Methamphetamine-induced lethal toxicity in zebrafish larvae

• Published in: Psychopharmacology Vol. 239; no. 12; pp. 3833 - 3846
• Main Authors: Chen, Yu, Wisner, Alexander S., Schiefer, Isaac T., Williams, Frederick E., Hall, F. Scott
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2022; Springer; Springer Nature B.V
• Subjects: Acute toxicity; Ammonia; Amphetamines; Animals; Biomedical and Life Sciences; Biomedicine; Cardiotoxicity; Danio rerio; Dopamine - pharmacology; Dopamine D2 receptors; Dosage and administration; Drug screening; Drugs; Excitatory Amino Acid Antagonists - pharmacology; Fertilization; Glutamatergic transmission; Health aspects; Heart rate; Larva; Larvae; Lethality; Methamphetamine; Methamphetamine - pharmacology; Neurosciences; Original Investigation; Pharmacology/Toxicology; Physiological aspects; Psychiatry; Psychotropic drugs; Raclopride; Seizures; Seizures - chemically induced; Testing; Zebra fish; Zebrafish - physiology; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; United States; Heart; Ammonia; Dopaminergic receptors; Methamphetamine; Zebrafish; Seizure; Glutamate
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-022-06252-z

Rationale The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical structure, it is necessary to develop an efficient and expeditious approach to examine the mechanisms underlying their pharmacological and toxicological effects. Zebrafish ( Danio rerio ) have become a popular experimental subject for drug screening due to their amenability to high-throughput approaches. Objectives In this study, we used methamphetamine (METH) as an exemplary psychoactive substance to investigate its acute toxicity and possible underlying mechanisms in 5-day post-fertilization (5 dpf) zebrafish larvae. Methods Lethality and toxicity of different concentrations of METH were examined in 5-dpf zebrafish larvae using a 96-well plate format. Results METH induced lethality in zebrafish larvae in a dose-dependent manner, which was associated with initial sympathomimetic activation, followed by cardiotoxicity. This was evidenced by significant heart rate increases at low doses, followed by decreased cardiac function at high doses and later time points. Levels of ammonia in the excreted water were increased but decreased internally. There was also evidence of seizures. Co-administration of the glutamate AMPA receptor antagonist GYKI-52466 and the dopamine D2 receptor antagonist raclopride significantly attenuated METH-induced lethality, suggesting that this lethality may be mediated synergistically or independently by glutamatergic and dopaminergic systems. Conclusions These experiments provide a baseline for the study of the toxicity of related amphetamine compounds in 5-dpf zebrafish as well as a new high-throughput approach for investigating the toxicities of rapidly emerging new psychoactive substances.