Concentrations of MDPV in rat striatum correlate with the psychostimulant effect

Abstract

3,4-methylenedioxypyrovalerone or MDPV is a synthetic cathinone with psychostimulant properties more potent than cocaine. We quantified this drug in the striatum after subcutaneous administration to rats. MDPV reached the brain around 5 min after its administration and peaked at 20-25 min later. The elimination half-life in the striatum (61 min) correlates with the decrease in the psychostimulant effect after 60 min. Around 11% of the administered dose reached the striatum and, considering a homogeneous brain distribution, we determined that around 86% of the plasma MDPV is distributed to the brain. MDPV induced a dose-dependent increase in locomotor activity, rearing behaviour and stereotypies, all prevented by haloperidol. A plot of locomotor activity or stereotypies versus MDPV striatal concentrations over time showed a direct relationship between factors. No free MDPV metabolites were detected in plasma, at any time, but hydrolysis with glucuronidase allowed us to identify mainly three metabolites, one of them for the first time in rat plasma. The present results contribute to evidence that MDPV induces hyperlocomotion mainly through a dopamine-dependent mechanism. Good correlation between behavioural effects and striatal levels of MDPV leads us to conclude that its psychostimulant effect is mainly due to a striatal distribution of the substance. The present research provides useful information on the pharmacokinetics of MDPV, and can help design new experiments with kinetics data as well as provide a better understanding of the effects of MDPV in humans and its potential interactions.

The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

“…These results suggest that the central mechanisms of the locomotor stimulant actions of MDPV at least partly involve dopaminergic stimulation, which was attenuated by cis-flupenthixol pretreatment. These results are consistent with a recent study showing that MDPV stimulated locomotor activity at the same doses and administration routes used in the present work (Novellas et al, 2015). Novellas et al (2015) found that pretreatment with haloperidol, an antagonist for dopamine and other amine neurotransmitter receptors, 10 min before MDPV administration completely blocked the locomotor stimulant actions of MDPV.…”

“…These results are consistent with a recent study showing that MDPV stimulated locomotor activity at the same doses and administration routes used in the present work (Novellas et al, 2015). Novellas et al (2015) found that pretreatment with haloperidol, an antagonist for dopamine and other amine neurotransmitter receptors, 10 min before MDPV administration completely blocked the locomotor stimulant actions of MDPV. When compared with the present partial effects of the more selective dopamine receptor blocker, this might suggest that other neurotransmitter systems are involved in MDPV's potent stimulant actions.…”

“…Therefore, it is not likely that these metabolites have a role in increased MDPV-induced locomotor activity and stereotypy. It is important to note that at this time point (1 h postadministration) striatal MDPV concentrations are still near peak levels, although plasma levels have dropped to below 50% peak concentrations (Novellas et al, 2015). Thus, activity of MDPV in striatal regions might account, in part, for our observed results.…”

“…This time point was chosen because there is potentiation of brain reward function by MDPV doses in the range of 0.32-3.2 mg/kg (subcutaneously) within the first 100 min after administration (Bonano et al, 2014), whereas the hyperthermia and putative effects on cerebral blood flow have subsided by 40 min . Plasma concentrations of major MDPV metabolites are still low at this time, whereas MDPV is highly concentrated in dorsal striatal tissue and is still present at almost 50% peak plasma concentrations (Anizan et al, 2014;Novellas et al, 2015). Rats were administered sterile saline (1 ml/kg, intraperitoneally) or a single dose of MDPV (in mg/kg: 0.3, 1.0, and 3.0; n = 7-8 rats per dose) 25 min before induction of anesthesia using 3-4% isoflurane delivered in medical grade air (70% nitrogen/30% oxygen; air flow rate 1.5 ml/min).…”

Locomotor Stimulant and Rewarding Effects of Inhaling Methamphetamine, MDPV, and Mephedrone via Electronic Cigarette-Type Technology

“…The attenuation of locomotor response by SCH23390 confirms the mechanistic involvement of D1-like receptors. SCH23390 has been previously shown to block expression of MA-, mephedrone-, and cocaine-induced hyperactivity in rodents after injection (Hall et al, 2009;Lisek et al, 2012;Rauhut, 2015;Schindler and Carmona, 2002), and MDPV-induced hyperactivity has also been shown to be mediated through a dopamine receptordependent mechanism (Marusich et al, 2014;Novellas et al, 2015). Our findings demonstrate that an increase in locomotor activity induced by the inhalation of MA, MDPV, and mephedrone is similarly mediated by a D1-like receptordependent mechanism.…”