title: Effects of neuronal Kv7 potassium channel activators on hyperactivity in a rodent model of mania.
abstract: In an effort to investigate the potential antimanic-like activity of K(v)7 channel openers, we decided to test: (1) the subtype non-selective K(v)7 opener retigabine, (2) the K(v)7.4-K(v)7.5 (and K(v)7.5/3 heteromers) preferring channel opener BMS-204352 (Maxipost), and (3) the novel K(v)7.2/3 preferring channel opener ICA-27243, in the amphetamine (AMPH)+chlordiazepoxide (CDP)-induced hyperactivity paradigm in mice, a test often used to assess potential antimanic-like activity of novel compounds. Lithium and lamotrigine were included as positive controls. Pretreatment with lithium attenuated AMPH/CDP-induced hyperactivity, without affecting the activity of AMPH- or CDP-alone, and thus confirmed some predictive validity for the test paradigm. Pretreatment with lamotrigine significantly attenuated AMPH/CDP-induced effects, but also reduced motility when tested in the presence of CDP-alone. Pretreatment with retigabine or ICA-27243 attenuated AMPH/CDP-induced hyperactivity without affecting basal locomotor activity. In contrast, pretreatment with BMS-204352 failed to decrease AMPH/CDP-induced hyperactivity at lower doses (3 and 10 mg/kg). At higher doses BMS-204352 attenuated hyperactivity induced by the AMPH/CDP mix, but only at doses decreasing basal locomotor activity (30 and 60 mg/kg). None of the K(v)7 openers tested significantly affected AMPH-induced hyperactivity. In contrast, retigabine and ICA-27243 were shown to induce significant reductions in motility when administered in combination with CDP-alone. In conclusion, the results with lithium confirm some predictive validity for the test paradigm. However, our data highlight an important confounder for interpreting a role for K(v)7 channels in the alleviation of manic-like symptoms when employing the AMPH/CDP hyperactivity model in mice. It is imperative that relevant control studies (AMPH- and CDP-alone) be incorporated and reported routinely to enable thorough interpretation of data generated by means of this behavioural test.
authors.affiliation: Department of Affective Disorders, NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark. redpau@hotmail.com
authors.forename: John P
authors.initials: JP
authors.lastname: Redrobe
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Nielsen
mesh_terms: D000661:Amphetamine / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use*; D018692:Antimanic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D002219:Carbamates / Q000627:therapeutic use; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity*; D002707:Chlordiazepoxide / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006948:Hyperkinesis / Q000188:drug therapy* / Q000523:psychology; D007211:Indoles / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D051656:KCNQ Potassium Channels / Q000819:agonists* / Q000145:classification; D000077213:Lamotrigine; D018020:Lithium Compounds / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010655:Phenylenediamines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D014227:Triazines / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D018692:Antimanic Agents; C424388:BMS204352; D001549:Benzamides; D002219:Carbamates; D000697:Central Nervous System Stimulants; D007211:Indoles; D051656:KCNQ Potassium Channels; D018020:Lithium Compounds; C527835:N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide; D010655:Phenylenediamines; D011725:Pyridines; D014227:Triazines; C101866:ezogabine; D002707:Chlordiazepoxide; D000661:Amphetamine; D000077213:Lamotrigine