Serotonin Transporter‐Independent Actions of the Antidepressant Vortioxetine as Revealed Using the SERT M172 Mouse

The most common antidepressants are serotonin (5‐HT) selective reuptake inhibitors (SSRIs), believed to provide benefit by antagonizing the 5‐HT transporter (SERT). To improve efficacy, drugs have been developed that target additional sites, which questions whether one (e.g. SERT) or more of the anticipated targets accounts for therapeutic efficacy. For example, the novel antidepressant vortioxetine (VORT) antagonizes SERT, but also interacts with 5‐HT1A, 3, and 7 receptors at clinically relevant doses. We assessed the SERT‐dependent actions of VORT using a novel transgenic mouse model (SERT Met172) that prior studies demonstrate limited high‐affinity interactions of many antidepressants, with normal 5‐HT transport function. Consistent with these findings, we documented a ~20x loss in potency for VORT at SERT in synaptosomal preparations compared to WT, consistent with evidence of reduced CNS SERT occupancy. Importantly, a loss of SERT interactions in the SERT M172 model could also be demonstrated in vivo following acute (10mg/kg i.p.) VORT injections, as monitored in chronoamperometry and microdialysis studies. Despite loss of VORT interactions with SERT in the M172 model, we found that, unlike citalopram and fluoxetine, VORT maintained its ability to reduce immobility in Tail Suspension and Forced Swim Tests. These findings indicate that the acute behavioral actions of VORT in these preclinical tests of antidepressant efficacy are independent of SERT antagonism, consistent with the potential for a novel mechanism of action in the treatment of depression