title: Effects of combined treatment with mephedrone and methamphetamine or 3,4-methylenedioxymethamphetamine on serotonin nerve endings of the hippocampus.
abstract: OBJECTIVE
  Mephedrone is a stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Although mephedrone does not damage dopamine nerve endings it increases the neurotoxicity of amphetamine, methamphetamine and MDMA. The effects of mephedrone on serotonin (5HT) nerve endings are not fully understood, with some investigators reporting damage while others conclude it does not. Presently, we investigate if mephedrone given alone or with methamphetamine or MDMA damages 5HT nerve endings of the hippocampus.
  
  
  METHODS
  The status of 5HT nerve endings in the hippocampus of female C57BL mice was assessed through measures of 5HT by HPLC and by immunoblot analysis of serotonin transporter (SERT) and tryptophan hydroxylase 2 (TPH2), selective markers of 5HT nerve endings. Astrocytosis was assessed through measures of glial fibrillary acidic protein (GFAP) (immunoblotting) and microglial activation was determined by histochemical staining with Isolectin B4.
  
  
  RESULTS
  Mephedrone alone did not cause persistent reductions in the levels of 5HT, SERT or TPH2. Methamphetamine and MDMA alone caused mild reductions in 5HT but did not change SERT and TPH2 levels. Combined treatment with mephedrone and methamphetamine or MDMA did not change the status of 5HT nerve endings to an extent that was different from either drug alone.
  
  
  CONCLUSIONS
  Mephedrone does not cause toxicity to 5HT nerve endings of the hippocampus. When co-administered with methamphetamine or MDMA, drugs that are often co-abused with mephedrone by humans, toxicity is not increased as is the case for dopamine nerve endings when these drugs are taken together.
authors.affiliation: Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USA; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Angoa-Pérez
authors.affiliation: Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USA; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kane
authors.affiliation: Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USA; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Nieves
authors.initials: N
authors.lastname: Herrera-Mundo
authors.affiliation: Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USA; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Dina M
authors.initials: DM
authors.lastname: Francescutti
authors.affiliation: Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI 48201, USA; Department of Psychiatry & Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: donald.kuhn@wayne.edu.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Kuhn
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D015198:Designer Drugs / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008694:Methamphetamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D009411:Nerve Endings / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; D015198:Designer Drugs; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D008694:Methamphetamine; C548233:mephedrone; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: Bath salts; MDMA; Mephedrone; Methamphetamine; Neurotoxicity; Serotonin
references.citation: Curr Neuropharmacol. 2011 Mar;9(1):58-62
references.pmid: 21886563
references.citation: Eur Neuropsychopharmacol. 2013 Sep;23(9):1085-95
references.pmid: 23051939
references.citation: J Neurochem. 2012 Mar;120(6):1097-107
references.pmid: 22191803
references.citation: Neurotox Res. 2007 Apr;11(3-4):183-202
references.pmid: 17449459
references.citation: NIDA Res Monogr. 1993;136:188-212
references.pmid: 8289911
references.citation: Forensic Sci Int. 2010 Oct 10;202(1-3):e62-3
references.pmid: 20685050
references.citation: Br J Pharmacol. 2012 Sep;167(2):407-20
references.pmid: 22509960
references.citation: Exp Neurol. 2004 May;187(1):47-57
references.pmid: 15081587
references.citation: Neuropsychopharmacology. 2012 Apr;37(5):1192-203
references.pmid: 22169943
references.citation: Crit Rev Neurobiol. 2005;17(2):87-117
references.pmid: 16808729
references.citation: Neurotoxicology. 2012 Oct;33(5):1305-13
references.pmid: 22922498
references.citation: J Pharmacol Exp Ther. 2004 Oct;311(1):1-7
references.pmid: 15163680
references.citation: J Pharmacol Exp Ther. 1994 Aug;270(2):741-51
references.pmid: 8071867
references.citation: J Psychopharmacol. 2011 Nov;25(11):1543-7
references.pmid: 20826554
references.citation: J Pharmacol Exp Ther. 2011 Nov;339(2):530-6
references.pmid: 21810934
references.citation: Pharmacol Biochem Behav. 2013 Jan;103(3):501-9
references.pmid: 23099177
references.citation: J Neurochem. 2010 Nov;115(3):595-605
references.pmid: 20722968
references.citation: Psychopharmacology (Berl). 2011 Apr;214(3):593-602
references.pmid: 21072502
references.citation: Br J Pharmacol. 2013 Jan;168(2):458-70
references.pmid: 22897747
references.citation: Addiction. 2011 Nov;106(11):1991-6
references.pmid: 21592252
references.citation: Lancet. 2010 Apr 17;375(9723):1333-4
references.pmid: 20405534
references.citation: Eur Addict Res. 2013;19(5):276-82
references.pmid: 23615495
references.citation: Psychopharmacology (Berl). 2004 May;173(3-4):249-63
references.pmid: 15083264
references.citation: Brain Res. 2006 Apr 26;1085(1):11-8
references.pmid: 16581041
references.citation: Synapse. 2011 Dec;65(12):1368-72
references.pmid: 21633976
references.citation: Ann N Y Acad Sci. 2008 Oct;1139:118-26
references.pmid: 18991856
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2012 Dec 3;39(2):227-33
references.pmid: 22564711
references.citation: PLoS One. 2012;7(9):e45473
references.pmid: 23029034
references.citation: Eur J Pharmacol. 1999 Sep 17;381(1):63-9
references.pmid: 10528135
references.citation: Br J Pharmacol. 2011 Dec;164(8):1949-58
references.pmid: 21615721
references.citation: J Neurochem. 2013 Apr;125(1):102-10
references.pmid: 23205838
references.citation: Ann Pharmacother. 2012 Mar;46(3):436-41
references.pmid: 22388331
references.citation: Neurosci Lett. 2004 Sep 9;367(3):349-54
references.pmid: 15337264
references.citation: J Med Toxicol. 2012 Mar;8(1):33-42
references.pmid: 22108839
references.citation: J Pharmacol Exp Ther. 2005 Sep;314(3):1002-12
references.pmid: 15937150
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:681-98
references.pmid: 17209801
references.citation: Biochem Pharmacol. 2013 Jun 15;85(12):1803-15
references.pmid: 23583454
references.citation: Forensic Sci Int. 2006 Sep 12;161(2-3):202-8
references.pmid: 16842946
references.citation: Addiction. 2011 Jan;106(1):154-61
references.pmid: 20735367
references.citation: Psychopharmacology (Berl). 2007 Jan;189(4):407-24
references.pmid: 16541247
references.citation: Addict Biol. 2012 Mar;17(2):409-22
references.pmid: 21995495
references.citation: Synapse. 2004 Sep 15;53(4):240-8
references.pmid: 15266556
references.citation: J Neurochem. 2008 May;105(3):605-16
references.pmid: 18088364
references.citation: Drug Alcohol Depend. 2012 Nov 1;126(1-2):257-62
references.pmid: 22652295
references.citation: J Neurochem. 2005 Feb;92(4):790-7
references.pmid: 15686480
references.citation: Drug Test Anal. 2011 Jul-Aug;3(7-8):439-53
references.pmid: 21755607
references.citation: Drug Alcohol Depend. 2006 Jul 27;83(3):247-54
references.pmid: 16364567
references.citation: Neuropsychopharmacology. 2006 Dec;31(12):2639-51
references.pmid: 16452989
references.citation: J Neurochem. 2009 Jun;109(6):1745-55
references.pmid: 19457119
references.citation: Eur J Pharmacol. 2007 Mar 22;559(2-3):132-7
references.pmid: 17223101
references.citation: J Pharmacol Exp Ther. 1994 Mar;268(3):1571-80
references.pmid: 8138969
references.citation: Eur Neuropsychopharmacol. 2012 Mar;22(3):231-6
references.pmid: 21824752