However, observing behavioral changes in exposed fish does not by itself reveal how a given drug caused that effect. Antidepressants often act on proteins called monoamine transporters, which help clear serotonin, dopamine, and norepinephrine from the synaptic cleft. The three main transporters are known as SERT for serotonin, DAT for dopamine, and NET for norepinephrine. Although fish possess versions of these proteins, it remains unclear whether they respond to human-targeted pharmaceuticals in a similar way to their human counterparts. Moreover, most mechanistic research has focused on a small number of fish species, so scientists are not sure whether pharmaceutical sensitivity is broadly shared across fish.
To address these questions, a research team led by Professor Shinichi Miyagawa of the Department of Biological Science and Technology, Faculty of Advanced Engineering at Tokyo University of Science, Japan, characterized monoamine transporters from two evolutionarily distinct fish species: medaka (Oryzias latipes) and ayu (Plecoglossus altivelis). The study, published in Environmental Science & Technology journal on August 24, 2026, was co-authored by Professor Masaru Ihara of the Faculty of Agriculture and Marine Science at Kochi University, Japan.
The researchers first identified and cloned genes encoding DAT, NET, and two types of SERT (SERTa and SERTb) from both fish species. The team produced these transporters in the lab by culturing genetically engineered human cells and then exposed them to a range of commonly used antidepressants. By measuring how effectively the transporters took up a fluorescent marker, the researchers could determine how strongly each drug inhibited transporter activity.
The results showed that SERTa was consistently much more sensitive to antidepressants than SERTb in both fish species. This lines up with the team’s genetic analysis, as human SERT belongs to the SERTa lineage, whereas SERTb is absent in mammalian species. SERTb also contains substitutions at several residues associated with antidepressant interactions.
Surprisingly, when the researchers compared fish SERTa with human SERT, the fish transporter often responded to lower drug concentrations, sometimes more than ten times lower than the human transporter. The team also found that some drugs not typically thought to act on these particular proteins in humans still affected the fish versions, hinting at side effects that could not be predicted from human pharmacology alone.
Another important finding was that drug concentrations needed to block fish SERTa in these lab tests overlapped with the concentrations of antidepressants already measured in polluted waterways. Duloxetine, fluoxetine, citalopram, and paroxetine, for example, inhibited medaka SERTa at concentrations ranging from a few hundred to roughly 1,300 nanograms per liter. “By demonstrating that key molecular targets in fish can be more sensitive than their human equivalents, our work offers crucial insights into the potential risks of pharmaceutical exposure to aquatic wildlife,” remarks Prof. Miyagawa.
Because the study included two fish species that are only distantly related, the shared sensitivity pattern observed suggests this heightened vulnerability to antidepressants may extend beyond a single fish species. The team suggests these findings could help guide regulators, as Prof. Miyagawa explains: “Our research provides a vital scientific basis for prioritizing specific pharmaceuticals in environmental monitoring programs and for deriving more protective, species-specific risk thresholds in water quality guidelines.” Future in vivo studies examining environmentally realistic exposures and pharmaceutical mixtures will be needed to determine how these molecular effects translate into biological and ecological outcomes.