Targeted Treatment for Alcohol Use Disorder Discovered

Manipulating postassium (K+) channels in the brain may be an effective treatment for patients with alcohol use disorder, according to a new study published by Alcohol.

Current drug therapies for alcohol use disorder are largely ineffective, and have not been observed to reduce the occurrence of relapses. There is a clear unmet need for effective pharmacological treatments for these patients.

In the study, the authors discovered there are potassium (K+) channel genes within the brain circuitry that are altered by alcohol dependence. The changes were observed to correlate with alcohol consumption in mouse models.

The investigators discovered that a KV7 channel-positive modulator validated Kcnq, a gene that encodes KV7 K+ channels, could present a personalized treatment option for alcohol use disorder, according to the study.

Alcohol is known to alter how neurons fire. K+ channels regulate neuron excitability by returning the cell membrane after the neuron has fired, which made it a clear treatment target. Prior research shows that K+ channels are associated with alcohol use disorder, but the current study takes an alternative approach.

Through the application of new genomic database technology, the researchers used genetic bioinformatics to determine the association between brain K+ channel gene expression and alcohol intake, according to the study.

"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 lead researcher Patrick J. Mulholland, PhD. "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."

The investigators exposed mice with diverse backgrounds and drinking behaviors to alcohol in their drinking bottles. Half of the mice consumed alcohol but were not dependent, while the other half were dependent because of a chronic intermittent ethanol exposure model, according to the study.

At 10 weeks, the researchers conducted microarray analyses in the prefrontal cortex and nucleus accumbens. Then, they performed another analysis of K+ genes and alcohol drinking in the mice.

Expression of K+ channel genes was seen to correlate with alcohol intake in non-dependent mice, and identified that Kcnq2 and other previously discovered genes were involved with alcohol use disorder, according to the study.

Low expression of Kcnq genes were observed to be linked with high alcohol consumption, which could provide a useful biomarker to determine high alcohol intake.

In dependent mice, Kcnq5 expression was dyregulated, and the alterations were linked to the degree of alcohol consumption during dependence, according to the study.

In a previous study, the team found that Kcnq genes and KV7 channels were involved with dependent and non-dependent drinking, which was confirmed in the current study. Previously, the investigators used retigabine, an approved KV7 channel-positive modulator, to reduce alcohol consumption in rats.

To further validate the study, the authors created mice models of chronic alcohol drinking. After 7 weeks, the mice were treated with retigabine, and reduced alcohol intake in non-dependent animals was seen, according to the study.

These findings are also consistent with clinical evidence that mutated KCNQ genes were linked with developing alcohol dependence at an early age. Findings from both studies suggest that KV7 channels and KCNQ genes are promising treatment targets for patients with alcohol use disorder.

"With all of the preclinical and clinical genetic evidence linking KV7 channels and heavy drinking, it would be great to have a precision medicine follow-up study examining the relationship of KCNQ single-nucleotide polymorphisms (ie, mutations) with retigabine's response at reducing heavy alcohol drinking and alcohol relapse," Dr Mulholland said.

Since retigabine is already approved by the FDA, obtaining an indication for alcohol use disorder would likely be speedy. However, the drug’s manufacturer recently announced they will stop making the drug, but alternative, preclinical drugs are available, according to the study.

"There are better drugs that target KV7 channels that are available on the preclinical side," said first author Jennifer A. Rinker, PhD. "For example, retigabine hits most of the KV7 channel subtypes. There are selective drugs that target just two of the subunits instead of all of them. That's where we are headed, to figure out which of the subunits are critical for the effects of retigabine to reduce drinking."