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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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Related in: MedlinePlus

Effect of mephedrone on immobility time in mouse forced swim test.Animals were randomly divided into two groups (12–16 animals/group) and administered subcutaneously with saline (5 ml/kg) or mephedrone (3 doses of 25 mg/kg for 2 days) and tested 1, 3 or 7 days after exposure. Each animal was recorded for 6 min and the total period of immobility (in seconds) was registered. Each mouse was used only once for each experimental session. Each bar represents mean±S.E.M. immobility time. *p<0.05 and ***p<0.001 vs saline (one-way ANOVA and post hoc Tukey test).
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pone-0099002-g007: Effect of mephedrone on immobility time in mouse forced swim test.Animals were randomly divided into two groups (12–16 animals/group) and administered subcutaneously with saline (5 ml/kg) or mephedrone (3 doses of 25 mg/kg for 2 days) and tested 1, 3 or 7 days after exposure. Each animal was recorded for 6 min and the total period of immobility (in seconds) was registered. Each mouse was used only once for each experimental session. Each bar represents mean±S.E.M. immobility time. *p<0.05 and ***p<0.001 vs saline (one-way ANOVA and post hoc Tukey test).

Mentions: In schedule 3, mephedrone significantly increased the immobility time in the FST as compared with saline group (F3,44 = 5.509, p<0.01). Post hoc Tukey's means comparison test demonstrated that 3 days post-exposition mephedrone significantly increased the immobility time (saline: 125.43±11.83 s; mephedrone: 217.83±19.55 s p<0.001). This increase was still significant 7 days post-exposition (178.80±22.45 s p<0.05). Moreover, mephedrone exposure failed to influence the immobility time in FST 24 h after the last administration (Fig. 7).


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 mephedrone on immobility time in mouse forced swim test.Animals were randomly divided into two groups (12–16 animals/group) and administered subcutaneously with saline (5 ml/kg) or mephedrone (3 doses of 25 mg/kg for 2 days) and tested 1, 3 or 7 days after exposure. Each animal was recorded for 6 min and the total period of immobility (in seconds) was registered. Each mouse was used only once for each experimental session. Each bar represents mean±S.E.M. immobility time. *p<0.05 and ***p<0.001 vs saline (one-way ANOVA and post hoc Tukey test).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0099002-g007: Effect of mephedrone on immobility time in mouse forced swim test.Animals were randomly divided into two groups (12–16 animals/group) and administered subcutaneously with saline (5 ml/kg) or mephedrone (3 doses of 25 mg/kg for 2 days) and tested 1, 3 or 7 days after exposure. Each animal was recorded for 6 min and the total period of immobility (in seconds) was registered. Each mouse was used only once for each experimental session. Each bar represents mean±S.E.M. immobility time. *p<0.05 and ***p<0.001 vs saline (one-way ANOVA and post hoc Tukey test).
Mentions: In schedule 3, mephedrone significantly increased the immobility time in the FST as compared with saline group (F3,44 = 5.509, p<0.01). Post hoc Tukey's means comparison test demonstrated that 3 days post-exposition mephedrone significantly increased the immobility time (saline: 125.43±11.83 s; mephedrone: 217.83±19.55 s p<0.001). This increase was still significant 7 days post-exposition (178.80±22.45 s p<0.05). Moreover, mephedrone exposure failed to influence the immobility time in FST 24 h after the last administration (Fig. 7).

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