Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter.

Abstract

Serotonin [i.e., 5-hydroxytryptamine (5-HT)]-targeted antidepressants are in wide use for the treatment of mood disorders, although many patients do not show a response or experience unpleasant side effects. Psychostimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (i.e., "ecstasy"), also impact 5-HT signaling. 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, slc6a4) 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.

DOI: 10.1073/pnas.1011920108
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@article{Thompson2011TransgenicEO, title={Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter.}, author={Brent J. Thompson and Tammy N. Jessen and L Keith Henry and Julie R. Field and Karen L Gamble and Paul J. Gresch and Ana M.D. Carneiro and Rebecca E. Horton and Peter J Chisnell and Yekaterina Belova and Douglas G. McMahon and Lynette C. Daws and Randy D. Blakely}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2011}, volume={108 9}, pages={3785-90} }