Determining the Role of Serotonin in Antidepressant Action, as Revealed Utilizing the SERT Met172 Mouse Model

Abstract

The most widely prescribed antidepressant medications are serotonin selective reuptake inhibitors (SSRIs), believed to provide therapeutic benefit by antagonizing the serotonin transporter (5-HT; SERT), which acts to terminate 5-HT synaptic transmission via transport of 5-HT back into the presynaptic neuron. SSRIs are not immediately efficacious in the clinic, even though these drugs are immediately able to increase extracellular 5-HT. SSRIs have been found to interact with a sizable number of non-trivial targets at physiologically relevant concentrations, raising the question whether all of the effects of SSRIs are 5-HT mediated. In order to separate the 5-HT-dependent effects from the off-target effects of SSRIs, I utilize a novel transgenic mouse strain SERT Met172 that confers insensitivity to many SERT blocking drugs in vitro and in vivo, without perturbing normal SERT expression or function. Utilizing behavioral and biochemical assays that are sensitive to acute and chronic SSRI administration, we find that SSRIs require SERT antagonism for actions supporting behavioral sensitivity and hippocampal neurogenesis. These findings provide the most specific analysis to date determining the requirement of SERT antagonism for the antidepressant actions of SSRIs, and that off-target activity is insufficient to produce effects supporting antidepressant efficacy. Through the use of this SERT Met172 mouse model, I also can assess the SERT dependence of mixed action drugs that target SERT. Here, I also describe the efforts to assess the SERT dependence of the mixed action drug vortioxetine, which modulates many 5-HT receptors in addition to SERT antagonism.