title: Methylone-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters.
abstract: Methylone (2-methylamino-1-[3,4-methylenedioxy-phenyl]propan-1-one), an amphetamine analog, has emerged as a popular drug of abuse worldwide. Methylone induces hyperthermia, which is thought to contribute toward the lethal consequences of methylone overdose. Methylone has been assumed to induce hyperthermic effects through inhibition of serotonin and/or dopamine transporters (SERT and DAT, respectively). To examine the roles of each of these proteins in methylone-induced toxic effects, we used SERT and DAT knockout (KO) mice and assessed the hyperthermic and lethal effects caused by a single administration of methylone. Methylone produced higher rates of lethal toxicity compared with other amphetamine analogs in wild-type mice. Compared with wild-type mice, lethality was significantly lower in DAT KO mice, but not in SERT KO mice. By contrast, only a slight diminution in the hyperthermic effects of methylone was observed in DAT KO mice, whereas a slight enhancement of these effects was observed in SERT KO mice. Administration of the selective D1 receptor antagonist SCH 23390 and the D2 receptor antagonist raclopride reduced methylone-induced hyperthermia, but these drugs also had hypothermic effects in saline-treated mice, albeit to a smaller extent than the effects observed in methylone-treated mice. In contradistinction to 3,4-methylenedioxymethamphetamine, which induces its toxicity through SERT and DAT, these data indicate that DAT, but not SERT, is strongly associated with the lethal toxicity produced by methylone, which did not seem to be dependent on the hyperthermic effects of methylone. DAT is therefore a strong candidate molecule for interventions aimed at preventing acute neurotoxic and lethal effects of methylone.
authors: aDepartment of Biological Psychiatry, Tohoku University Graduate School of Medicine, Sendai bDivision of Pharmacognosy, Phytochemistry, and Narcotics, National Institute of Health Sciences, Tokyo cDepartment of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan dDepartment of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio eLaboratory of Clinical Science, National Institute of Mental Health, Bethesda fMolecular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, USA gDepartment of Psychiatry, University of Wurzburg, Wurzburg, Germany hDepartment of Geriatrics, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors: Ying-Shan
authors: YS
authors: Piao
authors: Frank Scott
authors: FS
authors: Hall
authors: Yuki
authors: Y
authors: Moriya
authors: Miki
authors: M
authors: Ito
authors: Arihisa
authors: A
authors: Ohara
authors: Ruri
authors: R
authors: Kikura-Hanajiri
authors: Yukihiro
authors: Y
authors: Goda
authors: Klaus-Peter
authors: KP
authors: Lesch
authors: Dennis L
authors: DL
authors: Murphy
authors: George R
authors: GR
authors: Uhl
authors: Ichiro
authors: I
authors: Sora
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005334:Fever / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000633:toxicity; D018345:Mice, Knockout; D023421:Models, Animal; D020891:Raclopride / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001552:Benzazepines; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C534628:SCH 23390; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D020891:Raclopride; D008694:Methamphetamine; C400939:methylone