- Substantial progress was made on this project, and three papers were published. In particular, we have described the pharmacology and toxicology of the designer drugs, mephedrone and methylone. Both of these agents are widely abused bath salts cathinones. The drugs are transporter substrates that produce effects that are similar to those produced by MDMA, or Ecstasy. Thus, our data suggest that mephedrone and methylone have significant potential for abuse. The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. (2012) Neuropsychopharmacology 37:1192-1203. The nonmedical use of 'designer'cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study

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Marusich, Julie A; Antonazzo, Kateland R; Blough, Bruce E et al. (2016) The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue. Neuropharmacology 101:68-75
McLaughlin, Gavin; Morris, Noreen; Kavanagh, Pierce V et al. (2016) Synthesis, characterization and monoamine transporter activity of the new psychoactive substance mexedrone and its N-methoxy positional isomer, N-methoxymephedrone. Drug Test Anal :
Baumann, Michael H (2016) The Changing Face of Recreational Drug Use. Cerebrum 2016:
Hutsell, Blake A; Baumann, Michael H; Partilla, John S et al. (2016) Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats. Eur Neuropsychopharmacol 26:288-97
Carlier, Jeremy; Scheidweiler, Karl B; Wohlfarth, Ariane et al. (2016) Quantification of [1-(5-fluoropentyl)-1H-indol-3-yl](naphthalene-1-yl)methanone (AM-2201) and 13 metabolites in human and rat plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr A 1451:97-106
Mayer, F P; Wimmer, L; Dillon-Carter, O et al. (2016) Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters. Br J Pharmacol 173:2657-68
Hoffman, Alexander F; Lycas, Matthew D; Kaczmarzyk, Jakub R et al. (2016) Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid 'Spice' compounds: comparison with Δ(9) -tetrahydrocannabinol. Addict Biol :
Concheiro, Marta; Baumann, Michael H; Scheidweiler, Karl B et al. (2014) Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA) and its pharmacodynamic consequences in the rat. Drug Metab Dispos 42:119-25
Kiyatkin, Eugene A; Kim, Albert H; Wakabayashi, Ken T et al. (2014) Critical role of peripheral vasoconstriction in fatal brain hyperthermia induced by MDMA (Ecstasy) under conditions that mimic human drug use. J Neurosci 34:7754-62
Kiyatkin, Eugene A; Kim, Albert H; Wakabayashi, Ken T et al. (2014) Effects of Social Interaction and Warm Ambient Temperature on Brain Hyperthermia Induced by the Designer Drugs Methylone and MDPV. Neuropsychopharmacology :

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