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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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Representative hippocampal expression of glial fibrilliary acidic protein (GFAP).Sections of the dentate gyrus (×4 A, B; ×20, C, D) from mice exposed to saline (A, C) or mephedrone (3 doses of 25 mg/kg given subcutaneously for 2 days) (B, D). The animals were sacrificed 7 days after the last dose.
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pone-0099002-g006: Representative hippocampal expression of glial fibrilliary acidic protein (GFAP).Sections of the dentate gyrus (×4 A, B; ×20, C, D) from mice exposed to saline (A, C) or mephedrone (3 doses of 25 mg/kg given subcutaneously for 2 days) (B, D). The animals were sacrificed 7 days after the last dose.

Mentions: To assess the presence of astroglial activation, immunohistochemistry studies were carried out with the glial-specific marker, GFAP. There were no signs of striatal or cortical astroglial activation in mephedrone-treated animals. In the hippocampus, some astrocytes with the typical stellate morphology were observed in control animals, but an apparent increase in GFAP immunoreactivity could be seen in the dentate gyrus of the hippocampus in the mephedrone group, implying reactive astrocytes (Fig. 6).


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)

Representative hippocampal expression of glial fibrilliary acidic protein (GFAP).Sections of the dentate gyrus (×4 A, B; ×20, C, D) from mice exposed to saline (A, C) or mephedrone (3 doses of 25 mg/kg given subcutaneously for 2 days) (B, D). The animals were sacrificed 7 days after the last dose.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0099002-g006: Representative hippocampal expression of glial fibrilliary acidic protein (GFAP).Sections of the dentate gyrus (×4 A, B; ×20, C, D) from mice exposed to saline (A, C) or mephedrone (3 doses of 25 mg/kg given subcutaneously for 2 days) (B, D). The animals were sacrificed 7 days after the last dose.
Mentions: To assess the presence of astroglial activation, immunohistochemistry studies were carried out with the glial-specific marker, GFAP. There were no signs of striatal or cortical astroglial activation in mephedrone-treated animals. In the hippocampus, some astrocytes with the typical stellate morphology were observed in control animals, but an apparent increase in GFAP immunoreactivity could be seen in the dentate gyrus of the hippocampus in the mephedrone group, implying reactive astrocytes (Fig. 6).

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