Pharmacology of novel synthetic stimulants structurally related to the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV)

Abstract

There has been a dramatic rise in the abuse of synthetic cathinones known as "bath salts," including 3,4-methylenedioxypyrovalerone (MDPV), an analog linked to many adverse events. MDPV differs from other synthetic cathinones because it contains a pyrrolidine ring which gives the drug potent actions as an uptake blocker at dopamine and norepinephrine transporters. While MDPV is now illegal, a wave of "second generation" pyrrolidinophenones has appeared on the market, with α-pyrrolidinovalerophenone (α-PVP) being most popular. Here, we sought to compare the in vitro and in vivo pharmacological effects of MDPV and its congeners: α-PVP, α-pyrrolidinobutiophenone (α-PBP), and α-pyrrolidinopropiophenone (α-PPP). We examined effects of test drugs in transporter uptake and release assays using rat brain synaptosomes, then assessed behavioral stimulant effects in mice. We found that α-PVP is a potent uptake blocker at dopamine and norepinephrine transporters, similar to MDPV. α-PBP and α-PPP are also catecholamine transporter blockers but display reduced potency. All of the test drugs are locomotor stimulants, and the rank order of in vivo potency parallels dopamine transporter activity, with MDPV > α-PVP > α-PBP > α-PPP. Motor activation produced by all drugs is reversed by the dopamine receptor antagonist SCH23390. Furthermore, results of a functional observational battery show that all test drugs produce typical stimulant effects at lower doses and some drugs produce bizarre behaviors at higher doses. Taken together, our findings represent the first evidence that second generation analogs of MDPV are catecholamine-selective uptake blockers which may pose risk for addiction and adverse effects in human users. This article is part of the Special Issue entitled 'CNS Stimulants'.

Keywords: 3,4-Methylenedioxypyrovalerone; Functional observational battery; Locomotor activity; Monoamine transporter; Synthetic cathinones; α-PVP.

Figure 1

Chemical structures of pyrrolidinophenone compounds in comparison to MDPV.

Figure 2

Effects of test drugs on inhibition of [³H]transmitter uptake by DAT, NET, and SERT in rat brain tissue. Synaptosomes were incubated with different concentrations of test drug in the presence of 5 nM [³H]dopamine for DAT, 5 nM [³H]norepinephrine for NET, or 5 nM [³H]serotonin for SERT. Data are percentage of control uptake expressed as mean±SD for n=3 experiments performed in triplicate.

Figure 3

Effects of pyrrolidinophenone drugs on cumulative locomotor activity during 60 min sessions, plotted as a function of dose. Asterisks (*) represent doses that produced significant increases in beam breaks compared to saline.

Figure 4

Time course effects of pyrrolidinophenone drugs on locomotor activity, plotted as a function of 10 min bins during a 60-min test session. Values represent mean±SEM expressed as number of beam breaks for each dose (n=8 per dose except n=16 for saline). Asterisks (*) within each panel indicate doses and time points that showed significant increases in beam breaks compared to saline at the same time point. Panel A shows data for MPDV, panel B shows data for α-PVP, panel C shows data for α-PBP, and panel D shows data for α-PPP.

Figure 5

Effects of vehicle or SCH23390 (0.03 mg/kg) tested in combination with vehicle or a test drug on locomotor activity during 60 min sessions. Values represent mean±SEM expressed