Psychopharmacology

, Volume 195, Issue 2, pp 147–166

A pharmacological analysis of mice with a targeted disruption of the serotonin transporter

  • Meredith A. Fox
  • Anne M. Andrews
  • Jens R. Wendland
  • Klaus-Peter Lesch
  • Andrew Holmes
  • Dennis L. Murphy
Review

DOI: 10.1007/s00213-007-0910-0

Cite this article as:
Fox, M.A., Andrews, A.M., Wendland, J.R. et al. Psychopharmacology (2007) 195: 147. doi:10.1007/s00213-007-0910-0

Abstract

Rationale

Partial or complete ablation of serotonin transporter (SERT) expression in mice leads to altered responses to serotonin receptor agonists and other classes of drugs.

Objectives

In the current report, we review and integrate many of the major behavioral, physiological, and neurochemical findings in the current literature regarding pharmacological assessments made in SERT mutant mice.

Results

The absence of normal responses to serotonin reuptake inhibiting (SRI) antidepressants in SERT knockout (−/−) mice demonstrates that actions on SERT are a critical principle mechanism of action of members of this class of antidepressants. Drugs transported by SERT, (+)-3,4-methylenedioxymethamphetamine (MDMA) and 1-methyl-4-(2′-aminophenyl)-1,2,3,6-tetrahydropyridine (2′-NH2-MPTP), are also inactive in SERT −/− mice. Temperature, locomotor, and electrophysiological responses to various serotonin receptor agonists, including 8-hydroxy-2-(di-n-propylamino)-tetraline (8-OH-DPAT), ipsapirone, and RU24969, are reduced in SERT −/− mice, despite comparatively lesser reductions in Htr1a and Htr1b binding sites, G-proteins, and other signaling molecules. SERT −/− mice exhibit an ∼90% reduction in head twitches in response to the Htr2a/2c agonist (+/−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), associated with a profound reduction in arachidonic acid signaling, yet only modest changes in Htr2a and Htr2c binding sites. SERT −/− mice also exhibit altered behavioral responses to cocaine and ethanol, related to abnormal serotonin, and possibly dopamine and norepinephrine, homeostasis.

Conclusions

Together, these studies demonstrate a complex and varied array of modified drug responses after constitutive deletion of SERT and provide insight into the role of serotonin, and in particular, its transporter, in the modulation of complex behavior and in the pharmacological actions of therapeutic agents and drugs of abuse.

Keywords

SerotoninSerotonin transporter (SERT)Knockout micePharmacology

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Meredith A. Fox
    • 1
  • Anne M. Andrews
    • 2
  • Jens R. Wendland
    • 1
  • Klaus-Peter Lesch
    • 3
  • Andrew Holmes
    • 4
  • Dennis L. Murphy
    • 1
  1. 1.Laboratory of Clinical Science, National Institute of Mental HealthNational Institutes of HealthBethesdaUSA
  2. 2.Huck Institutes of the Life SciencesThe Pennsylvania State UniversityUniversity ParkUSA
  3. 3.Molecular and Clinical Psychobiology, Department of Psychiatry and PsychotherapyUniversity of WürzburgWürzburgGermany
  4. 4.Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol AbuseNational Institutes of HealthBethesdaUSA