Acute Effects of Four Major Trace Amines on Zebrafish Behavioral, Neurochemical, and Neuroendocrine Responses

Trace amines are biologically active compounds endogenously synthesized in the brain in small amounts and structurally resembling biogenic amines. Acting via specific trace amine-associated receptors (TAARs), they induce robust behavioral and physiological effects in humans and animals. However, although TAAR ligands have recently been suggested as novel putative anxiolytics, their central effects and evolutionary conservation of activity remain poorly understood. Here, we evaluated the acute effects of four major trace amines (beta-phenylethylamine, tryptamine, tyramine, and octopamine) on zebrafish anxiety-like and social (shoaling) behavior, as well as neurochemical and neuroendocrine (cortisol) responses. Beta-phenylethylamine, at a low concentration (12 μg/L), caused overt anxiolytic-like effects and reduced brain acetylcholine levels; at a high concentration (1000 μg/L) increased zebrafish anxiety-like behavior and whole-body cortisol levels. Acute tryptamine exposure (7 mg/L) evoked an anxiogenic-like effect, reduced shoaling and social interaction, and elevated brain acetylcholine and whole-body cortisol. Acute exposure to tyramine (15 μg/L) and octopamine (125, 500, and 1500 μg/L) induced similar anxiogenic-like effects, accompanied by increased whole-body cortisol without altering brain acetylcholine levels. Collectively, these findings not only emphasize the important role of trace amines in brain and behavior but support the growing complexity of their CNS effects in vivo across taxa and highlight the relevance of zebrafish models for drug screening based on targeting brain TAARs.