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

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.

Pubmed ID: 21282638

Authors

  • 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

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 1, 2011

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA7390
  • Agency: NIMH NIH HHS, Id: MH078028

Mesh Terms

  • 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