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To help dissect the contribution of 5-HT signaling to the actions of these and other agents, we developed transgenic mice in which high-affinity recognition of multiple antidepressants and cocaine is eliminated. Our animals possess a modified copy of the 5-HT transporter (i.e., SERT,\n                    <jats:italic>slc6a4<\/jats:italic>\n                    ) that bears a single amino acid substitution, I172M, proximal to the 5-HT binding site. Although the M172 substitution does not impact the recognition of 5-HT, this mutation disrupts high-affinity binding of many competitive antagonists in transfected cells. Here, we demonstrate that, in M172 knock-in mice, basal SERT protein levels, 5-HT transport rates, and 5-HT levels are normal. However, SERT M172 mice display a substantial loss of sensitivity to the selective 5-HT reuptake inhibitors fluoxetine and citalopram, as well as to cocaine. Through a series of biochemical, electrophysiological, and behavioral assays, we demonstrate the unique properties of this model and establish directly that SERT is the sole protein responsible for selective 5-HT reuptake inhibitor-mediated alterations in 5-HT clearance, in 5-HT1A autoreceptor modulation of raphe neuron firing, and in behaviors used to predict the utility of antidepressants.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1011920108","type":"journal-article","created":{"date-parts":[[2011,1,31]],"date-time":"2011-01-31T23:07:07Z","timestamp":1296515227000},"page":"3785-3790","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":45,"title":["Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter"],"prefix":"10.1073","volume":"108","author":[{"given":"Brent J.","family":"Thompson","sequence":"first","affiliation":[{"name":"Departments of aPharmacology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Jessen","sequence":"additional","affiliation":[{"name":"Departments of aPharmacology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. 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