Characterization of Fish Serotonin, Dopamine and Norepinephrine Transporters as a Potential Target for Environmental Pharmaceuticals

Antidepressants are environmental contaminants widely prevalent in the environment that can affect aquatic organisms, but their underlying molecular mechanisms and species-specific sensitivities remain poorly understood. To address this knowledge gap, we performed a comprehensive molecular and pharmacological characterization of monoamine transporters (MATs), the primary targets of these pharmaceuticals, from two phylogenetically distinct teleost fish, medaka (Oryzias latipes) and ayu (Plecoglossus altivelis). We first cloned the cDNAs for two serotonin transporters (SERTa and SERTb), a dopamine transporter (DAT), and a norepinephrine transporter (NET) from both species. Pharmacological assays showed that fish SERTa is substantially more sensitive than SERTb to several antidepressants. While the overall inhibitory profiles of the antidepressants were generally conserved across species, fish SERTa orthologs were consistently and markedly more sensitive to human-targeted pharmaceuticals than the human SERT ortholog. Notably, inhibitory effects were also observed for several pharmaceuticals not traditionally recognized as targeting MATs in human. These molecular mechanisms findings help illustrate the vulnerability of aquatic wildlife to environmentally relevant concentrations of these pharmaceuticals.