- Substantial progress was made on this project, with two original research articles and two reviews published. In particular, we have described the pharmacology of the designer drug 3,4-methylenedioxypyrovalerone (MDPV), which is a principle constituent of psychoactive bath salts products. MDPV is a powerful dopamine uptake blocker that increases extracellular concentrations of dopamine in the brain. Thus, this stimulant is predicted to pose significant risk for addiction and other adverse effects. Powerful cocaine-like actions of 3,4-Methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts'products (2013) Baumann MH, Partilla JS, Lehner KR, et al. Neuropsychopharmacology 38:552-562. The abuse of psychoactive 'bath salts'containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods. In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats. We found that MDPV blocks uptake of (3)Hdopamine (IC(50)=4.1 nM) and (3)Hnorepinephrine (IC(50)=26 nM) with high potency but has weak effects on uptake of (3)Hserotonin (IC(50)=3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats. Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts'preparations.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$609,062
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
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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