title: SK3 K+ channel-deficient mice have enhanced dopamine and serotonin release and altered emotional behaviors.
abstract: SK3 K(+) channels influence neuronal excitability and are present in 5-hydroxytryptamine (5-HT) and dopamine (DA) nuclei in the brain stem. We therefore hypothesized that SK3 channels affect 5-HT and DA neurotransmission and associated behaviors. To explore this, we used doxycycline-induced conditional SK3-deficient (T/T) mice. In microdialysis, T/T mice had elevated baseline levels of striatal extracellular DA and the metabolites dihydroxyphenylacetic acid and homovanillic acid. While baseline hippocampal extracellular 5-HT was unchanged in T/T mice, the 5-HT response to the 5-HT transporter inhibitor citalopram was enhanced. Furthermore, baseline levels of the 5-HT metabolite 5-hydroxyindoleacetic acid were elevated in T/T mice. T/T mice performed equally to wild type (WT) in most sensory and motor tests, indicating that SK3 deficiency does not lead to gross impairments. In the forced swim and tail suspension tests, the T/T mice displayed reduced immobility compared with WT, indicative of an antidepressant-like phenotype. Female T/T mice were more anxious in the zero maze. In contrast, anxiety-like behaviors in the open-field and four-plate tests were unchanged in T/T mice of both sexes. Home cage diurnal activity was also unchanged in T/T mice. However, SK3 deficiency had a complex effect on activity responses to novelty: T/T mice showed decreased, increased or unchanged activity responses to novelty, depending on sex and context. In summary, we report that SK3 deficiency leads to enhanced DA and 5-HT neurotransmission accompanied by distinct alterations in emotional behaviors.
authors.affiliation: Department of In Vivo Pharmacology, Neurosearch A/S, Ballerup, Denmark. jacobpade@hotmail.com
authors.forename: J P R
authors.initials: JP
authors.lastname: Jacobsen
authors.forename: P
authors.initials: P
authors.lastname: Weikop
authors.forename: H H
authors.initials: HH
authors.lastname: Hansen
authors.forename: J D
authors.initials: JD
authors.lastname: Mikkelsen
authors.forename: J P
authors.initials: JP
authors.lastname: Redrobe
authors.forename: D
authors.initials: D
authors.lastname: Holst
authors.forename: C T
authors.initials: CT
authors.lastname: Bond
authors.forename: J P
authors.initials: JP
authors.lastname: Adelman
authors.forename: P
authors.initials: P
authors.lastname: Christophersen
authors.forename: N R
authors.initials: NR
authors.lastname: Mirza
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001008:Anxiety Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D004644:Emotions / Q000502:physiology*; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019965:Neurocognitive Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012727:Sex Characteristics; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D015283:Citalopram; D004298:Dopamine; D004318:Doxycycline; D006897:Hydroxyindoleacetic Acid; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D051640:Small-Conductance Calcium-Activated Potassium Channels; C496900:Kcnn3 protein, mouse