Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive 'Bath Salts' Products.

Medicinal Chemistry Section of the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 8.68). 10/2012; DOI: 10.1038/npp.2012.204
Source: PubMed

ABSTRACT 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)H]dopamine (IC(50)=4.1 nM) and [(3)H]norepinephrine (IC(50)=26 nM) with high potency but has weak effects on uptake of [(3)H]serotonin (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.Neuropsychopharmacology advance online publication, 17 October 2012; doi:10.1038/npp.2012.204.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Predicting the effect that new compounds might have when administered to human beings is a common desire shared by researchers in the pharmaceutical industry and those interested in psychoactive compounds (illicit or otherwise). The experience of the pharmaceutical industry is that making such predictions at a usefully accurate level is not only difficult but that even when billions of dollars are spent to ensure that only compounds likely to have a desired effect without unacceptable side-effects are dosed to humans in clinical trials, they fail in more than 90% of cases. A range of experimental and computational techniques is used and they are placed in their context in this paper. The particular roles played by computational techniques and their limitations are highlighted; these techniques are used primarily to reduce the number of experiments that must be performed but cannot replace those experiments. Copyright © 2013 John Wiley & Sons, Ltd.
    Drug Testing and Analysis 12/2013; · 3.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the last few years, the variety and recreational use of 'legal high' designer stimulants has increased to unprecedented levels. Since their rapid emergence in drug markets, numerous adverse physical and psychological effects have been extensively reported. However, less is understood about the potential for compulsive use of and addiction to these drugs. Recently, a small collection of scientific studies assessing the abuse liability of these drugs has emerged. This new knowledge has been derived primarily from animal studies using behaviorally based procedures which include intravenous self-administration, conditioned place preference, intracranial self-stimulation, and drug discrimination. In this review we present a brief history of the recent rise in designer stimulant use followed by a short methodological description of the aforementioned procedures. We then review neurochemical and abuse liability studies on designer stimulants that have been examined to date. Finally, we conclude with a discussion of these collective findings, our current understanding of the abuse liability of these drugs in relation to each other and the illicit drugs they are designed to mimic, and recommend future research directions.
    Behavioural pharmacology 07/2013; · 2.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The birth of the twenty first century has provoked a substantial rise in the use of designer drugs, such as synthetic cathinones, because of a decrease in the availability and purity of other drugs of abuse. The Khat plant or Catha edulis, contains cathinone, the parent compound. Synthetic cathinones are sold under the name "bath salts" as a ploy to circumvent legislation from banning their use. Constant modification of the chemical structure by covert laboratories allows manufacturers to stay one step ahead of the legal process. Currently, the widespread distribution of "bath salts" has negative consequences for law enforcement officials and public health resources. Comparable mechanisms of action, between the synthetic cathinones and amphetamine, cocaine, and MDMA are attributed to the similarities in their chemical structures. Synthetic cathinone's potent stimulatory effects, coupled with their high abuse potential, and propensity for addiction demands additional pharmacological and toxicological evaluations for these existing and new designer drugs of abuse. If these drugs are designed carefully, they might also have a significant therapeutic value.
    Toxicology Letters 06/2014; · 3.15 Impact Factor


Available from
Jun 2, 2014