed as 'bath salts". There are discrepancies concerning its long-term effects. We have investigated the neurotoxicity of mephedrone in mice following different exposition schedules. Schedule 1: four doses of 50 mg/kg. Schedule 2: four doses of 25 mg/kg. Schedule 3: three daily doses of 25 mg/kg, for two consecutive days. All schedules induced, in some animals, an aggressive behavior and hyperthermia as well as a decrease in weight gain. Mephedrone (schedule 1) induced dopaminergic and serotoninergic neurotoxicity that persisted 7 days after exposition. At a lower dose (schedule 2) only a transient dopaminergic injury was found. In the weekend consumption pattern (schedule 3), mephedrone induced dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expression one week after exposition. Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs. In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect. Using repeated doses for 2 days in an elevated ambient temperature we evidenced a loss of frontal cortex dopaminergic and hippocampal serotoninergic neuronal markers that suggest injuries at nerve endings.

Show MeSH
Related in: MedlinePlus