Fish brain proteins can be more sensitive to antidepressants than human ones

Antidepressants that people take pass through the body and, even after wastewater treatment, can end up in rivers, lakes, and the sea. Because fish rely on the same brain chemicals as humans do, including serotonin, dopamine, and norepinephrine, drugs built to act on those chemicals in people can also act on fish. A study published in Environmental Science & Technology examined two fish species, the Japanese rice fish or medaka and a species called ayu, and tested how their versions of these chemical-clearing proteins respond to common antidepressants.

The proteins in question are called monoamine transporters. They normally clear serotonin, dopamine, and norepinephrine out of the gap between nerve cells once a signal has been sent, and antidepressants work in humans by blocking that clearing process so the signal lingers longer. The three main transporters are named SERT, DAT, and NET, for serotonin, dopamine, and norepinephrine respectively. The team, led by Professor Shinichi Miyagawa of Tokyo University of Science with Professor Masaru Ihara of Kochi University, found that one version of the serotonin transporter in fish, called SERTa, was often more sensitive to antidepressants than the same protein in humans, sometimes responding to drug concentrations more than ten times lower.

The researchers also found that some drugs not normally thought to act on these three particular proteins in humans still affected the fish versions. This suggests fish may be exposed to side effects that could not have been predicted just by looking at how the drugs behave in people, according to the study.

To find out how fish transporters respond to antidepressants, the team first identified and copied the genes that produce DAT, NET, and two forms of SERT, called SERTa and SERTb, from both medaka and ayu. They then inserted these genes into human cells grown in the lab, so the cells would manufacture the fish proteins. Exposing these engineered cells to a range of common antidepressants and tracking how well the transporters absorbed a glowing marker chemical let the researchers measure how strongly each drug blocked each transporter.

SERTa turned out to be consistently far more sensitive to antidepressants than SERTb in both fish species tested. That pattern matched what the team found when they compared the genes: human SERT belongs to the same lineage as SERTa, while SERTb has no equivalent in mammals and carries several differences at points known to matter for how antidepressants bind. Because medaka and ayu are only distantly related fish, seeing the same sensitivity pattern in both hints that this heightened response to antidepressants might be shared more widely among fish, though the study tested only these two species.

The drug levels needed to block fish SERTa in these lab tests overlapped with antidepressant concentrations already measured in polluted waterways. In the study, duloxetine, fluoxetine, citalopram, and paroxetine blocked medaka SERTa at concentrations ranging from a few hundred to roughly 1,300 nanograms per liter. Separately, a study of the Niagara River, which connects Lake Erie and Lake Ontario, found antidepressants or their breakdown products in the brains of every one of ten fish species examined, including smallmouth bass, walleye, and rock bass, with the highest single measurement reaching about 400 nanograms of a sertraline breakdown product per gram of brain tissue.

In that Niagara River study, researchers found the drugs had built up in fish brains to levels far higher than in the surrounding water itself, in some fish reaching sertraline concentrations estimated at 20 times or more above river levels, and even higher for its breakdown product. The lead scientist on that work, Diana Aga of the University at Buffalo, said the wastewater plants supplying these rivers focus on removing nitrogen, phosphorus, and organic carbon but do not prioritize antidepressants and similar chemicals. A broader review of antidepressants in fish, published in Frontiers in Endocrinology, notes that these drugs can also disrupt the fish reproductive system: exposure to fluoxetine, citalopram, and venlafaxine in various species has been linked to delayed sexual maturation, reduced estradiol levels, disrupted sperm production, and changes in egg output, though the review stresses that many of these studies used concentrations well above what is found in the environment, and that a clear cause-and-effect relationship for behavioral changes in fish has not been established.

The new molecular findings show that fish transporters can be blocked at concentrations found in real waterways, but the study did not test whether this translates into actual changes in fish behavior or health. Prof. Miyagawa said the results

offer crucial insights into the potential risks of pharmaceutical exposure to aquatic wildlife,

.The team says the work could help regulators set water quality guidelines that are specific to particular species and prioritize which pharmaceuticals get monitored in the environment. Follow-up studies exposing living fish to realistic concentrations, and to mixtures of multiple drugs rather than one at a time, will be needed to determine how these molecular effects play out biologically and ecologically. The endocrine review similarly notes that evidence linking environmentally realistic antidepressant levels to reproductive or developmental harm in fish remains sparse, and that early-life exposure in particular needs more study before firm conclusions can be drawn.