An evaluation of the serotonin system and perseverative, compulsive, stereotypical, and hyperactive behaviors in dopamine transporter (DAT) knockout mice

Meredith A. Fox, Micaella G. Panessiti, F. Scott Hall, George R. Uhl, Dennis L. Murphy

Research output: Contribution to journalArticle

Abstract

Rationale: Mice lacking the dopamine transporter (DAT) display major behavioral alterations that include hyperactivity, perseverative locomotor patterns, and reduced prepulse inhibition of the acoustic startle reflex. Objectives: The objectives of this study were to investigate perseverative, compulsive, stereotypical, and hyperactive behaviors, as well as serotonin and its involvement with these behaviors, in DAT gene-altered mice. Results: In the open field, mean turn angle and meandering were decreased in DAT knockout (DAT-KO) mice. DAT-KO mice displayed increased hyperactivity, increased velocity, less time immobile, and a failure to habituate over time in the open field unlike their DAT wildtype (DAT-WT) and heterozygous (DAT-HET) littermates. DAT-KO mice buried fewer marbles than DAT-WT and -HET mice in an assessment of compulsive-like behaviors, likely due to extreme hyperactivity and related inattention. Stereotypical head weaving was increased in untreated DAT-KO mice. Following administration of the 5-HT1A/7 agonist 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), stereotypical head weaving and forepaw treading were increased more in DAT-KO mice than in DAT-WT or -HET mice. By contrast, head twitches induced by treatment with the 5-HT2A/2C agonist (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) were similar in mice of all three DAT genotypes. 5-HT1A autoreceptor function was intact in DAT-KO mice. Compared to DAT-WT mice, serotonin levels were increased in DAT-HET and -KO mice in frontal cortex and hippocampus, respectively, and serotonin turnover rates were increased ∼30 % in the striatum of DAT-KO mice. Conclusions: These findings extend and confirm prior behavioral and biochemical characterization of DAT-KO mice. Hyperactivity, stereotypy, and perseverative behaviors are increased in these mice, with brain-area specific increases in serotonin levels and serotonin turnover, and marked increases in postsynaptic 5-HT1A receptor-mediated stereotypic responses.

Original languageEnglish (US)
Pages (from-to)685-695
Number of pages11
JournalPsychopharmacology
Volume227
Issue number4
DOIs
StatePublished - Jun 2013
Externally publishedYes

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Dopamine Plasma Membrane Transport Proteins
Knockout Mice
Serotonin
8-Hydroxy-2-(di-n-propylamino)tetralin
Head
Startle Reflex
Serotonin 5-HT2 Receptor Agonists
Compulsive Behavior
Serotonin 5-HT1 Receptor Agonists
Autoreceptors
Receptor, Serotonin, 5-HT1A
Calcium Carbonate
Frontal Lobe

Keywords

  • (±)-2,5-Dimethoxy-4-iodophenyl-2-aminopropane (DOI)
  • 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)
  • Compulsive behaviors
  • Dopamine transporter (DAT) knockout mice
  • High-performance liquid chromatography (HPLC)
  • Marble burying
  • Open field
  • Serotonin
  • Stereotypical behaviors
  • Temperature

ASJC Scopus subject areas

  • Pharmacology

Cite this

An evaluation of the serotonin system and perseverative, compulsive, stereotypical, and hyperactive behaviors in dopamine transporter (DAT) knockout mice. / Fox, Meredith A.; Panessiti, Micaella G.; Hall, F. Scott; Uhl, George R.; Murphy, Dennis L.

In: Psychopharmacology, Vol. 227, No. 4, 06.2013, p. 685-695.

Research output: Contribution to journalArticle

Fox, Meredith A. ; Panessiti, Micaella G. ; Hall, F. Scott ; Uhl, George R. ; Murphy, Dennis L. / An evaluation of the serotonin system and perseverative, compulsive, stereotypical, and hyperactive behaviors in dopamine transporter (DAT) knockout mice. In: Psychopharmacology. 2013 ; Vol. 227, No. 4. pp. 685-695.
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N2 - Rationale: Mice lacking the dopamine transporter (DAT) display major behavioral alterations that include hyperactivity, perseverative locomotor patterns, and reduced prepulse inhibition of the acoustic startle reflex. Objectives: The objectives of this study were to investigate perseverative, compulsive, stereotypical, and hyperactive behaviors, as well as serotonin and its involvement with these behaviors, in DAT gene-altered mice. Results: In the open field, mean turn angle and meandering were decreased in DAT knockout (DAT-KO) mice. DAT-KO mice displayed increased hyperactivity, increased velocity, less time immobile, and a failure to habituate over time in the open field unlike their DAT wildtype (DAT-WT) and heterozygous (DAT-HET) littermates. DAT-KO mice buried fewer marbles than DAT-WT and -HET mice in an assessment of compulsive-like behaviors, likely due to extreme hyperactivity and related inattention. Stereotypical head weaving was increased in untreated DAT-KO mice. Following administration of the 5-HT1A/7 agonist 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), stereotypical head weaving and forepaw treading were increased more in DAT-KO mice than in DAT-WT or -HET mice. By contrast, head twitches induced by treatment with the 5-HT2A/2C agonist (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) were similar in mice of all three DAT genotypes. 5-HT1A autoreceptor function was intact in DAT-KO mice. Compared to DAT-WT mice, serotonin levels were increased in DAT-HET and -KO mice in frontal cortex and hippocampus, respectively, and serotonin turnover rates were increased ∼30 % in the striatum of DAT-KO mice. Conclusions: These findings extend and confirm prior behavioral and biochemical characterization of DAT-KO mice. Hyperactivity, stereotypy, and perseverative behaviors are increased in these mice, with brain-area specific increases in serotonin levels and serotonin turnover, and marked increases in postsynaptic 5-HT1A receptor-mediated stereotypic responses.

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