Chronic Alcohol, Intrinsic Excitability, and Potassium Channels: Neuroadaptations and Drinking Behavior

Abstract

Neural mechanisms underlying alcohol use disorder remain elusive, and this lack of understanding has slowed the development of efficacious treatment strategies for reducing relapse rates and prolonging abstinence. While synaptic adaptations produced by chronic alcohol exposure have been extensively characterized in a variety of brain regions, changes in intrinsic excitability of critical projection neurons are understudied. Accumulating evidence suggests that prolonged alcohol drinking and alcohol dependence produce plasticity of intrinsic excitability as measured by changes in evoked action potential firing and after-hyperpolarization amplitude. In this chapter, we describe functional changes in cell firing of projection neurons after long-term alcohol exposure that occur across species and in multiple brain regions. Adaptations in calcium-activated (K_Ca2), voltage-dependent (K_V7), and G protein-coupled inwardly rectifying (K_ir3 or GIRK) potassium channels that regulate the evoked firing and after-hyperpolarization parallel functional changes in intrinsic excitability induced by chronic alcohol. Moreover, there are strong genetic links between alcohol-related behaviors and genes encoding K_Ca2, K_V7, and GIRK channels, and pharmacologically targeting these channels reduces alcohol consumption and alcohol-related behaviors. Together, these studies demonstrate that chronic alcohol drinking produces adaptations in K_Ca2, K_V7, and GIRK channels leading to impaired regulation of the after-hyperpolarization and aberrant cell firing. Correcting the deficit in the after-hyperpolarization with positive modulators of K_Ca2 and K_V7 channels and altering the GIRK channel binding pocket to block the access of alcohol represent a potentially highly effective pharmacological approach that can restore changes in intrinsic excitability and reduce alcohol consumption in affected individuals.

Keywords: After-hyperpolarization; Alcohol drinking; Alcohol use disorder; Intrinsic excitability; Potassium channels.

Figure 1 –

Activation of K_Ca2, K_V7, and GIRK channels in neural membranes. K_Ca2 channels are activated by elevations in intracellular calcium via influx through voltage-gated calcium channels (VGCCs), NMDA receptors (NMDARs), or release from intracellular stores. K_V7 channels are activated near the resting membrane potential and during membrane depolarization. Ligand binding of G-protein coupled receptors (GPCRs) releases G-proteins that bind to and activate GIRK channels. Opening of these K_Ca2, K_V7, and GIRK channels allows potassium ions to flow outside of the cell causing hyperpolarization and shunting of neuronal excitability. CaM, calmodulin; RyR, ryanodine receptors. Images were acquired with permission from www.servier.com and subsequently modified.

Figure 2 –

Chronic alcohol reduces K_Ca2, K_V7, and GIRK channel expression and signaling in cortex and striatum. K_Ca2 and K_V7 potassium channels are expressed in dendrites, axons, and along the soma of neurons where they function to reduce the action potential threshold, increase the after-hyperpolarization (AHP) amplitude, and hyperpolarize the resting membrane potential. GIRK channels localize to synaptic and perisynaptic regions of glutamatergic neurons where they function to dampen neuronal excitation. Chronic alcohol exposure and alcohol dependence reduce expression and function of K_Ca2 and K_V7 potassium channels in neurons leading to increased intrinsic excitability and reduced AMP amplitude. GIRK channel signaling in cortex is disrupted in alcohol dependent mice. Images were acquired with permission from www.servier.com and subsequently modified.