Effects of Antipsychotic Drugs and Potassium Channel Modulators on Cognition-related Local Field Potential Spectral Properties in Mouse Hippocampus and Frontal Cortex

Local field potentials (LFPs) recorded intracranially display a range of location specific oscillatory spectra which have been related to cognitive processes. Although the exact mechanisms producing LFPs are not completely understood, it is likely that voltage-gated ion channels which produce action potentials and patterned discharges play a significant role. It is also known that antipsychotic drugs (APDs) affect LFPs spectra and a direct inhibitory effect on voltage-gated potassium (Kv) channels has been reported. Additionally, Kv channels have been implicated in the pathophysiology of schizophrenia, a disorder for which APDs are primary therapies. In this study we sought to: i) better characterise the effects of two APDs on LFPs and connectivity measures and ii) examine the effects of potassium channel modulators on LFPs and potential overlap of effects with APDs. Intracranial electrodes were implanted in the hippocampus (HIP) and pre-frontal cortex (PFC) of C57BL/6 mice; power spectra, coherence and phase-amplitude cross frequency coupling were measured. Drugs tested were the APDs haloperidol and clozapine as well as voltage-gated potassium channel modulators (KVMs) 4-aminopyridine(4AP), tetraethylammonium (TEA), E-4031 and retigabine. All drugs and vehicle controls were administered intraperitoneally. Both APDs and KVMs significantly reduced gamma power with the exception of 4AP, which conversely increased slow-gamma power. Clozapine and retigabine additionally reduced coherence between HIP and PFC. Phase-amplitude coupling between theta and gamma oscillations in HIP was significantly reduced by the administration of haloperidol and retigabine. These results provide previously undescribed effects of APDs on LFP properties and demonstrate novel modulation of LFP characteristics by KVMs that intriguingly overlaps with the effects of APDs. The possibility of a common mechanism of action deserves further study.

Medicinal Chemistry of Potassium Channel Modulators: An Update of Recent Progress (2011-2017)

Background: Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function, hormone secretion, osmotic pressure, changes in gene expression, and are involved in critical biological functions, and in a variety of diseases. Potassium channels represent a large family of tetrameric membrane proteins. Potassium channels activation reduces excitability, whereas channel inhibition increases excitability. Objective: Small molecule K+ channel activators and inhibitors interact with voltage-gated, inward rectifying, and two-pore tandem potassium channels. Due to their involvement in biological functions, and in a variety of diseases, small molecules as potassium channel modulators have received great scientific attention. Methods: : In this review, we have compiled the literature, patents and patent applications (2011 to 2017) related to different chemical classes of potassium channel openers and blockers as therapeutic agents for the treatment of various diseases. Many different chemical classes of selective small molecule have emerged as potassium channel modulators over the past years. Conclusion: This review discussed the current understanding of medicinal chemistry research in the field of potassium channel modulators to update the key advances in this field.