Pathophysiological impacts of 5-MeO-MiPT on zebrafish (Danio rerio) via the Gαq/11-PLCβ signaling pathway

5-Methoxy-N-isopropyl-N-methyltryptamine (5-MeO-MiPT), a tryptamine-derived novel psychoactive substance detected in aquatic environments, alters gene expression and disrupts signaling pathways in zebrafish. After 30 days of injection with varying concentrations, RNA-seq, qPCR, metabolomics, and histopathology showed that 5-MeO-MiPT significantly affects the transcription of 13 genes, including ucp1, pet100, grik3, and grik4, via the Gα q/11-PLCβ signaling pathway. The substance inhibits DAG-Ca2+/Pkc/Erk, Pkc/Pla2/PLCs, and Ca2+/CamkII/NMDA pathways while enhancing Ca2+/Creb, mechanisms that may mediate behavioral inhibition and oxidative stress. These findings clarify toxicological and addiction mechanisms of 5-MeO-MiPT and suggest approaches for studying other tryptamine-based NPS and diagnosing liver-brain pathway diseases.

Study at a glance

Abstract

Novel Psychoactive Substances (NPS) derived from tryptamines has been detected in aquatic environments, leading to environmental toxicology concerns. However, the specific toxicological mechanism, underlying these NPS, remains unclear. In our previous work, we used 5-Methoxy-N-isopropyl-N-methyltryptamine (5-MeO-MiPT) as the representative drug for NPS, and found that, 5-MeO-MiPT led to obvious behavioral inhibition and oxidative stress responses in zebrafishes model. In this study, Zebrafish were injected with varying concentrations of 5-MeO-MiPT for 30 days. RNA-seq, qPCR, metabolomics, and histopathological analyses were conducted to assess gene expression and tissue integrity. This study confirms that 5-MeO-MiPT substantially influences the transcription and expression of 13 selected genes, including ucp1 , pet100 , grik3 , and grik4 , mediated by the Gα q/11 -PLC β signaling pathway. We elucidate the molecular mechanism that 5-MeO-MiPT can inhibit DAG-Ca 2+ /Pkc/Erk, Pkc/Pla2/PLCs and Ca 2+ /Camk Ⅱ/NMDA, while enhance Ca 2+ /Creb. Those secondary signaling pathways may be the mechanisms mediating 5-MeO-MiPT inhibiting normal behavior in zebrafish. These findings offer novel insights into the toxicological effects and addiction mechanisms of 5-MeO-MiPT. Moreover, it presents promising avenues for investigating other tryptamine-based NPS and offers a new direction for diagnosing and treating liver-brain pathway-related diseases. • The study investigated 5-MeO-MiPT's impact on zebrafish. • It caused oxidative stress and behavioral inhibition. • RNA-seq and qPCR analyses revealed gene expression changes. • Gα q/11 -PLC β signaling mediated these effects.