title: The combined effects of 3,4-methylenedioxymethamphetamine (MDMA) and selected substituted methcathinones on measures of neurotoxicity.
abstract: The rise in popularity of substituted methcathinones (aka "bath salts") has increased the focus on their neurotoxic effects. Two commonly abused methcathinones, 3,4-methylenedioxymethcathinone (methylone, MDMC) and 3,4-methylenedioxypyrovalerone (MDPV), are often concomitantly ingested with the illicit drug 3,4-methylenedioxymethamphetamine (MDMA). To examine potential neurotoxic effects of these drug combinations, C57BL/6J mice were administered 4 i.p. injection of the drugs, at 2h intervals, either singularly: MDMA 15 or 30mg/kg, methylone 20mg/kg, MDPV 1mg/kg; or in combination: methylone/MDMA 20/15mg/kg, MDPV/MDMA 1/15mg/kg. Drug effects on thermoregulation were characterized and striatal tissue analyzed after 2 or 7days for dopamine (DA) and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. Two days following drug administration, DA and TH were decreased only in the MDMA 30mg/kg group, whereas GFAP expression was dose-dependently increased by MDMA alone. While the combination of the methcathinones with the lower MDMA dose did not affect DA or TH levels, both blocked the MDMA-induced increase in GFAP expression. Seven days following drug administration, there were no significant differences in DA, TH, or GFAP for any treatment group, indicating that changes in DA, TH, and GFAP were transient. Five of the six drug groups exhibited acute hypothermia followed by gradually increasing temperatures. Animals treated with MDPV did not exhibit these biphasic temperature changes, and resembled the saline group. These results indicate that specific effects of both methylone and MDPV on DA depletion or astrocyte activation in the striatum are not additive with effects of MDMA, but block astrogliosis caused by MDMA alone. Additionally, MDPV modulates thermoregulation through a different mechanism than methylone or MDMA.
authors.affiliation: Research Service, VA Portland Health Care System, Portland, OR, USA; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Miner
authors.affiliation: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.affiliation: Research Service, VA Portland Health Care System, Portland, OR, USA; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA; The Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Phillips
authors.affiliation: Research Service, VA Portland Health Care System, Portland, OR, USA; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA; The Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, USA; Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA. Electronic address: janowsky@ohsu.edu.
authors.forename: Aaron
authors.initials: A
authors.lastname: Janowsky
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000633:toxicity*; D001833:Body Temperature Regulation / Q000187:drug effects*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000633:toxicity; D051379:Mice; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011759:Pyrrolidines / Q000633:toxicity*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D000094982:Synthetic Cathinone
chemical_list: D052117:Benzodioxoles; D005904:Glial Fibrillary Acidic Protein; D011759:Pyrrolidines; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C400939:methylone; D004298:Dopamine; D000094982:Synthetic Cathinone
keywords: Dopamine; GFAP; MDMA; MDPV; Methylone; Neurotoxicity