Environmentally-relevant concentrations of the antipsychotic drugs sulpiride and clozapine induce abnormal dopamine and serotonin signaling in zebrafish brain

The presence of drugs in surface and groundwaters adversely affects the physiological function of non-target organisms due special activities that can pose a serious threats to various forms of aquatic life. Psychotropic drugs are one of the most commonly used drugs in the world. Hence, the aim of this study was to investigate the effect of environmentally-relevant concentrations of the antipsychotic drugs, sulpiride and clozapine, on dopaminergic (DAergic) and serotonergic (5-HTergic) neurotransmitter systems in the brain of zebrafish. Adult zebrafish (AB strain) were exposed to the environmentally-relevant concentrations of sulpiride, clozapine, or a mixture of sulpiride and clozapine. The effects of the drugs on the mRNA and protein levels of major functional molecules in DAergic and 5-HTergic systems were then analyzed in the telencephalon and diencephalon. Both drugs induced abnormal mRNA and protein levels of important functional molecules of the DA and 5-HT signaling pathways in both telencephalon and diencephalon, as shown by the abnormal transcriptional levels of TH, DAT, DR D1, DR D2, MAO, TPH, serotonin transporter (SERT), 5-HTR 1AA, 5-HTR 1B, 5-THR 2AA, and 5-HTR 2B, and the abnormal translational levels of DAT, DR D2, SERT, 5-HTR 1A, 5-HTR 1B, and 5-HTR 2B. In addition, we observed a specificity in the adverse effects of these antipsychotic drugs, in terms of doses and brain parts. Compared to their effects alone, the drug mixture had a weaker effect on the DA and 5-HT systems, suggesting an antagonistic interaction between sulpiride and clozapine. Our findings suggest that sulpiride and clozapine interfere with DAergic and 5-HTergic neurotransmitter systems in the telencephalon and diencephalon of zebrafish, resulting in possible effects on brain functions and posing a serious threat to the health of zebrafish.