Introduction: Pyrovalerone (4-methyl-β-keto-prolintane) is a synthetic cathinone (beta-keto-amphetamine) derivative. Cathinones are a concern as drugs of abuse, as related street drugs such as methylenedioxypyrovalerone have garnered significant attention. The primary mechanism of action of cathinones is to inhibit reuptake transporters (dopamine and norepinephrine) in reward centers of the central nervous system.
Methods: We measured bioenergetic, behavioral, and molecular responses to pyrovalerone (nM-µM) in zebrafish to evaluate its potential for neurotoxicity and neurological impairment.
Results: Pyrovalerone did not induce any mortality in zebrafish larvae over a 3- and 24-hr period; however, seizures were prevalent at the highest dose tested (100 µM). Oxidative phosphorylation was not affected in the embryos, and there was no change in superoxide dismutase 1 expression. Following a 3-hr treatment to pyrovalerone (1-100 µM), larval zebrafish (6d) showed a dose-dependent decrease (70%-90%) in total distance moved in a visual motor response (VMR) test. We interrogated potential mechanisms related to the hypoactivity, focusing on the expression of dopamine-related transcripts as cathinones can modulate the dopamine system. Pyrovalerone decreased the expression levels of dopamine receptor D1 (~60%) in larval zebrafish but did not affect the expression of tyrosine hydroxylase, dopamine active transporter, or any other dopamine receptor subunit examined, suggesting that pyrovalerone may regulate the expression of dopamine receptors in a specific manner.
Discussion: Further studies using zebrafish are expected to reveal new insight into molecular mechanisms and behavioral responses to cathinone derivates, and zebrafish may be a useful model for understanding the relationship between the dopamine system and bath salts.
Keywords: MDPV; bath salts; behavioral screening; drug abuse; high-throughput.
© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
Conflict of interest statement
There are no conflicts of interest to declare.
Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones.Eur Neuropsychopharmacol. 2015 Mar;25(3):365-76. doi: 10.1016/j.euroneuro.2014.12.012. Epub 2015 Jan 5. Eur Neuropsychopharmacol. 2015. PMID: 25624004
The pyrethroid esfenvalerate induces hypoactivity and decreases dopamine transporter expression in embryonic/larval zebrafish (Danio rerio).Chemosphere. 2020 Mar;243:125416. doi: 10.1016/j.chemosphere.2019.125416. Epub 2019 Nov 22. Chemosphere. 2020. PMID: 31995874
Developmental neurotoxicity of maneb: Notochord defects, mitochondrial dysfunction and hypoactivity in zebrafish (Danio rerio) embryos and larvae.Ecotoxicol Environ Saf. 2019 Apr 15;170:227-237. doi: 10.1016/j.ecoenv.2018.11.110. Epub 2018 Dec 6. Ecotoxicol Environ Saf. 2019. PMID: 30529917
Bath salts, mephedrone, and methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention.Adv Pharmacol. 2014;69:581-620. doi: 10.1016/B978-0-12-420118-7.00015-9. Adv Pharmacol. 2014. PMID: 24484988 Free PMC article. Review.
Neurotoxicology of Synthetic Cathinone Analogs.Curr Top Behav Neurosci. 2017;32:209-230. doi: 10.1007/7854_2016_21. Curr Top Behav Neurosci. 2017. PMID: 27753008 Free PMC article. Review.
- Baumann M. H., Partilla J. S., Lehner K. R., Thorndike E. B., Hoffman A. F., Holy M., … Schindler C. W. (2013). Powerful cocaine‐like actions of 3, 4‐methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive ‘bath salts’ products. Neuropsychopharmacology, 38(4), 552–562. 10.1038/npp.2012.204 - DOI - PMC - PubMed