Treatment with the selective serotonin reuptake inhibitor, fluoxetine, attenuates the fish hypoxia response

Abstract

The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX), the active ingredient of the antidepressant drug Prozac, inhibits reuptake of the neurotransmitter, serotonin (5-HT; 5-hydroxytryptamine), into cells by the 5-HT transporter (SERT). Given the role of 5-HT in oxygen detection and the cardiovascular and ventilatory responses of fish to hypoxia, we hypothesized that treatment of the Gulf toadfish, Opsanus beta, with FLX would interfere with their response to hypoxia. Toadfish treated intra-arterially with 3.4 μg.g−1 FLX under normoxic conditions displayed a transient tachycardia and a biphasic caudal arterial blood pressure (PCA) response that are in direct conflict with the typical hypoxia response. Fish injected intraperitoneally with FLX under normoxia had resting cardiovascular and ventilatory parameters similar to controls. Upon exposure to hypoxia, control toadfish exhibit a significant bradycardia, reduction in PCA and an increase in ventilatory amplitude (VAMP) without any changes in ventilatory frequency (fV). Fish treated IP with 10 μg.g−1 FLX showed an interference in the cardiovascular and ventilatory response to hypoxia. Interestingly, when treated with 25 μg.g−1 FLX, the bradycardia and VAMP response to hypoxia were similar to control fish while the PCA response to hypoxia was further inhibited. These results suggest that SERT inhibition by FLX may hinder survival in hypoxia.

Molecular and functional characterization of the Gulf toadfish serotonin transporter (SERT; SLC6A4)

“…A tissue-based sequestration mechanism would be particularly important given our finding that toadfish blood does not contain appreciable levels of SERT transcriptas well as findings from other studies that neither fish thrombocytes (the evolutionary precursors to mammalian platelets) nor other blood cells appear to play a role in 5-HT storage and sequestration as a mechanism to control vascular resistance, as is observed for mammalian platelets (Fange, 1992;Caamaño-Tubío et al, 2007;Mercado and Kilic, 2010). As systemic inhibition of SERT with FLX attenuates cardiovascular aspects of the toadfish hypoxia response (Panlilio et al, 2016) in addition to the overall metabolic response to hypoxia in this fish (Amador et al, 2018), it is possible that cardiac SERT could play a specific role in the hypoxia response in hypoxia-tolerant species such as toadfish (Hall, 1929;Ultsch et al, 1981;McDonald et al, 2010) and goldfish (reviewed in Bickler and Buck, 2007).…”

Exposure to wastewater effluent disrupts hypoxia responses in killifish (Fundulus heteroclitus)

“…Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine could inhibit serotonin signaling by oxygen sensing neuroepithelial cells in the gills, which may have disrupted key cardiorespiratory adjustments to hypoxia exposure. Indeed, in gulf toadfish, hypoxia exposure during acute intraperitoneal treatment of 20 or 50 µg/g of fluoxetine have been shown to accentuate oxyconformation (i.e., decreased regulation index) and reduce the ventilatory response, respectively (Amador et al, 2018;Panlilio et al, 2016). Serotonin also regulates glycogenolysis in the brain of rainbow trout (Pérez-Maceira et al, 2012), so SSRI exposure could have also contributed to the effects of hypoxia and wastewater exposure on glycogen levels that were observed here.…”

“…For example, the pharmaceuticals in wastewater have molecular targets involved in oxygen sensing (e.g., serotonin reuptake inhibitors), homeostatic regulation by the sympathetic nervous system (e.g., beta blockers), and control of metabolic pathways (e.g., antidiabetics, lipid lowering drugs) (Arlos et al, 2015;Corcoran et al, 2010;Kolpin et al, 2002;Metcalfe, 2013;Metcalfe et al, 2003). Indeed, exposure to the serotonin reuptake inhibitor, fluoxetine, has been shown to attenuate the cardiovascular and ventilatory responses to hypoxia in Gulf toadfish (Opsanus beta) (Panlilio et al, 2016). Several industrial contaminants (e.g., polychlorinated biphenyls, polycyclic aromatic hydrocarbons) may also disrupt hypoxia signaling pathways that underlie the physiological adjustments to chronic hypoxia, such as the hypoxia inducible factor (HIF) pathway (Chan et al, 1999;Kraemer and Schulte, 2004;Vorrink and Domann, 2014;Silva et al, 2017).…”

The serotonin transporter and nonselective transporters are involved in peripheral serotonin uptake in the Gulf toadfish,Opsanus beta

“…We suggest that sequestration of 5-HT from the blood by the heart and gill may be an adaptation to help these fish survive in low-oxygen environments. Indeed, acute treatment with FLX attenuates the toadfish hypoxia response, suggesting the potential importance of SERT or the control of circulating 5-HT in tolerating hypoxia (3,67).…”