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

• Published in: Psychopharmacology 2013-06, Vol.227 (4), p.685-695
• Main Authors: Fox, Meredith A., Panessiti, Micaella G., Hall, F. Scott, Uhl, George R., Murphy, Dennis L.
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Amphetamines - pharmacology; Animals; Autoreceptors - metabolism; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Compulsive Behavior; Dopamine; Dopamine Plasma Membrane Transport Proteins - genetics; Genotype & phenotype; Hippocampus - metabolism; Hyperkinesis - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurosciences; Original Investigation; Pharmacology/Toxicology; Prefrontal Cortex - metabolism; Psychiatry; Receptor, Serotonin, 5-HT1A - metabolism; Reflex, Startle; Rodents; Serotonin; Serotonin - metabolism; Serotonin Receptor Agonists - pharmacology; Stereotyped Behavior; Time Factors
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-013-2988-x

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-HT 1A/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-HT 2A/2C agonist (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) were similar in mice of all three DAT genotypes. 5-HT 1A 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-HT 1A receptor-mediated stereotypic responses.