Pharmacological Actions of Potassium Channel Openers on Voltage-Gated Potassium Channels

<b>Background/Objectives:</b> Potassium (K⁺) channels are essential transmembrane proteins that regulate ion flow, playing a critical role in regulating action potentials and neuronal transmission. Although K⁺ channel openers (agonists, K⁺ Ag) are widely used in treating neurological and psychiatric disorders, their precise mechanisms of action remain unclear. Our study explored how K⁺ channel openers might influence the expression of voltage-gated K⁺ channels (Kv) in rat brain. <b>Methods</b>: Briefly, eight rats per group received intraperitoneal injections of diazoxide (Dia), chlorzoxazone (Chl), or flupirtine (Flu). Two hours post-injection, the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), dorsal hippocampus (dHIP), and ventral hippocampus (vHIP) were collected for mRNA expression analysis of various Kv. <b>Results</b>: Dia administration altered expression of <i>Kcna6</i> in the NAc, dSTR, and vHIP, and <i>Kcnq2</i> in the PFC, dSTR, and dHIP. The mRNA levels of <i>Kcna2</i> and <i>Kcna3</i> changed in the NAc, dHIP, and vHIP, while <i>Kcna6</i> expression increased in the PFC, dHIP, and vHIP of rats treated with Chl. Injection of Flu resulted in altered expression for <i>Kcna1</i> in the NAc, dSTR, and dHIP; <i>Kcna3</i> in the PFC, NAc, dHIP, and vHIP; <i>Kcna6</i> in the dSTR, dHIP, and vHIP; and <i>Kcnq2</i> and <i>Kcnq3</i> in the PFC, dHIP, and vHIP. We also found dose-dependent changes. <b>Conclusions</b>: To our knowledge, this is the first study to identify the effects of potassium channel openers on gene expression within the mesocorticolimbic and nigrostriatal dopaminergic systems. These findings reveal a novel molecular mechanism underlying the action of these drugs in the brain. Importantly, our results have broader implications for translational neuroscience, particularly in the context of repurposing FDA-approved drugs, such as diazoxide and chlorzoxazone, for the treatment of neurological disorders.