title: K(v) 7 (KCNQ) channel openers normalize central 2-deoxyglucose uptake in a mouse model of mania and increase prefrontal cortical and hippocampal serine-9 phosphorylation levels of GSK3β.
abstract: Several metabolic neuroimaging studies have indicated that bipolar patients with mania exhibit alterations in metabolic activity, suggesting that perturbations in corticolimbic function contribute to the functional deficits associated with the disease. Because pharmacological stimulation of K(v)7 channel function has shown anti-manic like efficacy in the D-amphetamine and chlordiazepoxide (AMPH+CDP) induced hyperactivity mouse model of mania, we addressed whether this effect of K(v)7 channels could be associated with changes in cerebral [¹⁴C]2-deoxyglucose (2-DG) uptake, a surrogate marker of brain metabolic activity. Acute administration of the Kv7 channel modulators, retigabine (pan K(v)7.2-K(v)7.5 channel opener) and ICA-27243 (K(v)7.2/K(v)7.3 channel-preferring opener) reduced 2-DG uptake in several mouse forebrain structures with a brain regional signature similar to the mood stabilizers, lithium and valproate. Combined administration of AMPH+CDP enhanced 2-DG uptake in the striatum, cortex and thalamus, and both retigabine and ICA-27243 fully prevented this stimulatory effect of AMPH+CDP. In addition, both K(v)7 channel openers dose-dependently increased phospho-serine-9 levels of GSK3β in the prefrontal cortex and hippocampus, a common molecular mechanism shared by anti-manic drugs. In combination, these data emphasize the potential of K(v)7 channel openers in the treatment of bipolar disorder, and suggest that heteromeric K(v)7.2/K(v)7.3 channels may present a novel anti-manic therapeutic target.
authors.affiliation: Pharmacology, Neurosearch A/S, Pederstrupvej 93, Ballerup, Denmark.
authors.forename: Line V
authors.initials: LV
authors.lastname: Kristensen
authors.forename: Karin
authors.initials: K
authors.lastname: Sandager-Nielsen
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
mesh_terms: D000818:Animals; D018692:Antimanic Agents; D001345:Autoradiography; D001549:Benzamides / Q000494:pharmacology; D001714:Bipolar Disorder / Q000139:chemically induced / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D000697:Central Nervous System Stimulants; D002707:Chlordiazepoxide; D003847:Deoxyglucose / Q000378:metabolism*; D003913:Dextroamphetamine; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism*; D006993:Hypnotics and Sedatives; D051656:KCNQ Potassium Channels / Q000819:agonists*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010655:Phenylenediamines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012694:Serine / Q000378:metabolism*
chemical_list: D018692:Antimanic Agents; D001549:Benzamides; D002219:Carbamates; D000697:Central Nervous System Stimulants; D006993:Hypnotics and Sedatives; D051656:KCNQ Potassium Channels; C527835:N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide; D010655:Phenylenediamines; D011725:Pyridines; C101866:ezogabine; D012694:Serine; D002707:Chlordiazepoxide; D003847:Deoxyglucose; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D003913:Dextroamphetamine