Behavioral alterations in adult zebrafish induced by venlafaxine: correlation with oxidative stress, gene expression, and brain histopathological damage.

Venlafaxine (VEN), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), is clinically used to treat affective disorders, including depression, generalized anxiety disorder, panic disorder, and social phobia. Environmental contamination by this pharmaceutical compound is attributed to its discharge via direct and indirect routes. Its persistence and potential toxicological effects are a rare case of study when VEN is analyzed in aquatic organisms. This study presents the potential adverse effects that environmental concentrations of VEN (500, 1000, and 1500 ng/L) have on adult specimens of Danio rerio following short-term exposure (96 h). VEN toxicity was assessed through two behavioral tests (the Novel Tank and Dark and Light test) and the acetylcholinesterase biochemical marker. Also, oxidative stress, gene expression, and histopathological damage were analyzed. Clearly, VEN induced significant alterations in the behavioral profile, manifesting in notable changes in the time spent in the upper and lower zones, freezing episodes, total distance traveled, frequency of transitions, preference for the dark zone (1500 ng/L), light zone (500, 1000 ng/L) in the dark-light test. After the histopathological analysis, it was found that the brain exhibited greater vulnerability to the effects of VEN concerning the eyes and gills. Thus, gene expression analysis revealed the upregulation of key antioxidant-related genes, including bax, bcl2, p53, nrf1a, nfe2l2a, and casp-3. These findings provide robust evidence for the induction of oxidative stress and its associated molecular pathways in different organs of zebrafish following acute VEN exposure. Finally, these findings demonstrate that VEN significantly compromised brain function. This cerebral damage was characterized by behavioral alterations, inhibition of acetylcholinesterase activity, induction of oxidative stress, dysregulation of antioxidant and apoptotic gene expression, and histopathological lesions that represent a clear example of neurotoxicity effects induced by antidepressants in aquatic systems.