Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator
| Autor: | Chiara Mutinelli, Andrea G. Gillman, Charles H. Large, Erika Zambello, Michelle M. Sidor, Darius Becker-Krail, Roberto Arban, Giuseppe Alvaro, Colleen A. McClung, Puja K. Parekh, Yanhua H. Huang, Letizia Bettelini |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Bipolar Disorder medicine.drug_class Pyridines Atypical antipsychotic CLOCK Proteins Substantia nigra Mice Transgenic 03 medical and health sciences Mice 0302 clinical medicine Dopamine Basal ganglia medicine Animals Pharmacology Mice Knockout Mice Inbred BALB C Behavior Animal Chemistry Dopaminergic Neurons Hydantoins Ventral Tegmental Area Potassium channel Ventral tegmental area Mice Inbred C57BL Psychiatry and Mental health Amphetamine Disease Models Animal 030104 developmental biology medicine.anatomical_structure nervous system Shaw Potassium Channels Knockout mouse GABAergic Central Nervous System Stimulants Original Article Neuroscience 030217 neurology & neurosurgery medicine.drug Akathisia Drug-Induced |
| Zdroj: | Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 43(2) |
| ISSN: | 1740-634X |
| Popis: | Kv3.1 and Kv3.2 voltage-gated potassium channels are expressed on parvalbumin-positive GABAergic interneurons in corticolimbic brain regions and contribute to high-frequency neural firing. The channels are also expressed on GABAergic neurons of the basal ganglia, substantia nigra, and ventral tegmental area (VTA) where they regulate firing patterns critical for movement control, reward, and motivation. Modulation of Kv3.1 and Kv3.2 channels may therefore have potential in the treatment of disorders in which these systems have been implicated, such as bipolar disorder. Following the recent development of a potassium channel modulator, AUT1—an imidazolidinedione compound that specifically increases currents mediated by Kv3.1 and Kv3.2 channels in recombinant systems—we report that the compound is able to reverse ‘manic-like’ behavior in two mouse models: amphetamine-induced hyperactivity and ClockΔ19 mutants. AUT1 completely prevented amphetamine-induced hyperactivity in a dose-dependent manner, similar to the atypical antipsychotic, clozapine. Similar efficacy was observed in Kv3.2 knockout mice. In contrast, AUT1 was unable to prevent amphetamine-induced hyperactivity in mice lacking Kv3.1 channels. Notably, Kv3.1-null mice displayed baseline hyperlocomotion, reduced anxiety-like behavior, and antidepressant-like behavior. In ClockΔ19 mice, AUT1 reversed hyperactivity. Furthermore, AUT1 application modulated firing frequency and action potential properties of ClockΔ19 VTA dopamine neurons potentially through network effects. Kv3.1 protein levels in the VTA of ClockΔ19 and WT mice were unaltered by acute AUT1 treatment. Taken together, these results suggest that the modulation of Kv3.1 channels may provide a novel approach to the treatment of bipolar mania. |
| Databáze: | OpenAIRE |
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