3,4-Methylenedioxypyrovalerone: Neuropharmacological Impact of a Designer Stimulant of Abuse on Monoamine Transporters

Abstract

Methylenedioxypyrovalerone (MDPV) is an abused synthetic cathinone, commonly referred to as a "bath salt." Because the dopamine (DA) transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) are key regulators of both the abuse and neurotoxic potential of structurally and behaviorally related agents, the impact of MDPV on these transporters was investigated. Results revealed that a single in vivo MDPV administration rapidly (within 1 hour) and reversibly increased both rat striatal DAT and VMAT-2 activity, as assessed via [ 3 H]DA uptake in synaptosomes and synaptic vesicles, respectively, prepared from treated rats. There was no evidence of an MDPV-induced increase in plasmalemmal membrane DAT surface expression. Plasma concentrations of MDPV increased dose-dependently as assessed 1 hour after 2.5 and 5.0 mg/kg (s.c.) administration and returned to levels less than 10 ng/ml by 18 hours after 2.5 mg/kg (s.c.). Neither pretreatment with a D1 receptor (SCH23390), a D2 receptor (eticlopride), nor a nicotinic receptor (mecamylamine) antagonist attenuated the MDPV-induced increase in DAT activity. In contrast, eticlopride pretreatment attenuated both the MDPV-induced increase in VMAT-2-mediated DA uptake and an associated increase in cytoplasmic-associated vesicle VMAT-2 immunoreactivity. SCH23390 did not attenuate the MDPV-induced increase in VMAT-2 activity. Repeated MDPV injections did not cause persistent DAergic deficits, as assessed 7 to 8 days later. The impact of MDPV on striatal and hippocampal serotonergic assessments was minimal. Taken together, these data contribute to a growing pharmacological rubric for evaluating the ever-growing list of designer cathinone-related stimulants. The profile of MDPV compared with related psychostimulants is discussed. SIGNIFICANCE STATEMENTPharmacological characterization of the synthetic cathinone, 3,4-methylenedioxypyrovalerone (MDPV; commonly referred to as a "bath salt"), is critical for understanding the abuse liability and neurotoxic potential of this and related agents. Accordingly, the impact of MDPV on monoaminergic neurons is described and compared with that of related psychostimulants.

Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature

“…From the five published studies on MDPV induced striatal toxicity (DA, DAT, TH, and GFAP levels) [ 22 , 26 , 27 , 62 , 71 ], three support our results, reporting no alterations 48 h after a high [ 26 ] or low [ 27 ] dose short binge regimen (4 × 30 or 1 mg/kg, every 2 h) or 24 h after a single MDPV administration (2.5 or 5 mg/kg) [ 71 ]. On the other hand, some alterations were reported after longer binge regimens (2 × 1.5 mg/kg, for seven days) [ 62 ] or single MDPV doses [ 22 , 71 ]. Duart-Castells et al reported unchanged DAT, but increased TH and D1 DA receptor (DRD1) 24 h after the last dose [ 62 ].…”

“…Duart-Castells et al reported unchanged DAT, but increased TH and D1 DA receptor (DRD1) 24 h after the last dose [ 62 ]. Increased DAT activity was reported as early as 1 h post MDPV-exposure [ 22 ]. This is in line with the observations of Lopez-Arnau et al that showed a rapid and reversible functional upregulation of DAT in synaptosomes (increasing 1–3 h after 1.5 mg/kg MDPV-exposure, but not 16 h later), more powerfully and lasting than cocaine [ 72 ].…”

“…Moreover, MDPV was shown to completely protect against METH neurotoxicity, by blocking DAT-mediated transport [ 10 ], preventing METH uptake and striatum DA nerve ending characteristic METH induced damage hallmarks (DAT and TH reduction and GFAP upregulation) [ 26 ]. The following MDPV pharmacological properties may account for its neurochemical profile: 1—MDPV is a DAT blocker (not a substrate [ 73 ]) with a strong molecular affinity and, therefore, is not internalized to the cytoplasm as quickly as METH [ 10 ]; 2—MDPV high lipophilicity and presumed transendothelial active transport [ 10 ] contributes to its short half-life (≈1–2 h, in men) [ 18 , 74 ] compared to METH (≈10 h, in men) [ 75 ]; 3—MDPV potential dual action on DAT (one to inhibit and a second to enhance DAT function) might contribute to its highly reinforcing properties while also mitigating persistent dopaminergic deficits due to aberrant DA transport [ 22 ]. Additionally, Araújo et al performed in vivo toxicometabolomics following a MDPV binge regimen similar to the one we used and consistently reported minor changes in the brain [ 76 ].…”

“…MDPV high lipophilicity may be held responsible for its enhanced blood–brain barrier (BBB) permeability [ 2 , 3 ] and drug brain levels [ 5 ], hence contributing to its potency at DAT and, therefore, to the dose-dependent increase of extracellular dopamine (DA) in the nucleus accumbens (NAc), often associated with locomotor and rewarding effects [ 7 , 12 , 13 ]. MDPV has been mostly studied for its psychostimulant features with abuse potential [ 6 ], namely the locomotor activity [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], self-administration behavior [ 14 , 19 , 21 , 22 ], conditioned place preference [ 20 , 23 ], and drug discrimination [ 14 , 17 , 24 ] parameters. Undoubtedly, this synthetic cathinone acts as a potent CNS stimulant, which raises obvious concerns about its potential neurotoxic effects, and possibly amphetamine-like effects, due to their structural similarity.…”

“…MDPV impact on the vesicular/plasma transporters and the synaptic levels of monoamines, thermoregulation, oxidative stress, and cytotoxicity may represent an important mechanism of action [ 25 ]. However, data on the underlying mechanisms of MDPV induced neurotoxicity is not abundant [ 4 , 22 , 26 , 27 ] and mostly circumscribed to in vitro studies [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ], hampering proper risk characterization and adverse effect management [ 2 , 5 , 25 ]. Indeed, the scarce data available suggests that synthetic cathinones may exert differential neurotoxic properties on monoaminergic neurons and elicit more complex responses than non-keto amphetamines (e.g., METH) [ 25 ].…”