- 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

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$135,003
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
Prekupec, Matthew P; Mansky, Peter A; Baumann, Michael H (2017) Misuse of Novel Synthetic Opioids: A Deadly New Trend. J Addict Med 11:256-265
Solis Jr, Ernesto; Partilla, John S; Sakloth, Farhana et al. (2017) N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability. Neuropsychopharmacology 42:1950-1961
Elmore, Joshua S; Dillon-Carter, Ora; Partilla, John S et al. (2017) Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats. Neuropsychopharmacology 42:649-660
Baumann, Michael H; Bukhari, Mohammad O; Lehner, Kurt R et al. (2017) Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), Its Metabolites, and Related Analogs. Curr Top Behav Neurosci 32:93-117
McLaughlin, Gavin; Morris, Noreen; Kavanagh, Pierce V et al. (2017) Synthesis, characterization and monoamine transporter activity of the new psychoactive substance mexedrone and its N-methoxy positional isomer, N-methoxymephedrone. Drug Test Anal 9:358-368
Hoffman, Alexander F; Lycas, Matthew D; Kaczmarzyk, Jakub R et al. (2017) Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid 'Spice' compounds: comparison with ?(9) -tetrahydrocannabinol. Addict Biol 22:390-399
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 26:288-297
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
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

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