title: Neuronal changes and oxidative stress in adolescent rats after repeated exposure to mephedrone.
abstract: Mephedrone is a new designer drug of abuse. We have investigated the neurochemical/enzymatic changes after mephedrone administration to adolescent rats (3×25 mg/kg, s.c. in a day, with a 2 h interval between doses, for two days) at high ambient temperature (26±2 °C), a schedule that intends to model human recreational abuse. In addition, we have studied the effect of mephedrone in spatial learning and memory. The drug caused a transient decrease in weight gain. After the first dose, animals showed hypothermia but, after the subsequent doses, temperature raised over the values of saline-treated group. We observed the development of tolerance to these thermoregulatory effects of mephedrone. Mephedrone induced a reduction of the densities of dopamine (30% in the frontal cortex) and serotonin (40% in the frontal cortex and the hippocampus and 48% in the striatum) transporters without microgliosis. These deficits were also accompanied by a parallel decrease in the expression of tyrosine hydroxylase and tryptophan hydroxylase 2. These changes matched with a down-regulation of D2 dopamine receptors in the striatum. Mephedrone also induced an oxidative stress evidenced by an increase of lipid peroxidation in the frontal cortex, and accompanied by a rise in glutathione peroxidase levels in all studied brain areas. Drug-treated animals displayed an impairment of the reference memory in the Morris water maze one week beyond the cessation of drug exposure, while the spatial learning process seems to be preserved. These findings raise concerns about the neuronal long-term effects of mephedrone.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona, Spain; Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: López-Arnau
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona, Spain; Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-Clemente
authors.affiliation: Animal Experimentation Unit of Psychology and Pharmacy, University of Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rodrigo
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona, Spain; Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pubill
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona, Spain; Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Spain. Electronic address: jcamarasa@ub.edu.
authors.forename: Jorge
authors.initials: J
authors.lastname: Camarasa
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona, Spain; Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Escubedo
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015198:Designer Drugs / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D013287:Illicit Drugs / Q000633:toxicity*; D008297:Male; D008568:Memory / Q000187:drug effects; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000633:toxicity; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D065853:Spatial Learning / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D015198:Designer Drugs; D050483:Dopamine Plasma Membrane Transport Proteins; D013287:Illicit Drugs; D050486:Serotonin Plasma Membrane Transport Proteins; D008694:Methamphetamine; C548233:mephedrone; D002374:Catalase; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase; D014365:Tryptophan Hydroxylase; C504570:tph1 protein, rat; C504569:tph2 protein, rat; D013482:Superoxide Dismutase
keywords: Frontal cortex; Hippocampus; Mephedrone; Neurotoxicity; Rat; Striatum