Integrated Assessment of the Cardiotoxic and Neurobehavioral Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in...

Synthetic cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) are potent psychostimulants with high abuse potential, yet their systemic toxicity and neurobehavioral effects remain poorly characterized during early development. Using Danio rerio (zebrafish) embryos and larvae, we performed an integrated assessment of the cardiotoxic, behavioral, and molecular effects of MDPV. Acute exposure of 3 days post-fertilization (dpf) embryos produced a marked, concentration-dependent bradycardia and atrioventricular (AV) conduction block, leading to reduced ventricular activity and complete AV dissociation at the highest concentrations (EC₅₀ = 228 µM). Quantitative analysis of ventricular motion revealed a significant decrease in cardiac output (CO) at all tested concentrations and a reduction in ejection fraction (EF) only at 480 µM, while fractional shortening (FS) and stroke volume (SV) remained unchanged, indicating predominant chronotropic and conduction effects with secondary contractile impairment. In 5 dpf larvae, MDPV caused a sustained, concentration-dependent decrease in basal locomotor activity (EC₅₀ = 2.51 µM) but did not affect prepulse inhibition (PPI) of the acoustic startle response (ASR), unlike dextroamphetamine, which enhanced PPI via dopaminergic D₂ receptor activation. Short-term (2 h) exposure of 3 dpf embryos to 0.4-400 µM MDPV induced transcriptional changes in dopaminergic and stress-responsive genes, whereas expression of major repolarizing potassium channel genes (kcnh6a and kcnq1) remained unaltered. Collectively, these results demonstrate that MDPV exerts potent negative chronotropic effects likely through direct functional interference with cardiac repolarization, while neurobehavioral effects occur at concentrations nearly two orders of magnitude lower than cardiotoxic thresholds, supporting zebrafish as a predictive model for the integrative assessment of psychostimulant toxicity.