Serotonin Transporter and Organic Cation Transporter 3 Contribute to Basolateral Amygdala Serotonin Clearance and Recent Fear Memory Recall

Abstract

Converging evidence implicates dysregulation of serotonin in emotion-related psychiatric disorders. Leading pharmacotherapies for such disorders, including general anxiety and posttraumatic stress disorders, target the serotonin transporter (SERT); yet, selective serotonin reuptake inhibitors (SSRIs) exhibit limited efficacy, suggesting that additional mechanisms contribute to these clinically prevalent psychopathologies. Recent evidence suggests that organic cation transporter 3 (OCT3) contributes to serotonin homeostasis; however, OCT3 contributions to serotonin clearance in basolateral amygdala (BLA), a central hub for emotional processing, are unknown. We utilized transgenic mice, in vivo neurochemical, and behavioral approaches to test OCT3 contributions to serotonin clearance in BLA and fear behaviors. Depletion of OCT3 from serotonin neurons prolonged serotonin clearance in BLA across a range of concentrations, in comparison to depletion of SERT from serotonin neurons, which prolonged serotonin clearance in BLA only at relatively low concentrations. The SSRI fluvoxamine prolonged serotonin clearance in BLA of wildtype mice and OCT3 knockdown mice to a similar degree, and this effect was lost in mice with SERT depletion. Behaviorally, depletion of SERT or OCT3 from serotonin neurons did not impact fear learning; however, depletion of SERT trended to attenuate cued fear memory, and depletion of OCT3 modestly attenuated cued and contextual fear memory. These findings indicate that OCT3 could serve as a novel therapeutic target for psychiatric disorders related to emotional dysregulation and encourage research into nonconventional treatments for these prevalent disorders.