SELECTIVE ACTIVATION OF GIRK POTASSIUM CHANNELS REDUCES BEHAVIORAL AND BRAIN RESPONSES TO ETHANOL IN MICE

Area of Science:

• Neuroscience
• Pharmacology
• Addiction Research

Background:

• Alcohol use disorder (AUD) presents significant challenges due to limited effective pharmacological treatments.
• Ethanol's effects on neuronal excitability involve modulating G-protein-gated inwardly rectifying potassium (GIRK/Kir3) channels, which are crucial in reward and stress pathways relevant to AUD.

Purpose of the Study:

• To investigate the therapeutic potential of directly activating GIRK channels for treating alcohol intoxication and AUD.
• To evaluate GiGA1, a selective GIRK1/GIRK2 activator with brain bioavailability, as a potential therapeutic agent.

Main Methods:

• Utilized mouse models of ethanol intoxication to assess the effects of GiGA1 administration.
• Measured ethanol-induced conditioned place preference (CPP), voluntary ethanol intake, and blood alcohol concentrations.
• Employed whole-brain c-Fos mapping to analyze neuronal activity in AUD-relevant brain regions.

Main Results:

• Systemic GiGA1 administration prevented the acquisition of ethanol-induced CPP in both male and female mice.
• GiGA1 significantly reduced voluntary ethanol intake and blood alcohol levels in mice with established ethanol preference.
• GiGA1 administration blunted ethanol-induced neuronal activation in key brain regions, including the central amygdala and paraventricular thalamus.

Conclusions:

• Pharmacological activation of GIRK channels, particularly GIRK1/GIRK2, effectively modulates neural circuits involved in ethanol reward and consumption.
• GiGA1 demonstrates broad efficacy in reducing ethanol's effects and intake, supporting its potential as a lead compound for targeted AUD therapy.