Novel synthetic psychoactive substances present major public health risks because their toxicology and potency are often unknown. Furthermore, testing in traditional mammalian models is ineffective as it cannot keep pace with their rapid emergence. A study in Neurotoxicology evaluated larval zebrafish as a rapid, scalable platform for early-stage hazard assessment of such compounds. Using locomotor behavior and uptake analysis, the team tested γ-aminobutyric acid (GABA)A positive allosteric modulators (benzodiazepines and a barbiturate) and N-methyl-D-aspartate receptor antagonists. Larval zebrafish reliably reproduced concentration-dependent locomotor profiles consistent with known mammalian pharmacodynamics for most compounds tested. Bioanalytical measurements revealed class- and compound-specific differences in uptake, helping to interpret behavioral outcomes and define translational limits. Atypical responses to diazepam and tiletamine highlighted the platform’s ability to flag pharmacological outliers. Overall, these results support larval zebrafish as a 3Rs-aligned, high-throughput tool for characterizing the behavioral effects and potential risks of emerging psychoactive substances.
Original reference: Hillman, C. et al. Neurotoxicology 113, 103386 (2026)
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