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 (K2), voltage-dependent (K7), and G protein-coupled inwardly rectifying (K3 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 K2, K7, 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 K2, K7, 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 K2 and K7 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.

Forced Abstinence from Alcohol Induces Sex-Specific Depression-like Behavioral and Neural Adaptations in Somatostatin Neurons in Cortical and Amygdalar Regions

“…The mPFC, including the prelimbic (PL) and infralimbic (IL) subregions, receives glutamatergic inputs from the BLA that can promote anxiety-like behaviors (Felix-Ortiz et al, 2016) and are modulated by chronic stress (Lowery-Gionta et al, 2018;Marcus et al, 2019). Acute withdrawal from alcohol exposure has been found to disrupt synaptic transmission and intrinsic excitability of pyramidal neurons of the mPFC at different stages of alcohol dependence; particularly, the dependence-inducing chronic intermittent ethanol (CIE) model enhances excitatory drive and intrinsic excitability in pyramidal neurons (Cannady et al, 2018; , whereas the drinking-in-the-dark (DID) model of pre-dependence binge-like drinking impaired excitatory transmission . Our FST-induced cFos expression data revealed that forced abstinence from alcohol dampened neuronal activation in the female PFC (Figure 3B).…”

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcript variants by excessive ethanol drinking and dependence

“…In the current study, we identified a DMR that maps to an ion channel gene previously implicated in excessive drinking, ethanol-seeking behaviors, and ethanol-induced plasticity of intrinsic excitability (6,10,11,13,17). Our analysis identified a DMR that spans exon 1 and part of intron 1 of monkey and mouse KCNN3 in a region containing CpGs that are highly conserved across species.…”

“…While the technicians were not blind to the treatment condition (ethanol or control), the intake data were collected and recorded in an automated fashion by computer and analyzed by individuals who did not interact with or know the drinking status of the monkeys. All of the animal 6 procedures used in this study were approved by the ONPRC IACUC and were performed in accordance with the NIH and the National Resource Council's Guide for the Care and Use of Laboratory Animals.…”

“…There are genetic factors that increase the propensity for risky drinking (3,4), and genetic background influences the efficacy of treatment options for individuals with AUD (5). In addition, prolonged excessive ethanol intake produces neuroadaptations in projection neurons and neural circuits that are proposed to sustain heavy drinking (6)(7)(8). Although there are three FDA-approved pharmacotherapies for treating AUD, only one (i.e., naltrexone) targets genetic variation in individuals with AUD and the others do not address adaptations that facilitate altered firing properties in neurons.…”

“…Small-conductance Ca 2+ -activated K + (KCa2 or SK) channels have emerged from preclinical pharmacogenetic studies as a target for treating AUD (6,(10)(11)(12)(13)(14). KCa2.3 channels are encoded by the KCNN3 gene and are enriched in nucleus accumbens core (NAcC) medium spiny neurons (MSNs) and substantia nigra dopamine neurons where they control neuronal firing patterns (15).…”