Behavioural, Pharmacokinetic, Metabolic, and Hyperthermic Profile of 3,4-Methylenedioxypyrovalerone (MDPV) in the Wistar Rat

Abstract

3,4-methylenedioxypyrovalerone (MDPV) is a potent pyrovalerone cathinone that is substituted for amphetamines by recreational users. We report a comprehensive and detailed description of the effects of subcutaneous MDPV (1–4 mg/kg) on pharmacokinetics, biodistribution and metabolism, acute effects on thermoregulation under isolated and aggregated conditions, locomotion (open field) and sensory gating (prepulse inhibition, PPI). All studies used male Wistar rats. Pharmacokinetics after single dose of 2 mg/kg MDPV was measured over 6 h in serum, brain and lungs. The biotransformation study recorded 24 h urinary levels of MDPV and its metabolites after 4 mg/kg. The effect of 2 mg/kg and 4 mg/kg on body temperature (°C) was measured over 12 h in group- vs. individually-housed rats. In the open field, locomotion (cm) and its spatial distribution were assessed. In PPI, acoustic startle response (ASR), habituation, and PPI were measured (AVG amplitudes). In behavioural experiments, 1, 2, or 4 mg/kg MDPV was administered 15 or 60 min prior to testing. Thermoregulation and behavioural data were analysed using factorial analysis of variance (ANOVA). Peak concentrations of MDPV in sera, lung and brain tissue were reached in under 30 min. While negligible levels of metabolites were detected in tissues, the major metabolites in urine were demethylenyl-MDPV and demethylenyl-methyl-MDPV at levels three-four times higher than the parent drug. We also established a MDPV brain/serum ratio ~2 lasting for ~120 min, consistent with our behavioural observations of locomotor activation and disrupted spatial distribution of behaviour as well as moderate increases in body temperature (exacerbated in group-housed animals). Finally, 4 mg/kg induced stereotypy in the open field and transiently disrupted PPI. Our findings, along with previous research suggest that MDPV is rapidly absorbed, readily crosses the blood-brain barrier and is excreted primarily as metabolites. MDPV acts as a typical stimulant with modest hyperthermic and psychomimetic properties, consistent with a primarily dopaminergic mechanism of action. Since no specific signs of acute toxicity were observed, even at the highest doses used, clinical care and harm-reduction guidance should be in line with that available for other stimulants and cathinones.

Naphyrone (naphthylpyrovalerone): Pharmacokinetics, behavioural effects and thermoregulation in Wistar rats

“…In the present study, concentrations of naphyrone in serum as well as in brain, liver and lung tissue were measured over 6 h. Based on its known high lipophilicity, 4 rapid transition of naphyrone concentrations from serum to brain was expected indicative of a rapid penetration of the blood–brain barrier, 7 as well as drug accumulation in the liver and particularly in the lungs, as with MDPV 11 …”

Cardiovascular effects of 3,4-methylenedioxypyrovalerone (MDPV) in male and female Sprague-Dawley rats

“…Several studies report the pharmacokinetic properties of MDPV in rats after different routes of administration. In male rats, the elimination half-life of MDPV is reported at 1-2 h among several studies using either SC, intraperitoneal (IP), or intravenous (IV) administration (Anizan et al, 2016;Baumann et al, 2016;Hambuchen et al, 2017a;Horsley et al, 2018). A study of the pharmacokinetics of MDPV after IP dosing of males and female rats (Hambuchen et al, 2017a).…”

Behavioral and Pharmacokinetic Profile of Indole-Derived Synthetic Cannabinoids JWH-073 and JWH-210 as Compared to the Phytocannabinoid Δ9-THC in Rats

“…More specifically, their potential anxiogenic- and/or anxiolytic-like effects were investigated in the open field test (OFT), an unconditioned test based on spontaneous behavior of animals which is usually used to assess anxiety, as well as exploration and locomotor activity (Micale et al, 2013b ). Given that chronic cannabis use in healthy individuals or systemic treatment with CB1/CB2 agonists (i.e., Δ 9 -THC or WIN55,212-2) in laboratory animals may affect sensorimotor gating (Kucerova et al, 2014 ), the prepulse inhibition (PPI) of the acoustic startle response (ASR) was also assessed (Micale et al, 2013a ; Horsley et al, 2018 ). Alongside this, the pharmacokinetic profiles of JWH-073, JWH-210, Δ 9 -THC (as well as Δ 9 -THC metabolites 11-OH-THC and THC-COOH) in serum were also evaluated.…”