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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 (3 doses of 25 mg/kg s.c. at 2 h interval for 2 days) on total tryptophan hydroxylase TPH2 expression (A) and its phosphorylated form (B) in hippocampus.Panel C shows a representative Western blot. Results are expressed as mean±S.E.M. from 8–10 animals. *p<0.05 and **p<0.01 vs. saline.
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pone-0099002-g004: Effect of a mephedrone exposure (3 doses of 25 mg/kg s.c. at 2 h interval for 2 days) on total tryptophan hydroxylase TPH2 expression (A) and its phosphorylated form (B) in hippocampus.Panel C shows a representative Western blot. Results are expressed as mean±S.E.M. from 8–10 animals. *p<0.05 and **p<0.01 vs. saline.

Mentions: The reduction of 5-HT terminal markers in mephedrone-treated animals was sustained and significant in the frontal cortex (Fig. 3D), and especially pronounced (50%) in the hippocampus after 7 days (Fig. 3C). Consequently, we analyzed another biochemical marker of terminal integrity, TPH2, and its Ser-19 phosphorylated form. In hippocampus, the decrease of [3H]paroxetine binding runs in parallel with a decrease of the total TPH2 (Fig. 4A). In frontal cortex, this expression was lower but not significant (Fig. 5A). In both experiments, the shape of the TPH2 band obtained from mephedrone-treated animals shows differences that can be attributed to a protein modification. As protein phosphorylation in Ser-19 has been described as a frequent mechanism that regulates TPH2 function, we proceeded to determine it. In both brain areas, the remaining enzyme was phosphorylated in the mephedrone group with respect to saline (Fig. 4B, 4C, 5B, 5C).


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 (3 doses of 25 mg/kg s.c. at 2 h interval for 2 days) on total tryptophan hydroxylase TPH2 expression (A) and its phosphorylated form (B) in hippocampus.Panel C shows a representative Western blot. Results are expressed as mean±S.E.M. from 8–10 animals. *p<0.05 and **p<0.01 vs. saline.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0099002-g004: Effect of a mephedrone exposure (3 doses of 25 mg/kg s.c. at 2 h interval for 2 days) on total tryptophan hydroxylase TPH2 expression (A) and its phosphorylated form (B) in hippocampus.Panel C shows a representative Western blot. Results are expressed as mean±S.E.M. from 8–10 animals. *p<0.05 and **p<0.01 vs. saline.
Mentions: The reduction of 5-HT terminal markers in mephedrone-treated animals was sustained and significant in the frontal cortex (Fig. 3D), and especially pronounced (50%) in the hippocampus after 7 days (Fig. 3C). Consequently, we analyzed another biochemical marker of terminal integrity, TPH2, and its Ser-19 phosphorylated form. In hippocampus, the decrease of [3H]paroxetine binding runs in parallel with a decrease of the total TPH2 (Fig. 4A). In frontal cortex, this expression was lower but not significant (Fig. 5A). In both experiments, the shape of the TPH2 band obtained from mephedrone-treated animals shows differences that can be attributed to a protein modification. As protein phosphorylation in Ser-19 has been described as a frequent mechanism that regulates TPH2 function, we proceeded to determine it. In both brain areas, the remaining enzyme was phosphorylated in the mephedrone group with respect to saline (Fig. 4B, 4C, 5B, 5C).

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