title: Evidence for antimanic efficacy of glycogen synthase kinase-3 (GSK3) inhibitors in a strain-specific model of acute mania.
abstract: There is a growing body of evidence suggesting that animal models can be developed to probe the specific domains of bipolar disorder (BD) using the endophenotype approach. Here we tested clinically active antimanic drugs to validate amphetamine-induced hyperactivity in Black Swiss mice as a putative model of the manic phase of BD. We also co-administered a mood stabilizer and an atypical antipsychotic drug in a manner akin to the clinical treatment regimens. Since lithium has been shown to potentially act through glycogen synthase kinase-3 (GSK3) inhibition, we evaluated the efficacy of selective GSK3 inhibitors in this model. Habituated animals were pretreated with a compound of interest before being challenged with amphetamine (2.0 mg/kg) and returned to activity cages for an additional 1.5 h. We tested lithium, sodium valproate, carbamazepine, olanzapine, ziprasidone as well as co-administered lithium and olanzapine at sub-efficacious doses. The GSK3 inhibitors tested included indirubin, alsterpaullone, TDZD-8, AR-A014418, SB-216763, and SB-627772. All mood stabilizers and antipsychotic drugs reduced hyperactivity without affecting spontaneous locomotion. While subactive doses of lithium and olanzapine were without effect, their co-administration produced robust reductions in hyperactivity. All GSK3 inhibitors were active in the model, producing selective inhibition of rearing hyperactivity. These data support the predictive validity of the model for the acute manic phase of BD and may have utility as an in-vivo model for identifying novel antimanic therapeutics.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. mikhail.kalinichev@addexpharma.com
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalinichev
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
mesh_terms: D000661:Amphetamine / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D018692:Antimanic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy*; D001812:Blood-Brain Barrier / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D009043:Motor Activity / Q000187:drug effects; D015203:Reproducibility of Results; D013830:Thiadiazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D007211:Indoles; D008301:Maleimides; C417521:SB 216763; D013830:Thiadiazoles; D013844:Thiazoles; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D000661:Amphetamine; D038362:Glycogen Synthase Kinase 3