Acute Octodrine (DMHA) Exposure Disrupts Cardiac Function, Locomotor Activity, and Neuronal Activity-Responsive Transcription in Zebrafish Larvae

Octodrine (2-amino-6-methylheptane; DMHA) is a sympathomimetic stimulant detected in sports-performance and weight-loss supplements despite limited toxicological characterization and regulatory concerns. Here, we used 7-day-post-fertilization zebrafish larvae to characterize the acute cardiac, neurobehavioral, and transcriptional effects of octodrine after 2 h of exposure. Cardiac responses were biphasic: 5 µM octodrine significantly increased atrial and ventricular rates, whereas concentrations ≥ 150 µM produced progressive cardiac depression and higher concentrations disrupted atrioventricular conduction. At 450 µM, all larvae showed complete absence of detectable cardiac activity; mortality was not independently assessed. Modelling of the inhibitory phase yielded IC50 values of 195.6 µM for atrial rate and 188.8 µM for ventricular rate. At substantially lower concentrations, octodrine significantly reduced spontaneous locomotor activity. After Holm correction across all 24 planned time-by-treatment comparisons, a transient effect remained detectable at 50 nM, with more sustained hypoactivity at 0.5 and 5 µM across most of the 2 h exposure period. At the transcriptional level, 3.5 µM octodrine significantly reduced fosab and egr1 expression, whereas fkbp5 was induced at selected concentrations; npas4a showed a significant overall treatment effect but no dose-specific comparison remained significant after blocked analysis and multiplicity correction. nr4a1 was significantly downregulated at 350 µM, whereas th1 and kcnh2a expression was not significantly altered. Together, these findings show that neurobehavioral/transcriptional responses and pronounced cardiac dysfunction occurred over different concentration ranges under the conditions tested. The results provide an initial in vivo hazard characterization of octodrine and support further investigation of its neuropharmacological mechanisms, internal exposure, and cardiovascular safety.