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Researcher identifies novel genetic targets for treating alcohol addiction

Staff Report | brazell@musc.edu | February 3, 2017

Dr. Patrick Mulholland
Photo by Sarah Pack
Research from the lab of Dr. Patrick J. Mulholland shows early promise in developing treatments that can reduce heavy alcohol drinking.

A handful of FDA-approved drugs exist for treating people with alcohol use disorder, but they have been largely ineffective at reducing the high rates of relapse. Recognizing that there remains a critical need to identify and develop alternative pharmacological treatment options, researchers at the Medical University of South Carolina targeted finding an answer to that problem.

The researchers, working through collaborative efforts with the National Institutes of Health-funded INIAstress Consortium, have identified novel potassium (K+) channel genes within addiction brain circuitry that are altered by alcohol dependence and correlate with drinking levels in a mouse model of alcohol drinking.

neurons 
This image shows fluorescent labeling of Kv7 channel expression in neurons. 

Patrick J. Mulholland, Ph.D., senior author on the article, said his team is excited by the findings. "We identified which potassium channel genes are changed by chronic alcohol in key nodes of the brain addiction circuitry and, in doing so, revealed exciting novel targets for therapeutic interventions to treat alcohol use disorder. Our hope is that understanding these brain adaptations in K+ channels will lead to better drugs that prevent relapse and prolong abstinence."

These preclinical findings, published in the February 2017 special issue of Alcohol on mouse genetic models of alcohol-stress interactions, suggest that K+ channels could be promising therapeutic targets that may advance personalized medicine approaches for treating heavy drinking in alcoholics.

Alcohol is known to affect the function of brain cells or neurons, and K+ channels play a crucial role in modulating a neuron’s excitability. Although there is old literature that links K+ channels and alcohol use disorder, the alcohol field has not actively pursued this line of research.

Recently, the MUSC research team lead by Mulholland, an associate professor of Neuroscience and Psychiatry & Behavioral Sciences, revisited this research area in a novel way. Research in the Mulholland Lab aims to unlock the molecular mechanisms by which chronic alcohol causes changes in the brain and leads to heavy drinking. “We combine various techniques, such as subcellular imaging, electrophysiology, biochemistry, pharmacology, proteomics, functional genomics and behavior, to understand the cellular and molecular changes that contribute to alcohol dependence and heavy alcohol drinking.”

For this study, the team queried existing genomic database technologies and became the first to use an experimental genetic bioinformatics approach to determine the relationship between expression levels of brain K+ channel genes with alcohol consumption.

“We looked at all 79 K+ channel genes in an alcohol drinking model using genetically diverse strains of mice and were trying to find the genes that might be risk genes for drinking and the genes that are changed by alcohol dependence,” said Mulholland. “More critically, we wanted to determine how alcohol changed expression of K+ channel genes and how those changes predicted how the mice drank after they were rendered dependent. In other words, we wanted to know what the mechanisms are that facilitate enhanced drinking in alcohol dependence mice.”

In this preclinical study, INIAstress researchers exposed strains of mice with diverse genetic backgrounds and varied drinking behaviors to an alcohol dependence model that produces increases in drinking. At the completion of the study, gene levels in the brain were measured, and the Mulholland Lab performed the genetic screen using the GeneNetwork software system.

Dr. Mulholland labe
Photo by Sarah Pack
 
Dr. Mulholland's lab aims to unlock the molecular mechanisms by which chronic alcohol causes changes in the brain and leads to heavy drinking.  

Under baseline conditions, expression levels of several K+ channel genes significantly correlated with the amount of alcohol consumed. These genes, including the Kcnq family of genes that encode for KV7 channels, may represent risk markers for heavy alcohol consumption. These findings were also consistent with clinical evidence in humans that mutations in KCNQ genes associate with early-onset alcohol dependence. Along with identifying novel genes, such as Kcnd2, the findings validated genes that were previously implicated in alcohol use disorder. They also identified changes in K+ channel gene expression induced by chronic exposure to alcohol. As the researchers expected, these gene adaptations correlated with the degree of escalated drinking during dependence.

Mulholland and his team were particularly excited by the findings implicating Kcnq genes and KV7 channels in mouse drinking behavior as these findings replicated their previous study in rats (published November 2016 in Addiction Biology). In this prior study, the drug retigabine, an FDA-approved KV7 channel activator, significantly reduced alcohol consumption in high-drinking rats. This study was the first to identify KV7 channels and Kcnq genes as a potential target to reduce heavy drinking.

To further validate Kcnq as a therapeutic target, the researchers treated a strain of mice with high drinking behavior with retigabine. Consistent with the rat studies, retigabine significantly reduced alcohol consumption only in high-drinking mice.

Together, these studies provide both genetically and pharmacologically strong evidence that KV7 channels and KCNQ genes are promising pharmacogenetic targets for treating alcohol use disorder.

Given that retigabine is an FDA-approved drug, its use in a clinical trial on alcohol use disorder is theoretically feasible. However, there is a roadblock to clinical trial development since retigabine’s manufacturer recently announced it will stop making the drug due to commercial reasons.

Fortunately, the path to translating these promising preclinical findings to humans does not end here. There are additional compounds that activate Kv7 channels that are more selective than retigabine. Although retigabine is well tolerated in adults, including moderate drinkers, the more selective drugs may offer fewer side effects and better therapeutic potential. “We will continue to validate these novel K+ channel genes and will also use advanced technologies to identify druggable targets and neural mechanisms that contribute to high rates of alcohol consumption in preclinical models,” said Mulholland.