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

Thompson BJ, Jessen T, Henry LK, Field JR, Gamble KL, Gresch PJ, Carneiro AM, Horton RE, Chisnell PJ, Belova Y, McMahon DG, Daws LC, Blakely RD
Proc Natl Acad Sci U S A. 2011 108 (9): 3785-90

PMID: 21282638 · PMCID: PMC3048100 · DOI:10.1073/pnas.1011920108

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.

MeSH Terms (15)

Animals Antidepressive Agents Behavior, Animal Cocaine Gene Knock-In Techniques In Vitro Techniques Kinetics Mice Mice, Transgenic Presynaptic Terminals Raphe Nuclei Serotonin Serotonin Plasma Membrane Transport Proteins Serotonin Uptake Inhibitors Synaptosomes

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