ica-27243 and Bipolar-Disorder

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.

Topics: Animals; Antimanic Agents; Autoradiography; Benzamides; Bipolar Disorder; Carbamates; Central Nervous System Stimulants; Chlordiazepoxide; Deoxyglucose; Dextroamphetamine; Dose-Response Relationship, Drug; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Hypnotics and Sedatives; KCNQ Potassium Channels; Male; Mice; Mice, Inbred C57BL; Phenylenediamines; Phosphorylation; Prefrontal Cortex; Pyridines; Serine

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.

Topics: Amphetamine; Animals; Anticonvulsants; Antimanic Agents; Benzamides; Bipolar Disorder; Carbamates; Central Nervous System Stimulants; Chlordiazepoxide; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Hyperkinesis; Indoles; Injections, Intraperitoneal; KCNQ Potassium Channels; Lamotrigine; Lithium Compounds; Male; Mice; Mice, Inbred C57BL; Motor Activity; Phenylenediamines; Pyridines; Triazines