Short- and long-term exposures of the synthetic cannabinoid 5F-APINAC induce metabolomic alterations associated with neurotransmitter systems and embryotoxicity confirmed by teratogenicity in zebrafish

Synthetic cannabinoids are abused substances with strong psychoactive effects. Little is known about the effects on neurotransmission and the toxicity of the second-generation cannabinoid 5F-APINAC. The objective was to assess the influence of short- and long-term exposures of 5F-APINAC on metabolites associated with neurotransmission on zebrafish. Short-term (“acute”, 4 h) and long-term (“chronic”, 96 h) exposures to 5F-APINAC were performed at 0.001, 0.01, 0.1, 1.0 and 10 μM. Intervention groups were compared with a vehicle control. Each group n = 20 zebrafish eggs/larvae. Metabolites related to neurotransmission were determined. In chronic exposure, larvae exposed to 10 μM 5F-APINAC presented morphological and developmental alterations. GABA had the lowest concentrations at higher exposure in acute ( p < 0.01) and chronic ( p < 0.001) experiments. Glutamine showed a descending trend in the acute experiment, but an ascending trend in the chronic exposure ( p < 0.05). In chronic exposure, tryptophan presented an overall descending trend, but with a neat increase at 10 μM 5F-APINAC ( p < 0.001). Tryptamine in acute exposure presented lower ( p < 0.05) concentrations at higher doses. Dopamine and acetylcholine presented highest (p < 0.05) concentrations in the acute and chronic exposures, but with a drop at the highest doses in the chronic experiments. In chronic exposure, xanthurenic acid decreased, except for the highest dose. Picolinic acid was increased at the highest doses in the chronic experiment ( p < 0.001). Short- and long-term exposures induced metabolomic alterations associated with the gamma-aminobutyric acid/glutamic acid, dopaminergic/adrenergic, cholinergic neurotransmitter systems, and the kynurenine pathway. Chronic exposure at 10 μM 5F-APINAC was associated with embryotoxicity confirmed by teratogenesis. • There is extensive evidence indicating cannabimimetics influence neurotransmission. • Metabolites related to neurotransmission in zebrafish embryos after exposure of 5F-APINAC were quantified. • Short and long-term 5F-APINAC exposures showed alterations on metabolites related with a variety of neurotransmitter systems. • Long-term exposure to 5F-APINAC presented embryotoxicity including morphological malformations in zebrafish larvae.