Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice

Prominent effects of dopamine transporter deletions

Maria T G Perona, Shonna Waters, Frank Scott Hall, Ichiro Sora, Klaus Peter Lesch, Dennis L. Murphy, Marc Caron, George R. Uhl

Research output: Contribution to journalArticle

Abstract

Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments. To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. To dissociate general activity from potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing, and swimming. In confirmation of earlier reports, both DAT KO and NET KO mice exhibited less immobility than wild-type littermates whereas SERT KO mice did not. Effects of DAT deletion were not simply because of hyperactivity, as decreased immobility was observed in DAT+/- mice that were not hyperactive as well as in DAT-/- mice that displayed profound hyperactivity. Climbing was increased, whereas swimming was almost eliminated in DAT-/- mice, and a modest but similar effect was seen in NET KO mice, which showed a modest decrease in locomotor activity. Combined increases in climbing and decreases in immobility are characteristic of FST results in antidepressant animal models, whereas selective effects on swimming are associated with the effects of stimulant drugs. Therefore, an effect on climbing is thought to more specifically reflect antidepressant effects, as has been observed in several other proposed animal models of reduced depressive phenotypes. A similar profile was observed in the tail suspension test, where DAT, NET, and SERT knockouts were all found to reduce immobility, but much greater effects were observed in DAT KO mice. However, to further determine whether these effects of DAT KO in animal models of depression may be because of the confounding effects of hyperactivity, mice were also assessed in a sucrose consumption test. Sucrose consumption was increased in DAT KO mice consistent with reduced anhedonia, and inconsistent with competitive hyperactivity; no increases were observed in SERT KO or NET KO mice. In summary, the effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.

Original languageEnglish (US)
Pages (from-to)566-574
Number of pages9
JournalBehavioural Pharmacology
Volume19
Issue number5-6
DOIs
StatePublished - Sep 2008
Externally publishedYes

Fingerprint

Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Knockout Mice
Antidepressive Agents
Animal Models
Depression
Hindlimb Suspension
Sucrose
Anhedonia
Gene Knockout Techniques
Membrane Transport Proteins
Locomotion
Dopamine
Serotonin
Norepinephrine
Cell Membrane
Phenotype
Therapeutics

Keywords

  • DAT knockout
  • Forced swim test
  • Mouse
  • NET knockout
  • SERT knockout
  • Sucrose intake
  • Tail suspension test

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice : Prominent effects of dopamine transporter deletions. / Perona, Maria T G; Waters, Shonna; Hall, Frank Scott; Sora, Ichiro; Lesch, Klaus Peter; Murphy, Dennis L.; Caron, Marc; Uhl, George R.

In: Behavioural Pharmacology, Vol. 19, No. 5-6, 09.2008, p. 566-574.

Research output: Contribution to journalArticle

Perona, Maria T G ; Waters, Shonna ; Hall, Frank Scott ; Sora, Ichiro ; Lesch, Klaus Peter ; Murphy, Dennis L. ; Caron, Marc ; Uhl, George R. / Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice : Prominent effects of dopamine transporter deletions. In: Behavioural Pharmacology. 2008 ; Vol. 19, No. 5-6. pp. 566-574.
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