Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter

Andrew Holmes, Rebecca J. Yang, Dennis L. Murphy, Jacqueline Crawley

Research output: Contribution to journalArticle

215 Citations (Scopus)

Abstract

Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL/6J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength. On the tail suspension test, 5-HTT -/- mice on the 129S6 background showed a baseline antidepressant-like reduction in immobility. In contrast, the same mice showed increased immobility in the forced swim test, possibly due to compromised neuromuscular strength. 5-HTT -/- mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT -/- mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT-/- mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg). 5-HTT knockout mice provide a valuable tool for delineating the neuropsychopharmacological actions of antidepressants.

Original languageEnglish (US)
Pages (from-to)914-923
Number of pages10
JournalNeuropsychopharmacology
Volume27
Issue number6
DOIs
StatePublished - Dec 1 2002
Externally publishedYes

Fingerprint

Serotonin Plasma Membrane Transport Proteins
Antidepressive Agents
Inbred C57BL Mouse
Hindlimb Suspension
Fluoxetine
Mutation
Desipramine
Imipramine
Serotonin Uptake Inhibitors
Knockout Mice
Genes
Norepinephrine
Body Weight
Phenotype

Keywords

  • Antidepressant
  • Depression
  • Desipramine
  • Fluoxetine
  • Gene knockout mouse
  • Serotonin transporter

ASJC Scopus subject areas

  • Pharmacology

Cite this

Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. / Holmes, Andrew; Yang, Rebecca J.; Murphy, Dennis L.; Crawley, Jacqueline.

In: Neuropsychopharmacology, Vol. 27, No. 6, 01.12.2002, p. 914-923.

Research output: Contribution to journalArticle

Holmes, Andrew ; Yang, Rebecca J. ; Murphy, Dennis L. ; Crawley, Jacqueline. / Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. In: Neuropsychopharmacology. 2002 ; Vol. 27, No. 6. pp. 914-923.
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